Amy S. Paller’s research while affiliated with Ann & Robert H. Lurie Children's Hospital of Chicago and other places

Reply to ‘Comment on “A Proposal for a New Pathogenesis-guided Classification for Inherited Epidermal Differentiation Disorders”’ by Eisner et al.

Atopic dermatitis ( AD ) is a common and burdensome disease. Treatment options for pediatric and adolescent patients (< 18 years old) with moderate‐to‐severe AD are limited, and real‐world data on disease burden are lacking. This study examined patient‐reported disease burden and treatments in pediatric and adolescent patients to identify opportunities for patient benefit. Data were drawn from the Adelphi Real World Pediatric AD Disease Specific Programme (DSP), a cross‐sectional survey of physicians and patients < 18 years old, conducted in Europe and the United States between February–June 2019. Physicians documented demographics, clinical characteristics, and treatment history. Patients and/or their caregivers described disease burden, the degree of symptomatic bother, and quality of life (QoL). Data from 772 patients with moderate–to‐severe AD were analyzed (pediatric; n = 393, 0–11 years, adolescent; n = 379, 12–17 years). Adolescents were more likely to be receiving a systemic corticosteroid (24% vs. 12%), phototherapy (15% vs. 6%), systemic immunosuppressant (15% vs. 6%) or a biologic treatment (5% vs. 1%) than pediatric patients ( p < 0.0001). Two‐thirds of patients had a high degree of “bother” from itch, and 38% reporting itch as the “most bothersome” symptom. More adolescent patients reported “bother” related to anxiety than pediatric patients (67% vs. 49%, p < 0.0001). Adolescent patients reported a significantly higher burden of embarrassment/self‐consciousness ( p < 0.0001) and AD impact on friendships ( p < 0.05). Disease burden differed between pediatric and adolescent patients with AD . Treatment considerations for pediatric and adolescent patients with AD should take into account these factors, with future research directed toward improving the QoL in these patients.

Disorders linked to heterozygous variants occupy a continuum in terms of the timing and severity of phenotypic emergence. An important question regarding this variability entails the effect stress has on the residual protein function. Using Darier disease (DD), caused by heterozygous variants of the SERCA2 calcium pump, as a model, we uncovered a potential connection between extrinsic stress and pathogenesis. The skin lesions characteristic of DD entail loss of intercellular adhesion and rarely appear pre-adolescence, suggesting that factors beyond heterozygosity contribute to disease pathogenesis. Testing whether age-related stressors contribute to DD, we show that DD patient-derived keratinocytes subjected to stress yield twice the reactive oxygen species of controls, accompanied by greater disruption of intercellular adhesion. Metabolic analysis of DD cells revealed perturbation of the pentose phosphate pathway (PPP), a stress response system responsible for regenerating antioxidants like glutathione. At baseline, DD cells had less free glutathione but an increase in protective glutathione-based modifications of SERCA2, a reversible form of protein oxidation. With stress, DD cells form an aberrant, heavily glutathionylated perinuclear halo consisting of keratin and the intercellular adhesion component, desmoplakin. We propose a model whereby SERCA2 heterozygosity causes mild oxidative stress that under homeostatic conditions can be buffered by glutathionylation. When stressed, the depleted glutathione store is shunted towards the desmoplakin-intermediate filament system at the expense of SERCA2, rendering it vulnerable to damage. A lesional flare, then, would represent a case of more complete SERCA2 inhibition and a novel example of how heterozygous disorders interact with stress to disrupt intercellular adhesion.

Patients with dystrophic epidermolysis bullosa have pathogenic variants in COL7A1, leading to skin fragility. Beremagene geperpavec-svdt (B-VEC) is a modified, herpes simplex virus type 1-based gene therapy vector that topically delivers COL7A1 to dystrophic epidermolysis bullosa wounds. In a phase III study, B-VEC significantly improved wound healing at 3 and 6 months compared with placebo. We aimed to evaluate the safety and tolerability of B-VEC beyond 6 months in patients with dystrophic epidermolysis bullosa. An open-label extension study was conducted with 47 subjects (24 rollover from phase III; 23 treatment naïve) receiving B-VEC weekly to target wound areas for up to 112 weeks (median 81 weeks). Safety was assessed by adverse events. Treatment satisfaction and quality of life were assessed with patient-reported outcomes as exploratory measures of efficacy. Selected wounds from phase III rollover subjects were assessed for closure. Thirty-five subjects (74.5%) reported one or more adverse events; most were mild or moderate in severity. Fourteen subjects experienced 17 serious adverse events and ten experienced 14 severe adverse events; none was considered treatment related. No adverse events led to treatment or study discontinuation. Patient-reported outcomes indicated high levels of treatment satisfaction, but were inconclusive with regard to quality of life. Among rollover subjects, wounds that received B-VEC during phase III maintained high closure rates during the open-label extension (range 61.1–89.5%, assessed baseline to month 12). This was an open-label design, with a variable follow-up. Patients undergoing extended B-VEC treatment maintained high satisfaction and continued to respond to treatment with no new safety signals detected in the open-label extension study, supporting the continuous use of B-VEC. NCT04917874 (date of trial registration: 8 June, 2021).

Existing wearable technologies rely on physical coupling to the body to establish optical1,2, fluidic3,4, thermal5,6 and/or mechanical7,8 measurement interfaces. Here we present a class of wearable device platforms that instead relies on physical decoupling to define an enclosed chamber immediately adjacent to the skin surface. Streams of vapourized molecular substances that pass out of or into the skin alter the properties of the microclimate defined in this chamber in ways that can be precisely quantified using an integrated collection of wireless sensors. A programmable, bistable valve dynamically controls access to the surrounding environment, thereby creating a transient response that can be quantitatively related to the inward and outward fluxes of the targeted species by analysing the time-dependent readings from the sensors. The systems reported here offer unique capabilities in measuring the flux of water vapour, volatile organic compounds and carbon dioxide from various locations on the body, each with distinct relevance to clinical care and/or exposure to hazardous vapours. Studies of healing processes associated with dermal wounds in models of healthy and diabetic mice and of responses in models using infected wounds reveal characteristic flux variations that provide important insights, particularly in scenarios in which the non-contact operation of the devices avoids potential damage to fragile tissues.

In 2019, a group of experts published the first European guidelines for the management of congenital ichthyoses after a multidisciplinary expert meeting held in 2016. An update of these guidelines and literature search was planned every 5 years, given the clinical, molecular and therapeutic advances, including the use of biologic therapies. We present here updated guidelines that have been developed by a reorganized multidisciplinary group of international experts after systematic review of recent literature, discussions, and consensus reached at an expert conference held in June 2023. The guidelines provide summarized evidence and expert-based recommendations that aim to guide clinicians in the management of these rare and often complex diseases. These guidelines consist of two sections. This Part II covers the management of complications (eye, Ear-Nose-Throat, pruritus, pain, cutaneous infections, vaccinations, growth failure and nutritional deficiency, hair and nail anomalies, reaction to hot and cold climates, physical limitations, comorbidities) and the particularities of the neonatal period and Netherton syndrome.

Background/Objectives Bullying of children with chronic disorders is associated with an increased risk of depression, anxiety, poor self‐esteem, and suicidal ideation. Congenital ichthyoses are genodermatoses with extensive visible scaling and inflammation. Bullying is a frequent concern of families with ichthyosis but is rarely discussed or investigated. Methods Bullying experience and the impact on children with ichthyosis and their caregivers were investigated utilizing survey methodology and validated questionnaires. Correlations were explored between demographic and ichthyosis characteristics, bullying exposure (Child Adolescent Bullying Scale‐9), child and caregiver psychosocial functioning (Patient‐Reported Outcomes Measurement Information System tools), and family quality of life (Family Dermatology Life Quality Index). Results Overall, 49 dyads completed the survey, with a mean child age of 12 years, 43% female, and 35% non‐white. Lamellar (27%), epidermolytic (16%), and with confetti (12%) ichthyosis subtypes were most common. Child‐reported bullying exposure correlated strongly with poor peer relationships ( r = −0.63) and moderately with stigma ( r = 0.53). Caregiver depression and anxiety scores were moderately correlated with caregiver's perception of child's bullying ( r = 0.46 and r = 0.52, respectively). Poor family quality of life (QoL) was moderately correlated with proxy severity, caregiver depression and anxiety, poor peer relationships, and poor mobility. Conclusions Recognition of bullying and its potential impact on QoL is an important component of exploring the psychosocial impact of ichthyosis and providing holistic care.