Emma Guttman-Yassky

BackgroundDedicator of cytokinesis 8 (DOCK8)-deficient patients have severe eczema, elevated IgE, and eosinophilia, features of atopic dermatitis (AD).ObjectiveWe sought to understand the mechanisms of eczema in DOCK8 deficiency.MethodsSkin biopsy samples were characterized by histology, immunofluorescence microscopy, and gene expression. Skin barrier function was measured by transepidermal water loss. Allergic skin inflammation was elicited in mice by epicutaneous sensitization with ovalbumin (OVA) or cutaneous application of Staphylococcus aureus.ResultsSkin lesions of DOCK8-deficient patients exhibited type 2 inflammation, and the patients’ skin was colonized by S aureus, as in AD. Unlike in AD, DOCK8-deficient patients had a reduced FOXP3:CD4 ratio in their skin lesions, and their skin barrier function was intrinsically intact. Dock8−/− mice exhibited reduced numbers of cutaneous T …

BackgroundDermoscopic and reflectance confocal microscopy (RCM) correlations between morphologic groups of melanoma have not yet been described.ObjectiveDescribe and compare dermoscopic and RCM features of cutaneous melanomas with histopathological confirmation.MethodsSingle center, retrospective analysis of consecutive melanomas evaluated with RCM (2015-2019). Lesions were clinically classified as typical, nevus-like, amelanotic/nonmelanoma skin cancer (NMSC)-like, seborrheic keratosis (SK)-like and lentigo/lentigo maligna (LM)-like. Presence or absence of common facial and nonfacial melanoma dermoscopic and RCM patterns were recorded. Clusters were compared with typical lesions by multivariate logistic regression.ResultsAmong 583 melanoma lesions, significant differences between clusters were evident (compared to typical lesions). Observation of dermoscopic features (>50 …

The vIGA-AD scale for atopic dermatitis: Uptake in the past 5 years and position of the International Eczema Council The vIGA-AD scale for atopic dermatitis: Uptake in the past 5 years and position of the International Eczema Council J Eur Acad Dermatol Venereol. 2024 Mar;38(3):e291-e295. doi: 10.1111/jdv.19627. Epub 2023 Nov 22. Authors Robert Bissonnette 1 , Eric Simpson 2 , Lawrence F Eichenfield 3 , Emma Guttman-Yassky 4 , Jonathan I Silverberg 5 , Lisa A Beck 6 , Lorena Mija 7 , Jacob P Thyssen 8 , Thomas Bieber 9 , Kenji Kabashima 10 , Elaine Siegfried 11 , Georg Stingl 12 , Peter van de Kerkhof 13 , Gil Yosipovitch 14 , Carle Paul 15 , Amy S Paller 16 Affiliations 1 Innovaderm Research Inc, Montréal, Quebec, Canada. 2 Oregon Health & Science University, Portland, Oregon, USA. 3 University of California San Diego School of Medicine and Rady Children's Hospital San Diego, San Diego, California, …

BackgroundRademikibart (CBP-201) is a next-generation IL-4 receptor alpha–targeting antibody.ObjectiveWe sought to evaluate rademikibart in adults with moderate to severe atopic dermatitis.MethodsA total of 226 patients were randomized, double-blind, to subcutaneous rademikibart (300 mg every 2 weeks [Q2W], 150 mg Q2W, 300 mg every 4 weeks [Q4W]; plus 600-mg loading dose) or placebo. Randomization began in July 2020. The trial was completed in October 2021.ResultsThe WW001 phase 2 trial achieved its primary end point: significant percent reduction from baseline in least-squares mean Eczema Area Severity Index (EASI) to week 16 with rademikibart 300 mg Q2W (−63.0%; P = .0007), 150 mg Q2W (−57.6%; P = .0067), 300 mg Q4W (−63.5%; P = .0004) versus placebo (−39.7%). EASI scores decreased significantly with 300 mg Q2W and Q4W at the earliest assessment (week 2), with no …

Die atopische Dermatitis (AD) ist die häufigste entzündliche Hauterkrankung und gilt als komplexe und heterogene Erkrankung. Kürzlich wurden verschiedene AD-Phänotypen beschrieben, die nach dem Alter des Patienten zu Beginn, dem ethnischen Hintergrund, der Krankheitsdauer und anderen Krankheitsmerkmalen definiert wurden und der Notwendigkeit eines personalisierten Behandlungsansatzes zugrunde liegen. Jüngste Fortschritte beim Verständnis der AD-Pathogenese führten zu einer echten translationalen Revolution und zu einer exponentiellen Erweiterung der therapeutischen Pipeline. Die Untersuchung von Biomarkern in klinischen Studien zu neuen Behandlungen trägt dazu bei, die Rolle jedes Zytokins und Immunwegs bei der AD zu klären und wird es ermöglichen, den einzigartigen immunologischen Fingerabdruck jeder AD-Untergruppe zu adressieren. Die personalisierte Medizin wird das …

Circulating skin‐homing cutaneous lymphocyte‐associated antigen (CLA)+ T cells constitute a small subset of human memory T cells involved in several aspects of atopic dermatitis: Staphylococcus aureus related mechanisms, the abnormal Th2 immune response, biomarkers, clinical aspects of the patients, pruritus, and the mechanism of action of targeted therapies. Superantigens, IL‐13, IL‐31, pruritus, CCL17 and early effects on dupilumab‐treated patients have in common that they are associated with the CLA+ T cell mechanisms in atopic dermatitis patients. The function of CLA+ T cells corresponds with the role of T cells belonging to the skin‐associated lymphoid tissue and could be a reason why they reflect different mechanisms of atopic dermatitis and many other T cell mediated skin diseases. The goal of this review is to gather all this translational information of atopic dermatitis pathology.

Skin barrier function (SBF) disorders are a class of pathologies which affect a significant portion of the world population. These disorders cause skin lesions with intense itch, impacting patients’ physical and psychological well-being, as well as their social functioning. It is in the interest of patients that their disorder be monitored closely while under treatment, in order to evaluate the effectiveness of the ongoing therapy and any potential adverse reactions. Symptom-based assessment techniques are widely used by clinicians; however, they carry some limitations. Techniques to assess skin barrier impairment are critical for understanding the nature of the disease and for helping personalize treatment.

Type 2 immune responses are central in the pathogenesis of allergic diseases, and targeted therapies that act as type 2 immune antagonists lead to marked clinical improvement in allergic diseases such as atopic dermatitis (AD), asthma, eosinophilic esophagitis, and chronic rhinosinusitis with nasal polyps. 1 The effectiveness of these agents stems from their blockade of key effector cytokines such as interleukin (IL)− 4, IL-5, IL-13, and IL-31. 1 Type 2 inflammation has a pathogenic role in many nonallergic diseases as well, such as alopecia areata, fibrosis, chronic hand dermatitis, keloids, and prurigo nodularis. The clinical use of targeting T helper 2 (TH2) cytokines in these conditions has been investigated, but there remain relatively few approved therapies for these patient populations compared with a large number of TH2-targeted biologics and small molecules available for the treatment of AD and asthma (Fig …

51 The relationship between alopecia areata (AA) and atopic dermatitis (AD) is increasingly being 52 investigated, with recent evidence implicating a Th2 pathway component in AA’s pathogenesis, 1 and a 53 genetic association identified between AD and AA. 2 Epidemiologic data have also linked the two 54 diseases, but measures of this association in a socioeconomically and racially/ethnically diverse 55 population are lacking. 5657 The All of Us (AoU) database is an NIH initiative designed to capture populations historically 58 underrepresented in biomedical research. Participants with AA in AoU were identified (SNOMED: 59 68225006) and matched to four controls using nearest neighbor propensity-score matching based on sex, 60 age, and race/ethnicity. AA cases were compared to controls using the Fisher’s exact test for categorical 61 variables and the unpaired t-test for continuous variables. Logistic …

BackgroundHidradenitis suppurativa (HS) has a high unmet need for better treatments. Biopsies are considered the gold standard for studying molecular alterations in skin. A reproducible, minimally invasive approach is needed for longitudinal monitoring in trials and in pediatric populations.ObjectiveTo determine whether skin tape strips can detect molecular alterations in HS and identify biomarkers of disease activity.MethodsWe performed RNA sequencing on tape strips collected from lesional and healthy-appearing (nonlesional) HS skin (n = 22) and healthy controls (n = 21). We correlated the expression of skin biomarkers between tape strips and a previously published gene-signature of HS biopsies.ResultsTape strips detected upregulation of known HS biomarkers (eg, Interleukin[IL]-17A) in nonlesional and/or lesional skin and also identified novel clinically actionable targets, including OX40 and JAK3. The …

Pemphigoid is a rare blistering autoimmune condition that primarily affects older adults. Afflicted 44 individuals may experience a prodrome with pruritus, urticaria, or eczematous plaques that can clinically 45 resemble atopic dermatitis (AD), yet characteristically progress to bullae. 1 While the Th2 pathway is 46 implicated in AD and allergic diseases, its involvement in pemphigoid pathogenesis has only recently 47 been suggested. Activation of Th2 cells produces IL-4,-5, and-13, thus eliciting an inflammatory 48 response with consequent IgE production and eosinophilia. The Th2 pathway may also be involved in 49 pemphigoid, as evidenced by elevated eosinophils and IgE seen histologically and in serum of 50 pemphigoid patients. 1 Furthermore, Th2-targeting biologics, like dupilumab (blocking IL-4/13 signaling) 51 and omalizumab (anti-IgE), have demonstrated efficacy in pemphigoid. 1, 2 52Nevertheless, the …

Background Our knowledge of etiopathogenesis of atopic dermatitis (AD) is largely derived from skin biopsies, which are associated with pain, scarring and infection. In contrast, tape‐stripping is a minimally invasive, nonscarring technique to collect skin samples. Methods To construct a global AD skin transcriptomic profile comparing tape‐strips to whole‐skin biopsies, we performed RNA‐seq on tape‐strips and biopsies taken from the lesional skin of 20 moderate‐to‐severe AD patients and the skin of 20 controls. Differentially expressed genes (DEGs) were defined by fold‐change (FCH) ≥2.0 and false discovery rate <0.05. Results We detected 4104 (2513 Up; 1591 Down) and 1273 (546 Up; 727 Down) DEGs in AD versus controls, in tape‐strips and biopsies, respectively. Although both techniques captured dysregulation of key immune genes, tape‐strips showed higher FCHs for innate immunity (IL‐1B, IL‐8 …

Introduction: Abrocitinib is efficacious and well tolerated in patients with moderate-to-severe atopic dermatitis (AD). Here, we describe the updated long-term integrated safety profile of abrocitinib in the JADE clinical program. Methods: Analysis included 3802 patients (exposure: 5213.9 patient-years [PY]) from 7 parent phase 2/3 trials and one long-term extension trial (data cutoff September 25, 2021). Incidence rates (IRs; number of unique patients with events/ 100 PY) of serious adverse events (SAEs) and treatment-emergent AEs of special interest were assessed. Results: Of the total 3802 patients in the pooled safety population, 3004 received the same abrocitinib dose throughout exposure; duration of exposure was >= 96 weeks in 26.3% of patients who received abrocitinib 200 mg (n = 1981) and 41.3% of patients who received abrocitinib 100 mg (n = 1023). Median age was 30.0 years. Incidence was higher in …

Background:In the SARS-CoV-2/COVID-19 pandemic, we need to understand the impact of immunomodulatory medications on COVID-19 symptom severity in patients with inflammatory diseases, including the Type 2/Th2 polarized skin disease, atopic dermatitis/AD. Since it is believed that Type 1/Th1immunity controls viral infections, and that there is a Th1/Th2 counter-regulation, we hypothesized that Th2 targeting with the IL-4Rα-antagonist, dupilumab, in patients with moderate-to-severe AD rebalances Th1/Th2 axis, potentially leading to attenuated COVID-19 symptoms.Methods:: 1,237 moderate-to-severe AD patients in the Icahn School of Medicine at Mount Sinai Department of Dermatology were enrolled in a registry. Patients were screened for COVID-19-related symptoms and assigned a severity score (asymptomatic [0]-fatal [5]). Scores were compared among 3 treatment groups: dupilumab (n= 632), other systemic treatments (n= 107), and limited/no treatment (n= 498). Demographic and comorbid covariates were adjusted by multivariate logistic regression models.Results:: The dupilumab-treated group showed reduced incidence and severity of COVID-19 symptoms versus other treatment groups. Dupilumab-treated patients were less likely to experience moderate-to-severe symptoms versus patients on other systemics (p= 0.01) and on limited/no treatment (p= 0.04), and less likely to experience any symptoms versus patients on other systemics (p= 0.01). This effect was seen in our entire cohort and in the subgroup of patients with verified COVID-19 or high-risk exposure.Conclusions:: Patients on dupilumab experienced less severe …

Sclerotic-type cutaneous chronic graft-versus-host disease is a severe complication of allogeneic hematopoietic stem cell transplantation, with profound morbidity. A dearth of effective, targeted treatment options necessitates further investigation into the molecular mechanisms underlying this T-cell–mediated disease. In this study, we compared the transcriptome in skin biopsies from pediatric and young adult (aged <25 years) patients with sclerotic-type cutaneous chronic graft-versus-host disease (n = 7) with that in demographically matched healthy controls (n = 8) and patients with atopic dermatitis (n = 10) using RNA sequencing with RT-PCR and immunohistochemistry validation. Differential expression was defined as fold change > 1.5 and false discovery rate < 0.05. Sclerotic-type cutaneous chronic graft-versus-host disease exhibited strong and significant T helper (Th)1 skewing through key related cytokines …

Background Tralokinumab is a monoclonal antibody that specifically neutralizes interleukin (IL)‐13, a key driver of skin inflammation and barrier abnormalities in atopic dermatitis (AD). This study evaluated early and 2‐year impacts of IL‐13 neutralization on skin and serum biomarkers following tralokinumab treatment in adults with moderate‐to‐severe AD. Methods Skin biopsies and blood samples were evaluated from a subset of patients enrolled in the Phase 3 ECZTRA 1 (NCT03131648) and the long‐term extension ECZTEND (NCT03587805) trials. Gene expression was assessed by RNA sequencing; protein expression was assessed by immunohistochemistry and immunoassay. Results Tralokinumab improved the transcriptomic profile of lesional skin by Week 4. Mean improvements in the expression of genes dysregulated in AD were 39% at Week 16 and 85% at 2 years with tralokinumab, with 15 …

Background RPT193 is an orally administered small molecule antagonist of the human C‐C motif chemokine receptor 4 (CCR4) that inhibits the migration and downstream activation of T‐helper Type 2 (Th2) cells. We investigated single‐ and multiple‐ascending doses of RPT193 in healthy subjects, and multiple doses of RPT193 in subjects with moderate‐to‐severe atopic dermatitis (AD). Methods This was a first‐in‐human randomized, placebo‐controlled Phase 1a/1b monotherapy study (NCT04271514) to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, and CCR4 surface receptor occupancy in eligible healthy subjects and subjects with moderate‐to‐severe AD. Clinical efficacy and skin biomarker effects of RPT193 monotherapy were assessed as exploratory endpoints in AD subjects. Results In healthy (n = 72) and AD subjects (n = 31), once‐daily RPT193 treatment was generally …

Immune checkpoint inhibitors (ICIs) induce antitumor effects by enhancing the host immune system to eliminate cancer cells. 1 Because of nonspecific immune activation, ICIs cause immunerelated adverse events (irAEs), including cutaneous irAEs (cirAEs), which affect approximately 40% of patients. 2 CirAEs are associated with increased progression-free survival, but can negatively impact patient quality of life or necessitate ICI discontinuation. 3 CirAEs typically occur within 4 to 8 weeks of ICI initiation and can occur at any point during or after treatment. 2, 4 Despite efforts to determine guidelines, the management of cirAEs is currently not standardized. 5 Given the safety and efficacy of many biologics, their potential for managing cirAEs merits investigation. Recent reports have highlighted successful treatment of various cirAE morphologies using biologics with no worsening of tumor outcomes. 5 However, to our …

Atopic dermatitis (AD) is a chronic, heterogeneous, inflammatory disease characterized by skin lesions, pruritus, and pain. Patients with moderate-to-severe AD experience chronic symptoms, intensified by unpredictable flares, and often have comorbidities and secondary complications, which can result in significant clinical burden that impacts the patient’s overall quality of life. The complex interplay of immune dysregulation and skin barrier disruption drives AD pathogenesis, of which T-cell-dependent inflammation plays a critical role in patients with AD. Despite new targeted therapies, many patients with moderate-to-severe AD fail to achieve or sustain their individual treatment goals and/or may not be suitable for or tolerate these therapies. There remains a need for a novel, efficacious, well-tolerated therapeutic option that can deliver durable benefits across a heterogeneous AD patient population. Expression of …

Introduction Tape‐strips, a minimally invasive method validated for the evaluation of several skin diseases, may help identify asthma‐specific biomarkers in the skin of children with allergic asthma. Methods Skin tape‐strips were obtained and analyzed with RNA‐Seq from children with moderate allergic asthma (MAA) (n = 11, mean age 7.00; SD = 1.67), severe allergic asthma (SAA) (n = 9, mean age 9.11; SD = 2.37), and healthy controls (HCs) (n = 12, mean age 7.36; SD = 2.03). Differentially expressed genes (DEGs) were identified by fold change ≥2 with a false discovery rate <0.05. Transcriptomic biomarkers were analyzed for their accuracy in distinguishing asthma from HCs, their relationships with asthma‐related outcomes (exacerbation rate, lung function‐FEV1, IOS‐R5‐20, and lung inflammation‐FeNO), and their links to skin (barrier and immune response) and lung (remodeling, metabolism …