Yeriel D. Estrada

Background: Atopic dermatitis (AD) is characterized by microbial dysbiosis, notably an overabundance of Staphylococcus species. This study aimed to evaluate the effects of abrocitinib, a Janus kinase 1‐selective inhibitor, on the skin microbiome and clinical outcomes in patients with moderate‐to‐severe AD. Methods: Patients enrolled in JADE MOA (NCT03915496) were randomly assigned to receive once‐daily abrocitinib (100 or 200 mg) or placebo for 12 weeks. Skin swabs collected at baseline and Weeks 2, 4, and 12 underwent 16S rRNA gene amplicon sequencing to determine microbial composition. Disease severity was assessed at the same time points using established clinical metrics. Associations between microbial abundance and clinical metrics, as well as inflammatory and skin barrier markers, were investigated. Results: Data from 43 patients were included. Alpha diversity increased significantly at Week 12 of treatment with abrocitinib 200 mg. Beta diversity analysis revealed clustering of the abrocitinib groups away from placebo as early as Week 2; divergence continued through Week 12. Staphylococcus and S. aureus relative abundance decreased in a dose‐dependent manner from Week 2 through Week 12 of abrocitinib treatment. Changes in skin microbial composition corresponded with improvements in clinical metrics of disease severity as well as immune markers of AD. Conclusions: Abrocitinib treatment is associated with beneficial changes in the skin microbiome, notably a reduction in S. aureus and increased microbial diversity. These findings provide insight into the mechanism of action of abrocitinib and the interplay of immunomodulation and the skin microbiome in AD. Trial Registration: ClinicalTrials.gov identifier: NCT03915496

Background: Clinical trials using monoclonal antibodies targeting the OX40/OX40L axis (AMG451, GBR830, KHK4083, and KY1005) have shown promise in long‐term disease modification of atopic dermatitis (AD). OX40/OX40L enhances survival of effector T cells and inhibits regulatory T cells (Tregs) function in other inflammatory diseases, but its mechanism of action in AD is unelucidated. We aimed to evaluate OX40‐ and OX40L‐expressing cells in the skin and blood of AD patients to understand how the axis promotes T cell activity and inflammation. Methods: Skin samples from AD and healthy controls (HCs) were evaluated using immunohistochemistry (IHC) and immunofluorescence (IF). Flow cytometry was used to analyze peripheral blood mononuclear cells (PBMCs), and RT‐qPCR and ELISA were performed on purified effector CD4 ⁺ T cells and from AD patients and HCs. RNA‐seq analysis was conducted on effector CD4 ⁺ T cells and Tregs stimulated with anti‐CD3/28, with and without OX40L, in both AD patients and HCs. Results: IHC showed increased OX40 ⁺ and OX40L ⁺ cell expression in AD skin lesions. Circulating CLA ⁺ CD4 ⁺ T cells and CLA ⁺ Tregs upregulate OX40 expression in AD patients compared to HCs. OX40 ⁺ CLA ⁺ CD4 ⁺ Tregs correlated with SCORAD. RNA‐seq, RT‐qPCR, and ELISA revealed that the OX40/OX40L axis maintained the Th2 phenotype of effector CD4+ T cells and decreased IL‐10 produced by Tregs. Conclusion: AD patients exhibit significant upregulation of OX40 expression in effector and regulatory CD4 ⁺ T cells. Both subsets interact with OX40L‐expressing cells in the skin, leading to the promotion of skin inflammation by downregulation of function and anti‐inflammatory capacity of Tregs.

Background: Alopecia areata (AA) is a chronic, nonscarring hair‐loss disorder associated with significant quality‐of‐life impairment and limited treatment options. AA has been recently linked to atopy and shown to exhibit both Th1‐ and Th2‐driven inflammation. However, a comprehensive molecular and cellular characterization across blood and scalp compartments in both atopic and nonatopic patients is lacking.Methods: Lesional and nonlesional scalp biopsies obtained from AA patients with (n = 16) or without (n = 20) atopic history, and 17 demographically matched healthy controls were analyzed with RNA‐seq, RT‐PCR, and immunohistochemistry. Flow cytometry was also performed on peripheral blood mononuclear cells (PBMCs) from a subset of patients. Differential expression was defined using |fold‐change| > 1.5 and false‐discovery rate IFNG, CXCL9, CXCL10, CXCL11) and Th2‐related products (CCL26, CCR4, IL10, IL13, TSLP, TNFRSF4/OX40) and shared downregulation of hair keratins, regardless of atopic background, with variable Th17/Th22 modulation. AA patients with atopy exhibited greater inflammatory tone and Th2‐skewing (IL10, IL13, IL33, CCR4, CCL26). Disease severity correlated significantly with immune and hair keratin biomarkers and with perifollicular cellular infiltrates. Cutaneous OX40/OX40L upregulation was paralleled by increases in circulating OX40⁺ and OX40L⁺ leukocytes, regardless of atopic background.Conclusion: Our results suggest some atopy‐associated immune differences in AA and highlight the OX40 axis as a potential novel therapeutic target that may broadly benefit AA patients.

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 p < .01). MAA and SAA shared downregulation of G‐protein‐coupled receptor (OR4A16, TAS1R3), upregulation of TGF‐β/ErbB signaling‐related (ACVR1B, EGFR, ID1/2), and upregulation of mitochondrial‐related (HIGD2A, VDAC3, NDUFB9) genes. Skin transcriptomic biomarkers correlated with the annualized exacerbation rate and with lung function parameters. A two‐gene classifier (TSSC4‐FAM212B) was able to differentiate asthma from HCs with 100% accuracy.Conclusion: Tape‐strips detected epithelial barrier and asthma‐associated signatures in normal‐appearing skin from children with allergic asthma and may serve as an alternative to invasive approaches for evaluating asthma endotypes.

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), dendritic cell (ITGAX/CD11C, FCER1A), Th2 (IL‐13, CCL17, TNFRSF4/OX40), and Th17 (CCL20, CXCL1) products, while biopsies showed higher upregulation of Th22 associated genes (IL‐22, S100As) and dermal cytokines (IFN‐γ, CCL26). Itch‐related genes (IL‐31, TRPV3) were preferentially captured by tape‐strips. Epidermal barrier abnormalities were detected in both techniques, with terminal differentiation defects (FLG2, PSORS1C2) better represented by tape‐strips and epidermal hyperplasia changes (KRT16, MKI67) better detected by biopsies.Conclusions: Tape‐strips and biopsies capture overlapping but distinct features of the AD molecular signature, suggesting their respective utility for monitoring specific AD‐related immune, itch, and barrier abnormalities in clinical trials and longitudinal studies.

Background: The incidence of adult‐onset atopic dermatitis (AOAD) is increasing. However, the unique characteristics of AOAD compared to pediatric‐onset AD persisting into adulthood (POAD) are underexplored, hampering the development of targeted‐therapeutics for this growing population. We thus assessed the profile of AOAD in skin and blood compared to that of POAD.Methods: We collected skin biopsies and blood from adults with AOAD, POAD, and healthy controls (n = 15 in each group). Skin samples were analyzed by RNA sequencing, qRT‐PCR, and immunohistochemistry, and Olink Proseek multiplex assay was used to identify the serum proteomic profile.Results: Compared to healthy controls, both AOAD and POAD showed cutaneous immune and barrier dysregulations with a shared Th2/Th22 hyperactivation. Overall, POAD showed greater inflammation in lesional skin, with more prominent expression of Th2/Th17/Th22 markers (CCL17/22, S100A8/9, IL‐36A, PI3/Elafin, DEFB4) in POAD compared to AOAD (p‐value < .05). In contrast, higher Th1‐(IFN‐γ, IL‐2, IL‐15, CCL5) upregulation and Th1‐skewing were seen in AOAD. The epidermal barrier was also more compromised in POAD, with greater epidermal hyperplasia and lower expression of markers related to terminal differentiation, lipids, and cell adhesion. In parallel with increased rates of cardiovascular comorbidities, AOAD demonstrated many more significantly dysregulated proteins in serum (n = 148) compared to POAD (n = 86), including pro‐inflammatory and cardiovascular‐risk markers. Th1‐related products showed significant correlations between their skin and blood expressions only in AOAD subjects.Conclusion: Age‐of‐onset delineates two distinct endophenotypes in adult AD potentially suggesting the need for broader (beyond Th2) therapeutic targeting in AOAD.