Joel Correa da Rosa

Background: Atopic dermatitis (AD) is characterized by pruritus, epidermal hyperplasia, and lichenification that significantly impairs quality of life. Nemolizumab, an anti–IL‐31Rα monoclonal antibody, is approved for treating moderate‐to‐severe AD in patients aged > 12 years. This study investigated nemolizumab's molecular mechanisms using patient samples from the ARCADIA 1 (NCT03985943) and 2 (NCT03989349) trials. Methods: Tape‐strips were collected from the lesional and non‐lesional skin of 71 nemolizumab‐treated and 39 placebo‐treated patients, all receiving background topical corticosteroids ± topical calcineurin inhibitors, at baseline and after 16 weeks of treatment for bulk RNAseq analysis. Single cell RNAseq was performed on a subset of untreated patients and used as a reference to map bulk RNA‐seq DEGs, providing cellular context for treatment‐associated transcriptional changes. Results: Bulk RNAseq revealed significant transcriptomic modulation following 16 weeks of nemolizumab treatment (797 downregulated/142 upregulated genes), while placebo‐treated patients showed minimal changes. Nemolizumab treatment attenuated expression of pruritus‐related genes (e.g., OSMR , TRPV3 , HRH1 , KLK6/7/9 ) and genes involved in epidermal hyperplasia and ECM remodeling (e.g., COL1A1/12A1 , IGFBP3 ). Inflammatory pathways were also modulated, with downregulation of Th17‐ and Th1‐related genes (e.g., S100A7/8/9 , PI3 , MX1 , OASL ). Pathway‐level analysis demonstrated normalization of pruritus and inflammatory gene signatures, including Th2 and Th22 pathways. Subgroup analysis showed that patients with severe baseline pruritus (PPNRS ≥ 7) had higher baseline expression of immune‐related genes and experienced greater downregulation following treatment compared to patients with moderate baseline itch. Single‐cell mapping of differentially expressed genes suggested enrichment of these genes in keratinocyte, fibroblast, endothelial, and nerve cell subpopulations. Clinically, improvements in EASI and pruritus scores (PPNRS) correlated with decreased expression of fibrosis‐ and pruritus‐associated genes. Conclusion: Our findings provide molecular evidence supporting nemolizumab's therapeutic efficacy across multiple disease domains, including pruritus, inflammation, and epidermal hyperplasia, highlighting its role in AD treatment and management.

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: An economon is a dyadic economic unit of two participants who exchange mutually reinforcing commodities (e.g., addictive drugs for money). A human economon often consists of a buyer providing money to a supplier, while the supplier reciprocally provides some commodity to the buyer. Here, we develop the Quantitative Economon Model (QEM) by reviewing basic principles of behavioral economics and translating those principles into a quantitative model characterizing transactional behavior between buyers and suppliers that would be applicable to transactions involving drugs specifically, as well as other commodities. According to the model, transactions between a buyer and supplier depend on their respective economic demand for the commodities exchanged. Additionally, the model assumes that demand for commodities fluctuates across sequential transactions due to satiation and deprivation associated with consumption of those commodities, of particular relevance to addictive drugs. Methods: We used a computational approach to simulate data from the QEM according to four conditions representing parametric manipulations of high or low levels of deprivation crossed with high or low levels of satiation (i.e., a 2×2 matrix of conditions). Results: Simulations revealed patterns of transactional behavior that may be characteristic of a range of commodities. In particular, when deprivation-effects were high and satiation-effects were low, simulated transaction rates were characteristic of the high consumption rates observed with addictive drugs. In other conditions, transaction rates varied along patterns characteristic of consumption for other commodities like food. In sum, the QEM provides a framework for modeling, investigating, and predicting patterns of human transactional behavior.

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: 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.

Atopic dermatitis (AD) is a common skin disorder, characterized by impaired skin barrier function and cutaneous inflammation. The pathophysiology of AD is incompletely understood, and has considerable genetic contributions. To obtain a detailed molecular understanding of AD, we integrated the genomic, skin transcriptomic, and clinical measurements from 30 AD and 30 healthy control (HC) subjects. We found that the AD group had mild-to-moderate disease severity and only showed slightly increased genetic risk compared with HC. When comparing within the AD group, we found that the lesional skin of patients with increased genetic risk was characterized by a possible “self-protection” mechanism, including elevation of the anti-inflammatory cytokine IL-34, activation of fibroblasts, wound healing, and the complement system. We hypothesize that this mechanism may contribute to halting further progression of AD.

Diphencyprone (DPCP) is a hapten that causes a delayed‐type hypersensitivity reaction when applied topically. It has clinical uses in the treatment of various conditions such as melanoma metastases, warts, and alopecia areata, but the mechanisms are currently not well understood in humans. To further characterize the immunologic effects of DPCP, the authors performed a proteomic analysis of normal skin of eight healthy volunteers following a single application of DPCP and compared them with placebo‐treated skin from the same volunteers. A total of 96 proteins were examined using the Olink immuno‐oncology panel at 3 days (peak response), 14 days (partially resolved response), and 120 days (completely resolved response). Our analysis revealed significant upregulation of markers of immune cell activation (interleukin [IL] 8), vascular and tissue remodeling (matrix metallopeptidase 12 [MMP12], nitric oxide synthase 3 [NOS3]), antineoplastic markers (granzyme B [GZMB]), and the Th1 axis (interferon gamma [IFNG], chemokine (C‐X‐C motif) ligand [CXCL] 9, CXCL10, CXCL11) at days 3 and 14 compared with placebo (p < 0.05). In addition, several negative regulators of immune function such as programmed cell death 1 (PD1), programmed cell death ligand 1 (PDL1) (p < 0.001), and lymphocyte activation gene 3 (LAG3) (p < 0.05) were significantly upregulated at days 3 and 14. This induction of negative regulators may explain the seemingly paradoxical therapeutic benefits of DPCP in autoimmune conditions such as alopecia areata. The current analysis also indicated IL‐4 upregulation only at day 3, followed by IL‐12 upregulation only at day 14, suggesting a transient Th2 response followed by Th1 polarization. Overall, these data suggest a complex and evolving immunological delayed‐type hypersensitivity response to a single application of DPCP over time. Future proteomic studies of samples from patients with melanoma metastases, warts, and alopecia areata treated long term with DPCP are needed to further evaluate its pharmacologic mechanisms.