Alopecia areata exhibits cutaneous and systemic OX40 activation across atopic backgrounds.

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 <0.05. RESULTS: AA scalp exhibited robust upregulation of Th1- (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.

A phase 2a trial of brepocitinib for cicatricial alopecia.

BACKGROUND: Cicatricial alopecias (CA) are chronic, progressive scarring hair-loss conditions. Molecular dysregulation is not fully understood, hindering treatment development. Th1/IFNγ signaling and JAK dysregulation has shown involvement, providing rationale for this phase 2a trial with TYK2/JAK1 inhibitor brepocitinib. METHODS: Randomized, placebo-controlled phase 2a trial spanning 52 weeks. Adults (18≥years of age) with lichen planopilaris, frontal fibrosing alopecia, or central centrifugal cicatricial alopecia diagnosis were randomized 3:1 to brepocitinib 45mg daily or placebo for 24 weeks, after which all patients received brepocitinib for another 24 weeks, with a safety follow up 4 weeks later. Lesional scalp biopsies were collected at baseline, week 24, and week 48. Co-primary endpoints were changes in lesional expression of CCL5, changes in lesional expression of fibrosis-related markers, and safety at week 24. RESULTS: Patients receiving brepocitinib showed significant downregulation in CCL5 expression at week 24 (p=0.004). Enrichment analysis of a subset of fibrosis markers showed trending upregulation in placebo patients (p<0.1). Brepocitinib was well tolerated and improved clinical severity scores. LIMITATIONS: Single-dose regimen, small placebo group. CONCLUSION: Brepocitinib significantly reduces CCL5 expression and was well tolerated at week 24, meeting co-primary endpoints. Brepocitinib reduces inflammatory biomarker expression and improves clinical severity, while maintaining favorable safety profile.

Rosacea and Gastrointestinal Diseases: A Case-Control Study in the All of Us Database.

INTRODUCTION: Recent reports have suggested a link between rosacea and several gastrointestinal diseases, although the evidence has largely been limited to European and Asian populations. This study seeks to confirm and expand upon the connection between rosacea and gastrointestinal conditions using the diverse All of Us database. METHODS: We identified 8,319 rosacea patients and selected 4:1 controls matched (n = 33,276) based on age, race, gender, smoking status, insurance status, annual income, education, and alcohol use. Conditional logistic regression was then performed on the matched cohort to assess the relationship between rosacea and Crohn's disease (CD), microscopic colitis, ulcerative colitis (UC), celiac disease (CED), irritable bowel syndrome (IBS), Helicobacter-associated disease, and gastroesophageal reflux disease (GERD). RESULTS: On logistic regression, rosacea patients were significantly more likely than matched controls to be diagnosed with IBS (odds ratio [OR]: 2.35, 95% confidence interval [CI]: 2.18-2.53, p < 0.001), CD (OR: 1.82, 95% CI: 1.53-2.15, p < 0.001), UC (OR: 1.70, 95% CI: 1.44-2.02, p < 0.001), CED (OR: 1.93, 95% CI: 1.59-2.34, p < 0.001), Helicobacter-associated disease (OR: 1.79, 95% CI: 1.50-2.14, p < 0.001), and GERD (OR: 2.07, 95% CI: 1.97-2.18, p < 0.001). However, there was no statistically significant association between rosacea and microscopic colitis (OR: 1.47, 95% CI: 0.91-2.37, p = 0.12). CONCLUSION: This study highlights the presence of notable gastrointestinal comorbidities among individuals with rosacea in a diverse cohort. Consequently, more targeted monitoring of gastrointestinal diseases in rosacea patients may be warranted, as well as potential further investigation into the gut-skin axis in terms of rosacea pathophysiology.

The evolving landscape of biologic therapies for atopic dermatitis: Present and future perspective.

Atopic dermatitis (AD) is one of the most common, chronic inflammatory skin diseases with a significant physical, emotional and socioeconomic burden. In recent years the understanding of AD pathogenesis has expanded from the Th2-centred perspective, with the recognition of the involvement of other immune axes. In different AD endotypes, influenced by environment, genetics and race, transcriptomic profiles have identified differing contributions of multiple immune axes such as, Th17, Th22 and Th1. The enriched pathogenic model of AD has catalysed the development of numerous biologic therapies targeting a range of key molecules implicated in disease progression. Currently, dupilumab and tralokinumab, which both target the Th2 pathway, are the only approved biologic therapies for AD in the United States and Europe. New biologic therapies in development, however, target different Th2-pathway molecules along with cytokines in other immune axes, including Th17 and Th22, offering promise for varied treatments for this heterogeneous disease. As the biologic pipeline advances, the integration into clinical practice and approval of these experimental biologics may provide more effective, tailored therapeutic solutions and illuminate on the pathologic processes of AD across a broader, more diverse patient population.

Delayed type hypersensitivity reactions to various allergens may differently model inflammatory skin diseases.

BACKGROUND: Treatment of inflammatory skin diseases, including atopic dermatitis (AD) and psoriasis, is undergoing transformative changes, highlighting the need to develop experimental models of skin inflammation in humans to predict treatment responses. METHODS: We topically or intradermally administered four common sensitizers (dust mite (DM), diphencyprone (DPCP), nickel (Ni), and purified protein derivative (PPD)) to the backs of 40 healthy patients and the skin hypersensitivity response was biopsied and evaluated using immunohistochemistry, RNA-seq, and RT-PCR. RESULTS: All agents induced strong increases in cellular infiltrates (T-cells and dendritic cells) as compared to untreated skin (p < .05), with variable T helper polarization. Overall, DPCP induced the strongest immune responses across all pathways, including innate immunity (IL-1α, IL-8), Th1 (IFNγ, CXCL10), Th2 (IL-5, CCL11), and Th17 (CAMP/LL37) products, as well as the highest regulatory tone (FOXP3, IL-34, IL-37) (FDR <0.01). Nickel induced Th17 (IL-17A), Th1 (CXCL10) and Th2 (IL-4R) immune responses to a lesser extent than DPCP (p < .05). PPD induced predominantly Th1 (IFNγ, CXCL10, STAT1) and Th17 inflammation (IL-17A) (p < .05). DM induced modulation of Th2 (IL-13, CCL17, CCL18), Th22 (IL-22), and Th17/Th22 (S100A7/9/12) pathways (p < .05). Barrier defects that characterize both AD and psoriasis were best modeled by DPCP and Ni, followed by PPD, including downregulation of terminal differentiation (FLG, FLG2, LOR, LCEs), tight junction (CLDN1/CLDN8), and lipid metabolism (FA2H, FABP7)-related markers. CONCLUSION: Our data imply that DPCP induced the strongest immune response across all pathways, and barrier defects characteristic of AD and psoriasis.

Oral Janus kinase inhibitors for atopic dermatitis.

Atopic dermatitis (AD) is one of the most common inflammatory skin conditions. The pathogenesis of AD involves skin barrier disruption and immune activation of T-helper (TH)2 and TH22 and varying degrees of TH1 and TH17 activation in various patient subtypes. Although AD is mainly driven by TH2, the molecular and clinical heterogeneity of AD underscores the need for more efficacious treatments that target multiple immune axes. Janus kinase (JAK) inhibitors are novel therapeutics that broadly block many AD-related proinflammatory cytokines (interleukin [IL]-4, IL-5, IL-13, IL-31, thymic stromal lymphopoietin, interferon gamma, IL-12, IL-23, IL-17) across different immune pathways. Oral JAK inhibitors have been found to be efficacious in AD, with 2 (abrocitinib and upadacitinib) recently gaining US Food and Drug Administration approval and several others under investigation in clinical trials with promising results. These systemic agents have surpassed conventional thresholds of treatment response, with many patients achieving complete or almost complete skin clearance, and provide a fast-acting alternative therapy for patients who are not responsive to biologics or other conventional therapies. However, systemic JAK inhibitors come with health concerns, requiring additional long-term clinical trials to characterize their safety profile in patients with AD. This review summarizes the current literature on the safety and efficacy of oral JAK inhibitors in AD and discusses future directions for research.

Trends in Accuracy and Appropriateness of Alopecia Areata Information Obtained from a Popular Online Large Language Model, ChatGPT.

BACKGROUND: Patients with alopecia areata (AA) may access a wide range of sources for information about AA, including the recently developed ChatGPT. Assessing the quality of health information provided by these sources is crucial, as patients are utilizing them in increasing numbers. OBJECTIVES: The aim of the study was to evaluate appropriateness and accuracy of responses to common patient questions about AA generated by ChatGPT. METHODS: Responses generated by ChatGPT 3.5 and ChatGPT 4.0 to 25 questions addressing common patient concerns were assessed by multiple attending dermatologists in an academic center for appropriateness and accuracy. Appropriateness of responses by both models for use in two hypothetical contexts as follows: (1) for patient-facing general information websites, and (2) for electronic health record (EHR) message drafts. RESULTS: The accuracy across all responses was 4.41 out of 5. Accuracy scores of responses ChatGPT 3.5 responses had a mean of 4.29, whereas those generated by ChatGPT 4.0 had mean accuracy score of 4.53. Assessments ranged from 100% of responses rated as appropriate for the general question category to 79% questions about management for an EHR message draft. Raters largely preferred responses generated by ChatGPT 4.0 versus ChatGPT 3.5. Reviewer agreement was found to be moderate across all questions, with a 53.7% agreement and Fleiss' κ co-efficient of 0.522 (p value <0.001). CONCLUSIONS: The large language model ChatGPT outputted mostly appropriate information for common patient concerns. While not all responses were accurate, the trend toward improvement with newer iterations suggests potential future utility for patients and dermatologists.

Cross-Sectional Study of Psoriasis, Atopic Dermatitis, Rosacea, and Alopecia Areata Suggests Association With Cardiovascular Diseases.

BACKGROUND: A growing body of evidence suggests that several inflammatory skin diseases (ISDs) are associated with systemic inflammation and cardiovascular disease (CVDs). METHODS: We used the TriNetX analytics platform to conduct a retrospective, cross-sectional, single-center study in the Mount Sinai Health System network. Cases (all patients ≥18 years of age with a diagnosis of 1 of the 4 ISDs studied) were compared with matched controls (no history of any of these ISDs) to evaluate odds ratios for being diagnosed with CVD. RESULTS: We identified a total of 70,090 patients with ISDs, including 35,160 patients with atopic dermatitis, 19,490 with psoriasis, 12,470 with rosacea, and 2,970 with alopecia areata, and 70,090 propensity score-matched controls without any of these ISDs. Patients with atopic dermatitis and psoriasis had significantly increased odds of all CVD diagnoses analyzed compared to controls (P<0.001 for all comparisons). Patients with rosacea had significantly increased odds of being diagnosed with all diseases of the circulatory system (P<0.001), hypertensive diseases (P<0.001), cerebrovascular diseases (P=0.037), and arterial disease (P<0.001) compared to controls. Patients with alopecia areata had increased odds for all diseases of the circulatory system (P<0.001), hypertensive diseases (P<0.001), and arterial disease (P<0.001). The prevalence of patients with elevated C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) levels was significantly greater in all ISD groups compared to controls. CONCLUSION: This study identified significant associations between ISDs and several CVD diagnoses. Furthermore, CRP and ESR were elevated in all ISD groups compared to controls. Pagan AD, Jung S, Caldas S, et al. Cross-sectional study of psoriasis, atopic dermatitis, rosacea, and alopecia areata suggests association with cardiovascular diseases. J Drugs Dermatol. 2023;22(6):576-581. doi:10.36849/JDD.7424.

Vascular inflammation in moderate-to-severe atopic dermatitis is associated with enhanced Th2 response.

BACKGROUND: In atopic dermatitis (AD), some studies have shown an association with increased cardiovascular disease in certain populations. However, other investigations found modest or no association. Despite conflicting results, molecular profiling studies in both AD skin and blood have demonstrated upregulation of atherosclerosis and cardiovascular risk-related markers. However, the underlying mechanisms connecting AD to vascular inflammation/atherosclerosis are unknown. In this study, we aim to determine factors associated with vascular inflammation/atherosclerosis in AD patients. METHODS: We used 18-FDG PET-CT to characterize vascular inflammation in AD patients and healthy subjects. In parallel, we assessed their skin and blood immune profiles to determine AD-related immune biomarkers associated with vascular inflammation. We also assessed levels of circulating microparticles, which are known to be associated with increased cardiovascular risk. RESULTS: We found significant correlations between vascular inflammation and Th2-related products in skin and blood of AD patients as well as atherosclerosis-related markers that were modulated by dupilumab. Circulating levels of endothelial microparticles were significantly higher in severe AD patients and tended to correlate with vascular inflammation assessed by PET-CT. CONCLUSION: Vascular inflammation in AD is associated with enhanced Th2 response and clinical severity, which may explain cardiovascular comorbidities observed in select AD populations. Larger prospective studies are needed to further evaluate vascular inflammation and cardiovascular events and mortality in AD patients. Finally, as dupilumab treatment demonstrated significant modulation of atherosclerosis-related genes in AD patients compared to placebo, these data suggest that modulation of vascular inflammation with systemic treatment should be explored in patients with AD.

The proteomic skin profile of moderate-to-severe atopic dermatitis patients shows an inflammatory signature.

BACKGROUND: Moderate-to-severe atopic dermatitis (AD) is increasingly recognized as a systemic disease, largely due to proteomic blood studies. There are growing efforts to develop AD biomarkers using minimal tissues. OBJECTIVE: To characterize the AD skin proteomic signature and its relationship with the blood proteome and genomic skin profile in the same individuals. METHODS: We evaluated lesional and nonlesional biopsy samples and blood from 20 individuals with moderate-to-severe AD and 28 healthy individuals using Olink Proteomics (Uppsala, Sweden), using 10 µg/10 µL for skin and blood and RNA sequencing of the skin. RESULTS: The AD skin proteome demonstrated significant upregulation in lesional and even in nonlesional skin compared with controls in inflammatory markers (matrix metalloproteinase 12; T-helper cell [Th]2/interleukin [IL]-1 receptor-like 1[IL1RL1]/IL-33R, IL-13, chemokine [C-C motif] ligand [CCL] 17; Th1/C-X-C motif chemokine 10; Th17/Th22/PI3, CCL20, S100A12), and in cardiovascular-associated proteins (E-selectin, matrix metalloproteinases, platelet growth factor, myeloperoxidase, fatty acid binding protein 4, and vascular endothelial growth factor A; false discovery rate, <0.05). Skin proteins demonstrated much higher and significant upregulations (vs controls) compared with blood, suggesting a skin source for the inflammatory/cardiovascular profile. Gene and protein expressions were correlated (r = 0.410, P < .001), with commonly upregulated inflammatory and cardiovascular risk-associated products, suggesting protein translation in skin. LIMITATIONS: Our analysis was limited to 354 proteins. CONCLUSIONS: The AD skin proteome shows an inflammatory and cardiovascular signature even in nonlesional skin, emphasizing the need for proactive treatment. Skin proteomics presents a sensitive option for biomarker monitoring.

Dupilumab progressively improves systemic and cutaneous abnormalities in patients with atopic dermatitis.

BACKGROUND: Dupilumab is an IL-4 receptor α mAb inhibiting signaling of IL-4 and IL-13, key drivers of type 2-driven inflammation, as demonstrated by its efficacy in patients with atopic/allergic diseases. OBJECTIVE: This placebo-controlled, double-blind trial (NCT01979016) evaluated the efficacy, safety, and effects of dupilumab on molecular/cellular lesional and nonlesional skin phenotypes and systemic type 2 biomarkers of patients with moderate-to-severe atopic dermatitis (AD). METHODS: Skin biopsy specimens and blood were evaluated from 54 patients randomized 1:1 to weekly subcutaneous doses of 200 mg of dupilumab or placebo for 16 weeks. RESULTS: Dupilumab (vs placebo) significantly improved clinical signs and symptoms of AD, was well tolerated, and progressively shifted the lesional transcriptome toward a nonlesional phenotype (weeks 4-16). Mean improvements in a meta-analysis-derived AD transcriptome (genes differentially expressed between lesional and nonlesional skin) were 68.8% and 110.8% with dupilumab and -10.5% and 55.0% with placebo (weeks 4 and 16, respectively; P < .001). Dupilumab significantly reduced expression of genes involved in type 2 inflammation (IL13, IL31, CCL17, CCL18, and CCL26), epidermal hyperplasia (keratin 16 [K16] and MKi67), T cells, dendritic cells (ICOS, CD11c, and CTLA4), and TH17/TH22 activity (IL17A, IL-22, and S100As) and concurrently increased expression of epidermal differentiation, barrier, and lipid metabolism genes (filaggrin [FLG], loricrin [LOR], claudins, and ELOVL3). Dupilumab reduced lesional epidermal thickness versus placebo (week 4, P = .001; week 16, P = .0002). Improvements in clinical and histologic measures correlated significantly with modulation of gene expression. Dupilumab also significantly suppressed type 2 serum biomarkers, including CCL17, CCL18, periostin, and total and allergen-specific IgEs. CONCLUSION: Dupilumab-mediated inhibition of IL-4/IL-13 signaling through IL-4 receptor α blockade significantly and progressively improved disease activity, suppressed cellular/molecular cutaneous markers of inflammation and systemic measures of type 2 inflammation, and reversed AD-associated epidermal abnormalities.