Sebum is a lipid mix produced and delivered to the skin surface by appendages called sebaceous glands (SG) in a holocrine secretion process. Sebum contributes to the skin barrier, lubricates hair and skin, provides antimicrobial protection and has pheromone functions. During the terminal differentiation of SG cells (sebocytes) macroautophagy, an intracellular process for major metabolic reconfiguration, is activated. Deletion of autophagy affects the hair sebum composition in mice. This study aimed to investigate lipid composition and localization within SG and the epidermis in Atg7 knockout (atg7ΔKC) and autophagy-competent mouse ears in situ using mass spectrometry imaging. Spatial lipidomics revealed lipid distribution with high spatial accuracy and identified lipid species with altered intensities in autophagy-deficient tissue. In SG regions of interest (ROIs), signals putatively annotated as ceramide phosphate species (including CerP 44:2;O2), showed higher signal intensities in atg7ΔKC mice. In contrast, selected sphingomyelin-associated signals showed lower intensities in the whole-tissue profile but not exlusively in SG ROIs. It is also demonstrated that spatially resolved ion mass signatures are suitable for identifying epidermis and SG in tissue ion images, a step towards “chemical analytical histology” of skin.
Cutaneous human papillomavirus (HPV)-specific cell-mediated immunity in patients with cutaneous squamous cell carcinoma (SCC) remains poorly understood, particularly in organ transplant recipients (OTRs), who often develop multiple viral warts and SCC under long-term immunosuppression. This study characterized HPV E6/E7-specific T-cell responses in OTRs with SCC and compared them with immunocompetent individuals with SCC. Participants were recruited in Singapore and included OTRs with a history of post-transplant primary SCC (n=28) and immunocompetent individuals with SCC (n=10). Fifteen-mer peptides spanning the E6/E7 regions of HPV8, HPV17, HPV49, and HPV98 were synthesized, and HPV-specific T-cell responses were measured using an Enzyme-linked immune absorbent spot(ELISpot) assay.Most participants showed positive responses to CMV peptide, the positive control, with response rates of 82% in OTRs and 70% in immunocompetent participants. Among OTRs, 28.57% responded to HPV17 E6/E7 peptides and 14.29% to HPV98, while responses to HPV8 and HPV49 were lower (7.14% and 3.57% respectively). In immunocompetent participants, 20% responded to HPV17 and HPV49, 10% to HPV8, and none to HPV98.This study provides preliminary evidence that circulating T cells reactive to selected β-HPV E6/E7 peptide pools can be detected in a subset of Asian participants with cutaneous SCC, including OTRs.
Loss of function (LOF) variants of the Filaggrin gene (FLG) are risk factors for atopic dermatitis (AD). However, due to the repetitive nature of exon 3 these variants are difficult to characterize. We sought to determine whether the use of long read technologies would enable better characterization of the FLG gene and improve detection of LOF variants. We sequenced a diverse clinical cohort of 192 samples collected in Belgium, Ireland and Rwanda using long read sequencing as well as publicly available data. We identified both common and rare LOF variants linked to AD in our clinical cohort, a number of compound heterozygotes, as well as one LOF variant previously undescribed. We also observed 20 previously undescribed FLG alleles, which varied in length by up to 13kb. These were mostly found in samples of Sub Saharan origin and appear to be products of non allelic homologous recombination. Despite the use of a long read based approach we did not detect any FLG LOF in our African cohort, highlighting differences in FLG LOF burden and AD genetic risk between populations. Our approach has the potential to be a useful tool to identify FLG variants contributing to AD, in various human populations.
Background and aim PF-07242813 (anti-CD1a) was designed to inhibit T-cell proinflammatory signaling. This analysis evaluated the safety and pharmacokinetics of single ascending doses (SAD) and multiple ascending doses (MAD) of PF-07242813 in healthy participants and pharmacodynamics of a single dose in patients with atopic dermatitis. Methods In Part 1, healthy participants (18–55 years) received PF-07242813 intravenously (IV; SAD), subcutaneously (SC; MAD) or IV (MAD), or placebo. In Part 2, patients with moderate-to-severe atopic dermatitis (18–65 years) were randomized (2:1) to receive PF-07242813 1000 mg IV or placebo. Endpoints included safety and pharmacokinetic outcomes in healthy participants and efficacy endpoints in patients with atopic dermatitis. Results Of the 122 participants (SAD: n = 57; MAD: n = 40; atopic dermatitis: n = 25), 41 reported treatment-emergent adverse events (mostly mild); headache (4.9%) and alanine transaminase increased (4.9%) were most common. Peak serum PF-07242813 concentrations were 0.6–2 hours (IV, SAD) and 73–169 hours (SC, MAD). Overall, PF-07242813 did not demonstrate clinical benefit in patients with atopic dermatitis. Conclusions CD1a blockade is not sufficient to produce a clinical effect in patients with atopic dermatitis. PF-07242813 was well-tolerated and may be useful for CD1a pathway analyses. ClinicalTrials.gov Identifier NCT04668066
Basal cell carcinoma (BCC) is the most common type of cancer, yet mouse models of BCC are limited. Existing BCC mouse models such as the Ptch1+/--K14-CreERT2p53fl/fl-tumor (GEM-BCC) model rely on genetic engineering. Spontaneous tumor models are essential for studying carcinogenesis, however the heterogeneous growth of multiple tumors requires large group sizes, making them challenging to implement in early-stage drug development. This study describes the establishment of an immunocompetent transplantable BCC (Tp-BCC) mouse model suitable for preclinical treatment evaluation. By in vivo passaging GEM-BCC tumor cells, we established a subcutaneous Tp-BCC model. We compared microstructural features, tumor microenvironment and transcriptional profile of the Tp-BCC model with its parental GEM-BCC model using histology, flow cytometry and RNA sequencing. Tp-BCC tumors displayed synchronized growth and shortened time until formation compared to GEM-BCC tumors. Tp-BCC tumors showed micro-nodular histological structure, maintained K14 expression and had a low immune infiltration similar to the GEM-BCC tumors. Hedgehog signaling pathway-related genes were similarly expressed except for Igf2. The transcriptional profile of Tp-BCC tumors was more homogenous than the GEM-BCC tumors. This study demonstrates that the Tp-BCC model retains key features of the GEM-BCC model and provides a complementary, immunocompetent, high-throughput platform for early-stage BCC therapeutic development.
Vitiligo is a chronic autoimmune disorder causing progressive melanocyte destruction and significant psychosocial burden. Topical JAK inhibitors (JAKi), including ruxolitinib cream, are FDA-approved treatment option. Real-world data on treatment response across diverse patient populations remain limited. This single-institution retrospective cohort study (April 2018-2024) included 120 vitiligo patients from a Southern California academic medical center. Eligibility included ≥2 dermatology visits, Vitiligo Area Scoring Index (VASI) scores, insurance documentation, and current topical JAKi treatment. Bivariate analyses and multivariable Firth logistic regression were performed. The cohort was 34.2% Asian, 16.6% Hispanic, and 49.2% White. On bivariate analyses, Hispanic ethnicity (50% vs 27% non-Hispanic, p=0.042) and longer treatment duration (p=0.010) were significantly associated with VASI improvement. On multivariable analysis, treatment duration remained an independent predictor (aOR 1.11/month, 95% CI 1.04–1.20, p<0.001), while non-Hispanic ethnicity had 69% lower odds of improvement (aOR 0.307, 95% CI 0.099–0.912, p=0.034). Publicly insured patients experienced higher JAKi denial rates (60% vs. 40%, p=0.018). In this diverse real-world cohort, Hispanic ethnicity and longer treatment duration were independently associated with VASI improvement. Insurance-related disparities and limited representation of certain minority groups highlight inequities in access to vitiligo care. Larger studies incorporating standardized outcomes are needed.
Alopecia areata (AA) is a common autoimmune disorder causing non-scarring hair loss. The quality and reliability of high-engagement educational AA-related videos (hereafter referred to as "AA-related videos") on Chinese social media remain unclear. Videos were retrieved from Douyin, RedNote, and Bilibili between March and May 2025 using standardized keywords, with engagement thresholds set for inclusion. Content features and video parameters were extracted. Two dermatologists independently assessed video quality using the Global Quality Score (GQS), Journal of the American Medical Association criteria (JAMA), and modified DISCERN (mDISCERN). Non-parametric tests and Spearman correlations explored associations between video characteristics and quality scores. Of 111 included videos, pathogenesis, treatment, and prognosis were most frequently addressed, while clinical manifestations and diagnosis were underrepresented. Douyin and RedNote demonstrated higher quality, reliability, and guideline adherence than Bilibili. Video parameters showed platform-dependent associations with quality scores. Videos produced by medical professionals scored higher across all three tools than those by non-medical creators. Our findings underscore the importance of professional involvement and platform algorithm optimization for disseminating accurate, evidence-based health information.
Atopic dermatitis (AD) is a chronic, multifactorial inflammatory skin disease with a complex, heterogeneous pathogenesis. Understanding its mechanisms, stratifying patients into biologically relevant endotypes, and predicting treatment responses remain challenging if we use empirical approaches alone. In silico approaches, including mathematical modeling, statistical and machine learning methods, enable the dissection of molecular and cellular interactions, the identification of key clinical and biological drivers, and the extraction of meaningful insights from high-dimensional, noisy datasets, while preserving a systems-level perspective. This review summarizes recent advancements in in silico approaches for AD and outlines strategies to enhance their translational and clinical utility in AD research.
Neurofibromatosis type 1 (NF1) is a multisystem disorder, but its hematological features remain incompletely characterized. We investigated whether erythrocyte-related indices show coordinated alterations in adults with NF1. In this retrospective single-institute study, 225 adults with NF1 were analyzed. Z-scores for erythrocyte-related parameters were calculated relative to a reference population. One-sample tests, correlation analyses, and comparisons across tumor burden (D-class) were performed. A composite score, defined as the mean of parameter-specific Z-scores, was used to assess coordinated changes. Z-scores for red blood cell count, hemoglobin, hematocrit, and mean corpuscular volume were modestly but significantly increased, whereas mean corpuscular hemoglobin concentration (MCHC) shifted in the opposite direction. Individual effect sizes were small; however, the composite score showed a moderate effect size (Cohen's d = 0.43), indicating a coherent directional shift. Mean corpuscular volume was inversely correlated with red blood cell count (r = −0.390, P < 0.001), and higher tumor burden was associated with lower MCHC. Adult NF1 patients exhibit subtle but coordinated erythrocyte alterations, suggesting a macrocytic and relatively hypochromic profile, with erythrocyte hemoglobin concentration tending to decrease with increasing tumor burden. These findings may represent a systemic feature of NF1 and warrant further investigation.
Although rituximab is clinically-approved for pemphigus, real-world data on predictors of treatment success and optimal dosing remain limited. We conducted a retrospective cohort study at NewYork-Presbyterian Hospital of pemphigus patients treated with rituximab with ≥1 year of follow-up. Patients initially received two 1,000 mg doses 2 weeks apart or four weekly weight-adjusted (375 mg/m2) infusions. Factors associated with complete remission off oral immunosuppressive therapy were analyzed using Kaplan-Meier and Cox proportional hazards analyses. Among 105 patients, 44.7% achieved complete remission off therapy after the first rituximab cycle, increasing to 74.3% after multiple cycles with median time to remission of 7.4 months. Weight-adjusted rituximab dosing was associated with a higher likelihood of achieving CROT after the first rituximab cycle compared with the fixed-dose regimen (hazard ratio 2.49, p=0.01). For subsequent treatment, maintenance rituximab infusions every 6 months was associated with shorter time to initial achievement of complete remission off therapy and longer time to relapse compared with an on-demand approach; however, both achieved similar overall rates of complete remission off therapy. These findings support the benefit of weight-adjusted dosing for the first rituximab cycle and provide real-world data on outcomes of maintenance versus on-demand rituximab infusions for pemphigus therapy.
Rituximab and corticosteroids remain the only clinically approved therapies for pemphigus vulgaris, although novel therapeutics are entering clinical development. A historical control dataset previously described clinical and serologic outcomes after rituximab therapy in pemphigus vulgaris, but whether these data are representative of other patient cohorts is currently unclear. A contemporary pemphigus vulgaris cohort (n = 97) was compared with the historical cohort (n = 107) to assess clinical outcomes as well as desmoglein 3 ELISA predictive performance for achieving complete remission off oral immunosuppressive therapy. A total of 41.2% of patients achieved complete remission off oral immunosuppressive therapy after the first rituximab cycle, with a maximum complete remission off oral immunosuppressive therapy prevalence of 52.8% at month 36, including multiple rituximab cycles. Despite differences in baseline characteristics and treatments (particularly rituximab dosing), the temporal patterns of remission, relapse, and retreatment were broadly similar across cohorts. A desmoglein 3 ELISA index value ≤ 130 RU/ml and > 90.7% titer reduction between months 3 and 9 demonstrated 90% specificity and 88% sensitivity for future achievement of complete remission off oral immunosuppressive therapy, with negative predictive values of 85% and 92%, respectively, suggesting that low and/or rapid large drops in autoantibody titers after rituximab may predict an absence of disease activity. These data describe the temporal outcomes of rituximab therapy in pemphigus vulgaris and validate the historical control dataset for future comparative effectiveness research and biomarker-driven management.
Pyoderma gangrenosum (PG) is a rare neutrophilic dermatosis characterized by painful, nonhealing cutaneous ulcers. Although dysregulated innate immunity and neutrophil activation are implicated in its pathogenesis, the underlying molecular mechanisms remain poorly defined. This study aimed to identify conserved pathogenic mechanisms by integrating analyses of human PG lesions and a brequinar-induced PG-like murine model and to assess therapeutic relevance. Skin biopsy specimens from patients with PG and publicly available RNA-sequencing data were analyzed alongside the murine model using histological and transcriptomic approaches. Cross-species transcriptomic integration identified shared inflammatory pathways between human and murine PG. Human PG lesions showed increased neutrophil infiltration, neutrophil extracellular trap formation, and a dominant type 1 inflammatory profile, all of which were recapitulated in the brequinar-induced mouse model, together with impaired wound healing. Transcriptomic analyses revealed enhanced oxidative stress responses and activation of the NLRP3/caspase-1 inflammasome pathway as a conserved pathogenic axis. In the murine model, both prednisolone and avacopan suppressed inflammatory cytokine expression and neutrophil activation; however, only avacopan significantly improved wound healing. Collectively, these findings suggest that NLRP3 inflammasome activation is associated with type 1 inflammation and neutrophil extracellular trap formation and may represent a PG-associated inflammatory pathway.
Skin is continually exposed to external stimuli, making this frontline barrier highly susceptible to inflammatory disorders. Foxp3+ regulatory T cells (Tregs) are considered guardians of skin homeostasis, with functions that extend beyond immune regulation to include neuroimmunological modulation, hair cycling, and wound healing. In the resting state, skin Tregs originate from the thymus; however, the composition of the Treg population under pathological conditions remains elusive. Notably, emerging studies show that Tregs can acquire proinflammatory characteristics during the development of allergic and autoimmune diseases, raising questions about their fate and function during disease progression. This review discusses the trafficking of Tregs into the skin, their plasticity driven by proinflammatory cytokines and T helper cell lineage-defining transcription factors, and their multifaceted roles in cutaneous immunity. Together, these insights offer a perspective on Treg dynamics in skin health and disease.
Generalized pustular psoriasis (GPP) is a rare, chronic, systemic inflammatory disease characterized by unpredictable chronic symptoms and periods of flaring. Assessing GPP severity is important for defining treatment goals and evaluating treatment responses, yet the rarity of the disease and the subjectivity of manual evaluation complicate its standardization. To address this, we developed the Automatic Generalized Pustular Psoriasis Physician Global Assessment (AGPPGA), a digital imaging tool powered by artificial intelligence. Based on the validated GPPGA scoring system, this framework rapidly assesses GPP severity in clinical images using a neural network trained on annotated clinical images of GPP, with consistent performance across diverse sexes, ages, and skin tones. Using two datasets (V1 and V2, comprising 332 and 4296 images, respectively, with diverse demographics), AGPPGA achieved a Cohen's kappa of 0.74 for V1 and 0.82 for V2, while dermatologists achieved 0.79 and 0.80, respectively. Accuracy values for AGPPGA were 0.62 for V1 and 0.64 for V2, versus 0.70 and 0.65 for dermatologists. These results support its potential use for assessing lesion severity from images during healthcare visits. AGPPGA offers a reproducible method that can address the subjectivity of manual-only evaluation and facilitate the standardization of GPP severity assessment.
Chronic pruritus is increasingly recognized as a complex neuroimmune disorder rather than a purely sensory symptom. Historically, itch research has progressed through successive mechanistic paradigms-from histamine and mast cells, through dedicated neuronal circuits, to cytokine-driven and intracellular signaling pathways. Yet, each advance revealed that chronic pruritus cannot be explained by a single mediator or pathway. In this review, we propose the immunopathogenic spiral of itch as an integrative framework that describes both the evolution of pruritus research and the interconnected biology of itch pathogenesis. It reflects not only the cumulative history of the field but also the biological progression within an individual patient: from acute, single-mediator itch to a self-sustaining neuroimmune network in which multiple mechanistic layers operate simultaneously. In contrast to the traditional itch-scratch cycle, the spiral model captures how barrier dysfunction, immune activation, and neuroimmune remodeling link successive mechanistic layers into self-reinforcing networks. We discuss how histaminergic signaling, sensory neuron specialization, type 2 immune polarization, IL-17-dependent pathways, and JAK-signal transducer and activator of transcription convergence represent interconnected rather than competing layers of itch biology. This framework may help explain why single-target therapies achieve meaningful but incomplete itch control, supporting the rationale for multi-target therapeutic strategies.
Combining spatial and molecular information enhances understanding of skin cancer biology. In this exploratory study, we investigated such associations in basal cell carcinoma (BCC) using two non-invasive approaches: line-field confocal optical coherence tomography (LC-OCT) to assess tumor morphology and tape stripping for gene expression profiling. With development, this combined image-transcriptomic approach could contribute to understanding of BCC pathogenesis in vivo. Histology-confirmed BCCs (n = 53) and control skin were scanned with LC-OCT for 44 morphological features and sampled via tape stripping for mRNA analysis. Differentially expressed genes (DEGs) were identified and examined through pathway-enrichment to uncover mechanisms. Seven LC-OCT image-features were associated with BCC compared to control skin (p ≤ 0.004). Seventy-two DEGs were identified in BCC (false discovery rate [FDR] < 0.001). A subset of 27 DEGs correlated with two LC-OCT features - the millefeuille pattern and collagen alterations - showing a 3.9 - to 11.8-fold increase in gene expression levels. Pathway-enrichment analysis highlighted BCL2A1, linked to tumorigenesis, in association with the millefeuille pattern, and FMO2, involved in collagen synthesis, with collagen alterations. This imaging–transcriptomic approach confirms the feasibility of tape stripping for detecting BCC-specific gene expression and, introduces LC-OCT-based imaging transcriptomics, for investigating BCC pathobiology in vivo.
Pyoderma gangrenosum (PG) is a rare dermatologic disease resulting in chronic, painful ulcerations, most commonly on the lower extremity. Pruritus is a common symptom in many dermatologic conditions but has not been thoroughly evaluated in patients with PG. We sought to characterize the prevalence, severity, and impact on QOL of lesional pruritus in patients with PG. Data were obtained from the "Pyoderma Gangrenosum Study" (IRB#16753) at Oregon Health and Science University. Standardized outcome data were prospectively collected during clinical encounters from December 2019 to May 2024. Inclusion criteria were adults who presented for at least 2 clinical visits and a PARACELSUS score ≥10. We analyzed data from 136 patients with 178 ulcers. At baseline, 69% of the patients reported moderate pruritus with a mean severity of 3.3 (0-10 scale, 95% confidence interval = 2.9-3.8), which decreased with healing (from 3.7 to 2.6). QOL scores (Skindex-Mini, Wound-QoL) improved in parallel with healing. Higher pruritus severity was associated with younger age and inflammatory arthritis, whereas analgesic use and systemic therapies showed no consistent associations. In summary, our findings suggest that lesional pruritus is a common symptom among patients with PG and significantly affects their QOL. These findings support routine assessment and antipruritic interventions in the management of PG.
Although artificial intelligence is rapidly advancing, its application in translational dermatological research remains limited. In this study, we established an artificial intelligence-based image analysis workflow for the quantification of proliferation and apoptosis within the human epidermis using 3,3'-diaminobenzidine-based immunohistochemical staining. Human skin cultured in a 3-dimensional in vivo model was processed using paraffin embedding and immunohistochemical staining for Ki-67 and cleaved Caspase-3. We implemented an artificial intelligence-based 2-model workflow: a custom-trained convolutional neural network-based model for cell detection and a semantic-segmentation model that specifically segregates the epidermis. By combining both models, we restricted cell annotation and classification to the epidermis-our structure of interest-enabling epidermis-constrained quantification on whole-slide images. Validation against manual counts showed high agreement for both markers (Ki-67 mean accuracy = 95.43%; cleaved Caspase-3 = 97.0%) across staining batches and time points. To test the experimental applicability of our workflow, we treated human skin cultured on the chorioallantoic membrane with hydroxytyrosol. The artificial intelligence-based workflow minimized subjective bias and provided a coherent readout, showing reduced proliferation without inducing apoptotic responses in hydroxytyrosol-treated samples. Overall, the workflow achieved strong performance with modest training effort and annotation, offering a scalable approach that supports translational dermatological research and holds potential for dermatopathological applications.
Cutaneous squamous cell carcinoma occurs with increasing incidence in the aging United States population and, depending on the tumor stage, can require multimodal treatment. Neoadjuvant cemiplimab has shown promise in improving pathological response and event-free survival, but its cost effectiveness compared with starting with upfront wide local excision has not been explored. This health economics evaluation aims to determine whether adding neoadjuvant cemiplimab may be a more economically valuable intervention in the management of head and neck locoregionally advanced cutaneous squamous cell carcinoma using a decision tree combined with a state-transition Markov model over a 10-year horizon. In the model's base-case analysis, the expected long-term cost per patient was $19,021 lower with the addition of neoadjuvant immunotherapy than with upfront wide local excision alone and yielded 0.11 more quality-adjusted life years, with adjusted time horizon and health utilities leading to the greatest differences in mean costs and quality-adjusted life years, respectively. In this model, neoadjuvant immunotherapy followed by wide local excision was associated with lower expected costs and modestly higher quality-adjusted life years over a 10-year horizon, although the results were sensitive to modeling parameters and assumptions. Future research is needed to clarify long-term costs, outcomes, and corresponding health state utilities.
