The Journal of investigative dermatology最新文献

Segmental vitiligo (SV) is characterized by unilateral depigmentation, frequent leukotrichia, early stabilization, and unique pathomechanisms that differentiate it from nonsegmental vitiligo. This review systematically examines the epidemiology, clinical features, diagnosis, pathogenesis, and therapeutic advances in SV, emphasizing its classification as a distinct disease entity. Emerging evidence has provided significant insights into SV pathogenesis, including neurovascular factors, immune dysregulation, oxidative stress, and melanocyte dysfunction. Clinically, SV requires differentiation from other hypopigmentation disorders owing to its distinct progression and therapeutic challenges. Although conventional therapies exhibit limited efficacy, emerging approaches such as cellular grafting and targeted immunomodulation hold promise. This review advocates for future research to focus on the integration of multiomics data to establish SV-specific biomarkers and personalized diagnostic and therapeutic strategies.

Background: Upadacitinib, an oral selective Janus kinase inhibitor, showed significantly greater facial repigmentation vs placebo as assessed by Facial Vitiligo Area Scoring Index (F-VASI) in a phase 2 clinical trial. A nested substudy explored a 3-dimensional (3D) imaging platform as an objective tool to quantify facial vitiligo repigmentation.

Methods: Adults with non-segmental vitiligo received upadacitinib 6mg, 11mg, or 22mg or placebo for 24 weeks (period 1). For weeks 24-52 (period 2), upadacitinib-treated patients continued upadacitinib at assigned doses; patients receiving placebo switched to upadacitinib 11mg or 22mg. In this substudy, efficacy was assessed by the percent change from baseline in facial vitiligo area with 3D imaging and F-VASI.

Results: The substudy included twenty-seven patients. Patients receiving upadacitinib showed facial repigmentation at weeks 24 and 52 as assessed by 3D imaging and F-VASI. There was a high correlation between 3D imaging and F-VASI measurements at baseline (r=0.85; P<.0001). At week 24, there was a high correlation (r=0.71; P=.0003) between the percent change from baseline in 3D imaging and F-VASI measurements, which diminished by week 52 (r=0.01; P=.9600).

Conclusions: 3D imaging shows potential as an objective tool for evaluating changes in facial vitiligo after upadacitinib treatment.

Clinical trial registration number: NCT04727975.

Dermatological conditions can become extremely serious and cause life-threatening situations for affected patients, thereby necessitating intensive care. However, data regarding the specialized dermatology intensive care unit remain scarce. We conducted a retrospective analysis of electronic medical records from July 2017 to September 2023, covering 825 patients admitted to the dermatology intensive care unit at Huashan Hospital, one of China's largest tertiary hospitals and the only facility in the country equipped with a dedicated dermatology intensive care unit. The median (interquartile range) patient age was 60.0 (43.0-72.0) years, with a male-to-female ratio of 1.4. The predominant diagnoses were severe cutaneous adverse reactions to drugs (29.2%), bullous skin diseases (18.4%), and psoriasis (16.5%). The overall in-hospital mortality rate was 0.36%. The median (interquartile range) length of stay was 11.0 (7.0-15.0) days, and the median (interquartile range) total cost per patient was $4196 ($2655-7278). Analysis indicated that the length of stay and total hospitalization costs were primarily influenced by the main diagnosis and comorbidities. This study provides insights into the clinical characteristics, outcomes, and economic implications of managing severe dermatoses in a specialized intensive care setting, highlighting the significant impact of comorbidities on resource utilization.

Localized scleroderma (LoS) is a chronic dermal disease with fibrotic skin and subcutaneous tissues. Owing to the largely undefined pathogenesis, there is no specific medical treatment for LoS. Recent investigator-initiated tests have revealed the clinical efficacy of botulinum neurotoxin type A1 (BoNT/A1) on treating LoS. However, the mechanism of action of BoNT/A1-based LoS intervention has not been fully illustrated. In this study, we used a bleomycin-induced skin fibrosis mouse model for evaluating the therapeutic effects and mechanism of actions of BoNT/A1 relevant to LoS. It was found that BoNT/A1 treatment could alleviate the pathological changes in mice in a dose-dependent manner. Further analysis showed that BoNT/A1 could suppress the proliferation of primary human dermal fibroblasts by arresting the cell cycle at G0/G1 phase. RNA sequencing and subsequent western blotting analysis of human dermal fibroblasts revealed phosphatidylinositol 3-kinase-protein kinase B signaling as one of the most affected pathways in BoNT/A1 treatment groups. Experiments with phosphatidylinositol 3-kinase-protein kinase B agonist 740Y-P showed that BoNT/A1 suppressed skin fibrosis by inhibiting phosphatidylinositol 3-kinase-protein kinase B signaling. Collectively, our study provides experimental evidence at the animal, cellular, and molecular levels for the clinical use of BoNT/A1 for treating LoS.

Pachyonychia congenita (PC) is a rare and painful skin disorder caused by dominant pathogenic variants in keratin genes (KRT6A/KRT6B/KRT6C/KRT16/KRT17), with no effective treatment. We developed a scalable, in-depth and miniaturized MS-based proteomics and phospho-proteomics analysis of full-thickness skin biopsies applied to 10 PC patients to elucidate pathogenic mechanisms and pinpoint therapeutic targets. We quantified 7200 Protein Groups (PGs) on average from 2mm snap-frozen skin samples, the most in-depth proteome coverage reported to date from a single-shot MS analysis. Among the identified PGs, ∼1400 proteins were differentially abundant in lesional vs. non-lesional samples. Enrichment analysis points towards impaired mitochondrial function, hyper-keratinization, enhanced immune response and a significant increase in cholesterol biosynthesis. Phosphoproteomics revealed hyper-phosphorylation of specific sites in PC-related keratins, confirmed the hyper-activation of EGFR and downstream kinases, including PKC and Src, and disclosed p38 MAPK activation. All of these kinases have been reported to phosphorylate keratins. Our study expands upon current understanding of the consequences of EGFR pathway activation, including increased cholesterol biosynthesis, thereby renewing interest in the use of statins for PC. Above all, it provides a solid foundation for the continued exploration of EGFR inhibitors and offers therapeutic avenues, particularly those using multikinase inhibitors.

Prediction models that accurately predict patient prognosis and treatment response enable the development of personalized treatment plans in dermatology as well as outside dermatology. This can improve patient care and reduce the use of ineffective, potentially harmful treatments. Developing representative models for all patients can be a significant challenge, particularly in cases involving rare outcomes or expensive molecular biomarkers. The former requires large cohorts, whereas the latter requires a significant budget to measure these in a large volume of samples. Nested case-control and case-cohort designs are cost-effective designs that enable the development and validation of prediction models using only a proportion of samples of the source cohort, without compromising their applicability to the total population. These epidemiological designs are relatively unknown, and there is a lack of clear guidance on how to develop and validate models using these studies. We aim to inspire other researchers to apply these designs to their (skin) disease of interest and facilitate the development of prediction models that can have a high clinical impact on patient care.

Although regulatory T cells (Tregs) control autoimmune diseases, the role of evolutionarily older Foxp3⁺ γδTregs is much less understood. We noted that both lesional and nonlesional skin of patients with alopecia areata (AA), one of the most common autoimmune diseases, contains significantly more Vδ1⁺/Foxp3⁺ γδTregs than healthy scalp skin. Therefore, we investigated how human γδTregs impact experimentally induced AA in human scalp skin xenotransplants on SCID/beige mice in vivo. Peripheral autologous human Vδ2⁺/Foxp3⁺ γδTregs were expanded and preactivated in vitro and then injected intradermally into scalp skin xenografts before or after induction of AA. These γδTregs reduced the perifollicular lymphocytic infiltrate, restored hair follicle immune privilege, prevented AA onset, and promoted hair regrowth in established AA lesions. In parallel, γδTregs cocultured with organ-cultured, MICA/B-overexpressing human scalp hair follicles suppressed pathogenic CD8⁺/NKG2D⁺ T-cell activity and counteracted all AA hallmarks ex vivo-including hair follicle immune privilege collapse, hair follicle dystrophy, and premature IFNγ-induced catagen-through IL-10 and TGF-β1 secretion, contact-dependent inhibition, and adenosine generation through CD39/CD73. These findings in a model human autoimmune disease introduce human γδTregs as clinically important regulatory lymphocytes and invite the use of autologous peripheral Vδ2⁺/Foxp3⁺ γδTregs as a cell-based therapy for AA and possibly other CD8⁺ T cell-dependent autoimmune diseases characterized by immune privilege collapse.