British Journal of Dermatology最新文献

Background: The age of psoriasis onset is bimodally distributed with distinct peaks at < 40 (early onset) and ≥ 40 years (late onset) of age. Although the age of psoriasis onset is associated with distinct disease profiles, few well-controlled studies have reported the efficacy of biologics in patients with early- vs. late-onset disease. The efficacy and safety of tildrakizumab, an interleukin-23 p19 inhibitor, for the treatment of moderate-to-severe plaque psoriasis were investigated in the reSURFACE 1 (NCT01722331) and reSURFACE 2 (NCT01729754) phase III trials.

Objectives: To determine the efficacy and safety of tildrakizumab in patients with early- vs. late-onset psoriasis through 28 weeks of treatment.

Methods: This was a post hoc subgroup analysis of patients from reSURFACE 1 and reSURFACE 2. Patients aged ≥ 50 years were grouped by age of psoriasis onset (< 40 years vs. ≥ 40 years). Efficacy endpoints included absolute Psoriasis Area and Severity Index (PASI) and Dermatology Life Quality Index (DLQI), and the proportions of patients who achieved a ≥ 75%, ≥ 90% or 100% improvement from baseline in PASI (PASI 75, PASI 90 and PASI 100, respectively), a Physician Global Assessment score of 0 or 1 (PGA 0/1) and DLQI of 0 or 1 (DLQI 0/1), adjusted for potential confounders. Safety was assessed based on treatment-emergent adverse events (TEAEs).

Results: Higher percentages and adjusted responder rate estimates of patients with late- (n = 130) vs. early-onset (n = 111) psoriasis achieved an absolute PASI < 1 (36.2% vs. 27.9%; estimate was 32.2% vs. 25.0%), PASI 90 (50.8% vs. 39.6%; estimate was 49.4% vs. 40.2%) and PASI 100 (21.5% vs. 8.1%; estimate was 13.7% vs. 7.9%) at week 28 (all P < 0.05). Age of onset did not significantly affect change from baseline in absolute PASI or DLQI, or the achievement of PASI < 5, PASI < 3, PASI 75, DLQI 0/1 or PGA 0/1 (all P > 0.05). Efficacy findings were supported in a subset of patients matched by disease duration. TEAEs and serious TEAEs occurred in 65.8% vs. 66.2% and 3.6% vs. 6.9% of patients with early- vs. late-onset psoriasis, respectively.

Conclusions: Treatment with tildrakizumab was effective with no safety signals found in either of the patient subgroups. Patients with late-onset psoriasis were more likely to achieve complete or near-complete clearance than patients with early-onset psoriasis.

Background: Dual specificity phosphatase 1 (DUSP1) has recently been shown to regulate keratinocyte (KC) proliferation through extracellular regulated kinase (ERK) signalling.

Objectives: To delineate the genetic basis underlying inherited palmoplantar keratoderma (PPK) in two families.

Methods: We used whole-exome and direct sequencing, quantitative real-time polymerase chain reaction, protein modelling, immunofluorescence confocal microscopy, immunoblotting, three-dimensional skin equivalents and the dispase-based KC dissociation assay.

Results: Whole-exome sequencing revealed two variants in DUSP1 (c.809T>G, p.Leu270Arg and c.251T>A, p.Val84Glu), encoding DUSP1, in four individuals with PPK belonging to two unrelated families affected by a semidominant form of PPK. Bioinformatics and protein modelling predicted the variants to be pathogenic. Primary human KCs transfected with constructs expressing the PPK-causing pathogenic variants in DUSP1 showed decreased DUSP1 expression and concomitant increased expression of phosphorylated (p-)ERK1/2, as well as reduced desmoglein 1 (DSG1) expression. Accordingly, primary human KCs downregulated for DUSP1 displayed disrupted cell-cell adhesion, increased p-ERK1/2 and reduced DSG1 expression. Three-dimensional organotypic skin equivalents downregulated for DUSP1 demonstrated reduced DSG1 expression and increased epidermal thickness, reminiscent of the human phenotype. ERK1/2 inhibition rescued this abnormal phenotype.

Conclusions: This study attributes to DUSP1 a hitherto unrecognized role in epidermal differentiation and expands the spectrum of genetic defects known to cause inherited PPK.

Background: Cutaneous squamous cell carcinoma (cSCC) is a common cancer with a high morbidity rate and poor prognosis for metastatic disease. Disease may progress from premalignant actinic keratosis to invasive and metastatic cSCC, but it is perhaps best characterized as a disease continuum progressing from a differentiated to a progenitor-like state. The critical molecular mediators of this process remain poorly defined. Long noncoding (lnc)RNAs, a relatively unexplored class of RNA molecules > 200 nucleotides long, are likely to have important functional roles in cSCC.

Objectives: To provide a comprehensive landscape of lncRNA expression during the cSCC continuum and to identify potentially functional lncRNA drivers of disease progression.

Methods: We interrogated bulk RNA sequencing (RNAseq) data from 110 patient samples, encompassing healthy sun-exposed skin (n = 26), actinic keratosis (n = 14), primary cSCC (n = 66) and metastases (n = 4), to identify changes in lncRNA expression during disease progression. We developed a bioinformatics pipeline to infer lncRNA function based on co-expression patterns and generated a lncRNA signature score, which we validated in head-and-neck squamous cell carcinoma (HNSC) and pancreatic adenocarcinoma (PAAD). We performed bulk RNAseq on 15 patient-derived cell lines and integrated these data to identify tumour cell-specific lncRNAs and validated our findings in multiple other cSCC gene expression cohorts. Using in vitro knockdown approaches we investigated the functional role of LINC00941.

Results: We found that lncRNA expression alone is sufficient to identify disease states and progression along the cSCC disease continuum. Correlation analysis revealed potentially functionally relevant lncRNAs and the processes they may regulate. We developed a 267 lncRNA signature that correlates with a progenitor-like state and predicts poor prognosis in HNSC and PAAD. Bulk RNAseq of patient-derived cell lines revealed tumour cell-specific lncRNAs, and knockdown of LINC00941 indicated that it is required for cell proliferation and colony formation in vitro.

Conclusions: Our findings provide a comprehensive description of lncRNA transcriptomic changes in cSCC and demonstrate their functional relevance as biomarkers and drivers of disease progression in this and, potentially, other cancers.

Background: Hair density traits, including follicular unit density (FUD) and hairs per follicular unit (HFU), are influenced by environmental and genetic factors. Understanding these determinants can refine our knowledge of hair growth patterns and enable more targeted interventions. Historically, large-scale research has been constrained by difficulties in precise phenotyping.

Objectives: To identify environmental and genetic factors associated with hair density in East Asian populations and to explore shared genetic influences among other hair traits and hair disorders.

Methods: We performed quantitative assessments of FUD and HFU using trichoscopic images from 5735 East Asian individuals. Accurate phenotyping was achieved through deep learning-based analyses with manual correction. We used multiple regression to evaluate demographic, lifestyle and reproductive factors, and conducted genome-wide association studies (GWAS), meta-analysis and a combined GWAS (C-GWAS) for hair density, hair curliness, eyebrow thickness and beard thickness. Significant associations were compared with published results on male pattern baldness (MPB). Gene-finasteride use interactions were evaluated via mixed linear models in longitudinal UK Biobank data.

Results: Age, sex, body mass index and menopausal status were significantly associated with FUD and HFU. Three genetic loci, rs11940736 at 4q28.1 (near SPRY1), rs10908366 at 1p34.3 (near RSPO1) and rs3771033 at 2q23.3 (intron NRP2), showed significant associations with hair density, with functional annotations implicating these genes in hair follicle development. In particular, rs3771033 was a significant expression quantitative trait locus for NRP2, where the T allele correlated with lower NRP2 expression but higher FUD. We also found substantial genetic overlap among hair density traits, hair curliness, eyebrow thickness, beard thickness and MPB. In UK Biobank analyses, rs3771033 exhibited allele-specific treatment effects on finasteride response in MPB.

Conclusions: We identified three loci that shape hair density in East Asian populations. Our results clarify the genetic and environmental architecture underlying hair density traits and suggest that genotype-specific responses to finasteride may open new avenues for the personalized management of hair disorders.

Mutant NRAS is the second-most common type of mutation in melanoma. The prognosis in patients with NRAS mutant melanoma is poor, and effective targeted treatment strategies are still lacking. Mutant NRAS mainly acts by activating RAF-MEK-ERK signalling to promote carcinogenesis in melanoma. In recent years, significant clinical advances have been made in targeting the NRAS-MAPK (mitogen-activated protein kinase) pathway, with novel therapies such as the MEK inhibitor tunlametinib and a combination therapy of the pan-RAF inhibitor naporafenib + trametinib leading the way. In this review, we systematically summarize the recent advances made in the direct targeting of mutant NRAS proteins and their downstream RAF and MEK proteins, as well as targeting the MAPK pathway in combination with other therapeutic targets, including immunotherapy, to treat NRAS mutant melanoma. Additionally, we discuss the current issues and emerging countermeasures related to targeted therapy for NRAS mutant melanoma.