British Journal of Dermatology最新文献

Background: Polymorphic light eruption (PLE) is the most frequent photodermatosis in Europe with an estimated prevalence of 10 to 20%, particularly in temperate climates. Itching or burning lesions appear only in sun-exposed areas, predominantly on the chest, the arms and forearms within a few hours following exposure. The disease's cause is still unknown, yet studies have suggested that skin microbial elements may play a role in its pathogenesis.

Objectives: We investigated in this cohort the skin microbiome of PLE patients upon exposure to ultraviolet radiation (UVR), to assess its role in the onset of PLE lesions.

Methods: Forty-one skin swabs have been collected from eleven PLE patients at baseline and following a three-day exposure to UVR and from healthy controls. The collected swabs were analyzed for their microbial composition using a 16S amplicon sequencing approach.

Results: The PLE skin showed a dysbalanced microbiome, already at baseline, with significantly reduced microbial diversity and noticeable colonization by bacterial pathogens as Staphylococcus aureus. Upon UVR exposure, the PLE microbiome exhibited a further loss of diversity and decline of beneficial skin commensals. In line with this, we observed that UVR exerted strong antimicrobial effects in vitro against representative skin residents.

Conclusions: Taken together, UVR can lead to profound skin microbiome changes, allowing the proliferation of dysbiotic members that can release a variety of elements able to trigger PLE lesions. This is the first study investigating the cutaneous microbiome changes in PLE patients upon UVR, offering new insights into disease pathogenesis, so far unexplored.

Background: The pathogenesis of psoriasis, an inflammatory skin disease, is incompletely understood. Growing evidence substantiates the involvement of stromal cells in the inflammatory process.

Objectives: To investigate the roles of stromal cells, including fibroblasts, vascular endothelial cells (VECs) and smooth muscle cells (VSMCs), in the psoriatic inflammatory microenvironment and the possible underlying mechanisms involved.

Methods: This study employed combination of single-cell, spatial transcriptome and bulk RNA sequencing using lesional and nonlesional skin samples from patients with psoriasis vulgaris (PV) and healthy skin samples from unaffected individuals.

Results: Through the analysis of transcriptome from 364,098 single cells, we uncovered WNT5A+ fibroblasts, ITIH5+ VECs and VCAN+ VSMCs with the significantly increased cell proportions in the papillary dermis of lesional skin. We defined eight unique subclusters of fibroblasts in the skin and observed a shift of WIF1+ fibroblasts towards WNT5A+ fibroblasts, with abnormal activation of the non-canonical Wnt signaling pathway and increased capabilities of angiogenesis and pro-inflammatory. For the microvascular cells, VSMCs could undergo phenotypic transformation from a contractile phenotype to a synthetic phenotype in the development of psoriatic inflammation. ITIH5+ VECs and VCAN+ VSMCs were identified with an essential role in regulating angiogenesis and vascular remodeling involved in the mechanism of psoriatic pathological changes. Ligand receptor analyses demonstrated WNT5A+ fibroblasts were extensively implicated in interactions with various cell types in skin, especially with ITIH5+ VECs and VCAN+ VSMCs within the papillary dermis.

Conclusions: Interactions of stromal cells in the papillary dermis were identified as possible pathogenic elements in psoriasis vulgaris. Improving the inflammatory microenvironment by targeting stromal cells might be a potential treatment strategy for psoriasis.

Chronic wounds, defined by their prolonged healing process, significantly impair patient quality of life and impose a hefty financial burden on healthcare systems worldwide. Sex/gender-specific mechanisms regulate inflammation and infection, angiogenesis, matrix synthesis, and cell recruitment contribute to cutaneous wound healing, but remain largely understudied. This review is aimed to spotlight the innovative realm of bioengineering and nanomedicine, which is at the helm of revolutionizing complex chronic wound care. It underscores the significance of integrating patient sex into the development and (pre)clinical testing of these avant-garde treatment modalities, in order to enhance healing prospects for both women and men. Moreover, we explore the representation of both sexes in clinical trials of bioengineered and nanomedicine products. Finally, we examine the primary reasons for the historical neglect in translating sex-specific wound healing research into clinical practice and propose strategic solutions. By tackling these issues, the article advocates for advanced treatment frameworks that could significantly improve healing outcomes for individuals of all sexes, thereby optimizing both efficacy and inclusivity in chronic wound management.

Background: The lack of evidence under routine clinical settings limited the widespread adoption of adalimumab biosimilars for psoriasis treatment.

Objective: This study compared the drug survival and safety of adalimumab biosimilars to Humira for psoriasis treatment.

Methods: We conducted a prevalent new-user cohort study using data from the French National Health Data System (SNDS), the British Association of Dermatologists Biologics and Immunomodulators Register (BADBIR), and the Spanish Registry of Systemic Therapy in Psoriasis (BIOBADADERM). Adalimumab-naïve patients initiating adalimumab biosimilars (new users) were compared with Humira new users. Patients switching from Humira to biosimilars (switchers) were compared with those who continued Humira treatment. Patients were matched 1:1 based on previous adalimumab exposure time to create equal-sized cohorts of biosimilar and Humira users. Co-primary outcomes included drug discontinuation and serious adverse events (SAEs). Hazard ratios (HR) were calculated using Cox proportional hazard models. Meta-analyses using random effect models were performed to combine results from 3 databases.

Results: 7387 biosimilar new users and 3654 switchers were matched and compared with Humira users. No differences in all-cause discontinuation were found between biosimilars and Humira new users (HR: 0.99, 95% CI: 0.94-1.04). Switching from Humira to biosimilars was associated with a higher discontinuation rate compared to remaining on Humira (HR: 1.35, 95% CI: 1.19-1.52). Similar results were observed for discontinuation due to ineffectiveness or adverse events. Risks of SAEs were similar between biosimilar new users and Humira new users (Incidence rate ratio IRR: 0.91, 95% CI: 0.80-1.05) or between switchers and continuous Humira users (IRR: 0.92, 95% CI: 0.83-1.01).

Conclusion: Adalimumab biosimilars can be considered viable alternatives to Humira for new patients with comparable effectiveness and safety. However, due to the higher likelihood of discontinuation, patients who switch from Humira to biosimilars may require closer monitoring and support.

Background: Monilethrix is a rare hereditary hair disorder that is characterized by a beaded hair shaft structure and increased hair fragility. Patients may also present with keratosis pilaris and nail changes. Research has identified three genes responsible for autosomal dominant monilethrix (KRT81, KRT83, KRT86) and one responsible for the autosomal recessive form (DSG4).

Objectives: To investigate the genetic basis of autosomal dominant monilethrix in families with no pathogenic variants in any of the known monilethrix genes, and to understand the mechanistic basis of variant pathogenicity using a cellular model.

Methods: Nine affected individuals from four unrelated families were included. A clinical diagnosis of monilethrix was assigned based on clinical examination and/or trichoscopy. Exome sequencing was performed in six individuals to identify pathogenic variants; Sanger sequencing was used for co-segregation and haplotype analyses. Cell culture experiments [immunoblotting, immunofluorescence and reverse transcription quantitative real-time polymerase chain reaction (RT-qPCR) analyses] were used to confirm variant pathogenicity, to determine the expression and subcellular localization of proteins, and to identify possible nonsense-mediated mRNA decay.

Results: In six affected individuals with clinically suggested monilethrix, exome sequencing led to the identification of the nonsense variant c.1081G>T; p.(Glu361*) in KRT31, which was subsequently identified in other affected members of these families by Sanger sequencing. This variant led to the abolition of both the last three amino acids of the 2B subdomain and the complete C-terminal tail domain of keratin 31. Immunoblotting demonstrated that when co-expressed with its binding partner keratin 85, the truncated keratin 31 was still expressed, albeit less abundantly than the wildtype protein. Immunofluorescence revealed that p.(Glu361*) keratin 31 had an altered cytoskeletal localization and formed vesicular-like structures in the cell cytoplasm near the cell membrane. RT-qPCR analysis did not generate evidence for nonsense-mediated decay of the mutant transcript.

Conclusions: This study is the first to identify pathogenic variants in KRT31 as a cause of autosomal dominant monilethrix. This highlights the importance of hair keratin proteins in hair biology, and will increase the molecular diagnostic yield for rare ectodermal phenotypes of hair and nail tissues.