British Journal of Dermatology最新文献

Background: Hidradenitis suppurativa (HS) is a chronic, relapsing inflammatory skin disease associated with significant comorbidities and poor quality of life. Despite uncertainty about pathways driving inflammation in HS lesions, the cytokines IL-17A and IL-17F have been shown to be upregulated in patients with HS. Previous studies demonstrated that the monoclonal IgG1 antibody bimekizumab selectively inhibits IL-17F in addition to IL-17A.

Objectives: To further investigate the roles of IL-17A and IL-17F in HS pathogenesis.

Methods: RNA sequencing was conducted on skin biopsies taken at baseline and after treatment at Week 12 of the phase 2 proof of concept study of bimekizumab in patients with moderate to severe HS. Differentially expressed genes were identified between baseline lesional and non-lesional samples and between lesional samples before and after bimekizumab treatment to describe molecular disease mechanisms and treatment effect.Human hair follicular keratinocytes (HHFK) were cultured and treated with the supernatant of stimulated Th17 cells in combination with anti-IL-17A, anti-IL-17F, anti-IL-17A and anti-IL-17F, or IgG control antibodies. Total mRNA was analysed by RNA sequencing (RNAseq). Cellular supernatants from the stimulated HHFKs were used as a source of Th17-induced chemoattractants in neutrophil chemotaxis assays.

Results: RNAseq revealed that the most prominently upregulated genes within HS lesions included those associated with neutrophil biology. Bimekizumab treatment resulted in reduced expression of these genes. Extent of reduction in gene expression was dependent on HiSCR50 fulfilment. In vitro, dual inhibition of IL-17A and IL-17F had greater attenuation of Th17-induced HS-associated genes and neutrophil migration in HHFKs compared to IL-17A or IL-17F inhibition alone. In situ hybridisation revealed IL-17A and IL-17F producing cells in HS lesions can lack IL-23R and IL-1β could induce IL-23-independent IL-17F expression in vitro. Furthermore, mucosal-associated invariant cells in HS tunnels expressed IL-17F and IL-1R1. IL-1β, IL-17A and IL-17F expressing cells were found to be co-localised in HS lesions.

Conclusions: These data support the hypothesis that IL-17A and IL-17F play central roles in HS, a neutrophilic dermatosis. The presence of IL-1β may partly explain the high expression of IL-17F in lesional HS tissue.

Disabling pansclerotic morphea (DPM) is a rare systemic inflammatory disorder at the severe end of the localized scleroderma spectrum which primarily affects children under 14 years of age. The disease is characterized by rapid sclerosis with circumferential involvement that frequently extends to the fascia, muscle, and bone. Disease progression often involves development of sclerotic plaques, chronic skin ulcers, and painful joint contractures leading to patient immobility with a high mortality rate. Internal organ fibrosis is typically absent. The aggressive and systemic nature of the disease leads patients to seek multidisciplinary care where current therapies are targeted towards immunomodulation and measures to preserve mobility while limiting infection, but often have limited efficacy. Here, we summarize all DPM patients in the English literature, common clinical symptoms, laboratory investigations, and treatments reported to date. Assessment of published cases suggest that the number of therapies does not influence disease outcome and that female patients were younger at the time of reported death. Clinician familiarity and awareness of common DPM symptoms are important for an accurate and early diagnosis. Furthermore, knowledge of the treatments that have been reported to be effective in mitigating disease progression may be helpful in expanding the treatment options available to patients.

Background: Artificial daylight photodynamic therapy (ADL-PDT) is an alternative, all-year applicable, nearly painless treatment approach for actinic keratoses (AK) with comparable effectiveness to daylight or conventional PDT. At the time this study was initiated, methyl aminolevulinate (MAL) was the only photosensitizer approved for ADL-PDT in Germany.

Objective: To gain comprehensive insights into the practicability of MAL-ADL-PDT in patients with AK using different artificial daylight sources under real-world conditions.

Methods: This prospective, non-interventional, multicenter study (ArtLight, NCT05725213) enrolled patients with Olsen grade 1 or 2 AK on the face and scalp in Germany. Patients were treated with MAL-ADL-PDT (160mg/g MAL cream). The primary outcome measure was the practicability of MAL-ADL-PDT assessed as rate of resolved AK lesions in the focus area (10x10 cm area within the treatment area). Secondary outcomes included treatment-associated pain (numeric rating scale, NRS-11), Actinic Keratosis Area and Severity Index (AKASI), total lesion count over time, skin preparation, safety, overall assessment of effectiveness, tolerability, adherence, and patient satisfaction.

Results: In total, 224 patients (median age: 75.0 years (range 50-91), 85.3% male, 62.5% AK Olsen grade 2, 55.4% treatment-naïve) were included and treated with MAL-ADL-PDT. Three months after treatment, lesion counts were reduced in the focus area by 71% (p<0.001) indicating practicability of the treatment. Nearly all patients (93.3%) experienced none or mild pain during PDT (NRS score 0-3). Median AKASI decreased from 6.2 at baseline to 3.4 at month 3 (95% CI 2.4-3.0; p<0.001). The majority of investigators (82.8%) and patients (80.0%) were satisfied with the treatment. No new safety signals were reported.

Conclusions: The clinical practicability of MAL-ADL-PDT was demonstrated under real-world conditions by effective lesion reduction and predominantly none to mild procedural pain. Thus, MAL-ADL-PDT is a convenient way for healthcare professionals to deliver PDT treatment to patients with AK located on the face and scalp.

Background: Skin cancer is the most common cancer worldwide. Early diagnosis is crucial for improving patient survival and morbidity. Artificial intelligence (AI)-assisted smartphone applications (apps) for skin cancer potentially offer accessible, early risk assessment of suspicious skin lesions. However, the integration of novel technologies into dermatology pathways raises ethical concerns. Although ethical principles for AI governance are well known, how these principles should be applied to real-life AI apps readily available for public use is less well understood.

Objectives: We conducted an ethical use-case analysis of commercially available skin cancer apps to better understand the ethical issues arising from their development and use in a real-world context.

Methods: Established methods for ethical analysis of clinical AI applications were applied to two popular skin cancer apps in the UK: SkinVision and Scanoma. Systematic searches of published literature, regulatory documents, and websites were conducted to review the evidence regarding app development, effectiveness, and use. Screening for inclusion was undertaken by two researchers independently. Ethical concerns were identified with reference to previously described ethical concerns and principles for AI-assisted healthcare.

Results: By conceptualising ethical principles within the use-context of skin cancer apps, we identified specific ethical issues arising throughout the AI lifecycle of both apps. One company provided extensive detail regarding algorithm development and decision-making, this information was insufficiently reported for the other app. Other concerns identified related to number, quality, and consistency of studies assessing algorithm efficacy. Limited efforts to address potential skin tone biases and exclusion of individuals with darker skin tones as target users by one app risks perpetuating existing inequalities. Inadequate regulatory oversight was identified.

Conclusions: Findings from our ethical use-case analysis of two patient-facing AI-assisted skin cancer apps suggest inadequate incorporation of bioethical norms such as justice, responsibility and transparency into the development and deployment of both apps. Improved regulation should increase accountability. Ensuring ethics by design through integration between technology developers, dermatologists, ethicists, and the public is urgently needed to prevent the potential benefits of AI-assisted skin cancer apps being overshadowed by potential ethical harms.

Background: As a drug-induced hypersensitivity syndrome, drug reaction with eosinophilia and systemic symptoms (DRESS) is potentially fatal. Most patients with DRESS recover within a few weeks; however, some patients may suffer from a prolonged disease course and develop autoimmune sequelae.

Objective: We investigated the immune mechanism and therapeutic targets of patients with recalcitrant DRESS with a prolonged disease course.

Methods: A total of 32 patients with recalcitrant DRESS with a prolonged treatment course ≥8 weeks, 28 patients with short-duration DRESS with a treatment course <2 weeks, and 26 healthy individuals were enrolled in the study for analysis.

Results: Bulk transcriptome results demonstrated that mRNA expression levels of CCR8 and CXCR3 were significantly increased in the blood samples from patients in the acute stage of prolonged DRESS (adjusted p-values: CCR8=1.50×10-9 and CXCR3=2.60×10-4, respectively, for comparison of patients with prolonged DRESS to the healthy donor group). Serum and skin lesional concentrations of CCL1 and CXCL10, as the ligands of CCR8 and CXCR3, respectively, were significantly elevated in patients with prolonged DRESS as compared to those patients with short-duration DRESS. The results from high-parameter flow cytometry and autoantibody screening also identified significant escalations of CD8+ GNLY+CXCR3+effector memory T cells, CD8+central memory T cells, CD4+CCR8+Th2 cells, and IgG-anti-HES6 autoantibodies in patients with prolonged DRESS. Furthermore, in vitro blocking assays revealed that JAK inhibitors (mainly tofacitinib and upadacitinib) significantly decreased the release of CCL1 and CXCL10, and some patients with prolonged DRESS were successfully treated with JAK inhibitors.

Conclusions: JAK inhibitors (tofacitinib and upadacitinib) were associated with decreased concentrations of CCL1 and CXCL10, suggesting that they may attenuate CCR8/CCL1- and CXCR3/CXCL10-axis-mediated memory T cell activation, which contribute to disease pathogenesis for patients with recalcitrant DRESS and a long-term treatment course.