British Journal of Dermatology最新文献

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.

Objectives: To investigate the immune mechanism and therapeutic targets of patients with recalcitrant DRESS with a prolonged disease course.

Methods: Thirty-two patients with recalcitrant DRESS with a prolonged treatment course (≥ 8 weeks; 'prolonged DRESS'), 28 patients with DRESS with a short treatment course (< 2 weeks; 'short-duration DRESS') and 26 healthy donors (HDs) were enrolled.

Results: Bulk transcriptome results showed that the mRNA expression levels of CCR8 and CXCR3 were significantly increased in blood samples from patients in the acute stage of prolonged DRESS [Padj = 1.50 × 10-9 (CCR8) and Padj = 2.60 × 10-4 (CXCR3), patients with prolonged DRESS compared with the HD group]. Serum and skin lesion concentrations of CCL1 and CXCL10 (ligands of CCR8 and CXCR3, respectively) were significantly increased in patients with prolonged DRESS compared with patients with short-duration DRESS. The results from high-parameter flow cytometry and autoantibody screening also identified significant increases in CD8+ GNLY+ CXCR3+ effector memory T cells, CD8+ central memory T cells, CD4+ CCR8+ T helper 2 cells and IgG anti-HES-6 autoantibodies in patients with prolonged DRESS. Furthermore, in vitro blocking assays revealed that Janus kinase inhibitors (JAKi; mainly tofacitinib and upadacitinib) significantly decreased the release of CCL1 and CXCL10. Some patients with prolonged DRESS were successfully treated with JAKi.

Conclusions: JAKi (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 contributes to disease pathogenesis in patients with recalcitrant DRESS and a long-term treatment course.

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Background: Combination immune checkpoint blockade targeting programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte associated protein 4 (CTLA-4) leads to high response rates and improved survival in patients with advanced cutaneous melanoma (CM). Less is known about the efficacy of this combination in acral lentiginous melanoma (ALM).

Objectives: To determine the efficacy of combination immune checkpoint blockade targeting PD-1 and CTLA-4 in a diverse, real-world population of patients with ALM.

Methods: This multi-institutional retrospective study analysed patients with histologically confirmed ALM treated with a combination of PD-1 and CTLA-4 inhibitors between 2010 and 2022. The primary objective of the study was the objective response rate (ORR) as per the RECIST criteria. The secondary objectives were progression-free survival (PFS) and overall survival (OS).

Results: In total, 109 patients with advanced ALM treated with combined PD-1 and CTLA-4 blockade in any line of treatment were included. The majority of patients had stage IV disease (n = 81; 74.3%). The ORR for the entire cohort was 18.3% [95% confidence interval (CI) 11.6-26.9], with 9 (8.3%) complete and 11 (10.1%) partial responses. A further 22 patients (20.2%) had stable disease, and the disease control rate was 38.5%. Median PFS was 4.2 months (95% CI 3.25-5.62), while median OS was 17 months (95% CI 12.4-23.1). Ninety-five patients (87.2%) had a treatment-related adverse event, with 40.4% (n = 44/109) experiencing at least one grade 3 or 4 toxicity. Elevated lactate dehydrogenase (P = 0.04), ≥ 2 lines of prior treatment (P = 0.03) and Asian ethnicity (P = 0.04) were associated with worse OS, while Hispanic/Latino ethnicity was associated with better OS (P = 0.02).

Conclusions: Combination PD-1 and CTLA-4 blockade is less effective for ALM than for CM, despite similar toxicity. In particular, Asian patients appear to derive less benefit from this regimen. Novel treatment approaches are needed for this rare melanoma subtype.

Background: Large language models (LLMs) have a potential role in providing adequate patient information.

Objectives: To compare the quality of LLM responses with established Dutch patient information resources (PIRs) in answering patient questions regarding melanoma.

Methods: Responses from ChatGPT versions 3.5 and 4.0, Gemini, and three leading Dutch melanoma PIRs to 50 melanoma-specific questions were examined at baseline and for LLMs again after 8 months. Outcomes included (medical) accuracy, completeness, personalization, readability and, additionally, reproducibility for LLMs. Comparative analyses were performed within LLMs and PIRs using Friedman's Anova, and between best-performing LLMs and gold-standard (GS) PIRs using the Wilcoxon signed-rank test.

Results: Within LLMs, ChatGPT-3.5 demonstrated the highest accuracy (P = 0.009). Gemini performed best in completeness (P < 0.001), personalization (P = 0.007) and readability (P < 0.001). PIRs were consistent in accuracy and completeness, with the general practitioner's website excelling in personalization (P = 0.013) and readability (P < 0.001). The best-performing LLMs outperformed the GS-PIR on completeness and personalization, yet it was less accurate and less readable. Over time, response reproducibility decreased for all LLMs, showing variability across outcomes.

Conclusions: Although LLMs show potential in providing highly personalized and complete responses to patient questions regarding melanoma, improving and safeguarding accuracy, reproducibility and accessibility is crucial before they can replace or complement conventional PIRs.

Background: Congenital ichthyoses comprise a heterogeneous group of genetic diseases that require lifelong treatment and have a major impact on patients' quality of life. Conventional treatments reduce scaling and skin discomfort; however, they usually have little or no effect on erythema and pruritus. The identification of cytokine alterations in congenital ichthyoses has raised the possibility of repurposing currently available biologics. Several case reports have reported success with different biologics.

Objectives: To report the real-life effects of biologics on congenital ichthyoses.

Methods: This was a retrospective observational international multicentric study of patients with congenital ichthyoses treated with at least one biologic for a minimum of 3 months. The effect of the biologics was evaluated using an Investigator Global Assessment for change (IGA-C) scale. A comprehensive literature search was performed in parallel.

Results: Ninety-eight patients were included [mean (SD) age of 19.7 years, 50 female patients]. Patients with Netherton syndrome (NS) or congenital ichthyosiform erythroderma (CIE) represented the majority of patients (30% and 21%, respectively). Most patients (85%) had a severe or very severe form of congenital ichthyoses. The most frequently used biologics were inhibitors targeting interleukin (IL)-17, IL-12/IL-23 or the IL-4 receptor (IL-4R). The mean (SD) duration of treatment was 22.1 (20.1) months. There were 45 responders (46%), including 18 (18%) who were good responders; all had a subset of erythrodermic congenital ichthyoses and received one of the three main biologics. In patients with NS and CIE, IL-12/IL-23 and IL-4R inhibitors tended to be most effective. The literature review revealed a shorter mean (SD) duration of biologic treatment [11.5 (8.5) months] and higher percentage of responders (86%), suggesting reporter bias.

Conclusions: This series identified subsets of congenital ichthyoses that may respond to biologics and will help with the design of future clinical trials of biologics for congenital ichthyoses.