British Journal of Dermatology最新文献

Introduction: Non-segmental vitiligo (NSV) is an autoimmune condition characterized by melanocyte loss. While skin-specific mechanisms are well-studied, systemic immune dysregulation contributing to NSV pathogenesis remains unclear.

Objective: This study employs a multi-omic single-cell approach to investigate circulating immune cells in NSV, integrating transcriptional and chromatin accessibility data.

Methods: An integrative scRNA-seq/scATAC-seq analysis was conducted on PBMCs from NSV patients (n=11) and controls (n=5), identifying transcriptional markers, cell-cell interactions, chromatin accessibility, and transcription factor (TF) dynamics. Key findings were validated in an expanded cohort (NSV, n=16; controls, n=9) using spectral flow cytometry, with additional stratification by sex, age, disease activity, severity, and duration.

Results: Analysis of 59,192 PBMCs identified 8,204 gene expression markers and 13,925 ATAC peaks across 25 immune cell subtypes. A broadly activated immune response was observed, characterized by cytotoxicity, antigen presentation, cell exhaustion, and stress, predominantly in monocytes, NK cells, CD8+ T cells, and dendritic cells (DCs). Multi-omic integration revealed Th1/Th17 polarization and dysfunctional regulatory T cell (Treg/mTreg) responses. Chromatin accessibility highlighted enriched TF binding sites for FOXO3, SP1, AP1, STAT1/STAT3, IRF1, and IRF4, regulating pathways linked to cytotoxicity, antigen processing, NF-κB, Toll-like receptor, and JAK-STAT signaling.Flow cytometry validated these findings, showing that disease activity and shorter duration were associated with heightened immune dysregulation. Robust TCR activation drove Th1/Th17 polarization and elevated IFN-γ and TNF-α production in CD4+ and CD8+ T cells. CLA+ skin-homing Th1/Th17-polarized CD4+ T cells, CD8+ T cells, and mTregs exhibited persistent activation, marked by basal PD1+ expression. OX40/OX40L-mediated interactions between monocytes and effector T cells amplified inflammation. Regulatory dysfunction, including reduced IL-4 and IL-13 production in mTregs, was prominent in moderate-severe and active disease.

Conclusion: This is the first multi-omic single-cell study in PBMCs of NSV patients, revealing systemic immune dysregulation driven by cytotoxicity, antigen presentation, exhaustion, and regulatory failure. Disease severity, activity, and evolution influence these pathways, highlighting the OX40/OX40L axis as a potential therapeutic target to mitigate immune dysregulation and relapse risk.

Background: Randomised controlled trials (RCTs) evaluating new systemic treatments for atopic dermatitis (AD) have increased dramatically over the last decade. These trials often incorporate topical therapies either as permitted concomitant or rescue treatments. Differential use of these topicals post-randomisation introduces potential bias as they may nullify or exaggerate treatment responses.

Objectives: To determine the proportion of RCTs that clearly report the allowance or prohibition of concomitant and rescue topical treatments. Secondary outcomes involved examining the reporting of specific key parameters for these topicals.

Methods: We included AD systemic medication RCTs included in the living systematic review of Drucker et al (updated in March 2023, available at the time of this review). Inclusion criteria were published RCTs evaluating systemic immunomodulatory treatments in AD. Only anti-inflammatory topical therapies were included therapies in this review; emollients were not considered.

Results: We screened 83 AD trials and included 67 RCTs, published between 1991 and 2023. The majority adequately reported the allowance or prohibition of concomitant topical treatments (95.5%, N=64/67), but this clarity was less prevalent regarding rescue topicals (73.1%, N=49/67). All trials permitting concomitant therapies consistently reported the type, though details on potency (88.6%, N=31/35), duration (54.3%, N=19/35), application frequency (34.3%, N=12/35), and quantity (5.7%, N=2/35) were less frequently reported. Similarly, trials allowing rescue treatments often specified the type (91.2%, N=31/34) but provided limited information on potency (52.9%, N=18/34), duration (8.8%, N=3/34), application frequency (5.9%, N=2/34), and quantity (0%, N=0/34). Notably, only 23.5% (N=8/34) clearly reported the criteria for using rescue topical treatments, with the phrase "at investigator's discretion" being used in most cases (61.8%, N=21/34). In the multivariable logistic regression analysis including impact factor, journal's policy on adhering to CONSORT guidelines, publication year, funding, number of patients randomised and blinding status, only the publication year (≥ 2020) was associated with having better reporting for rescue topical treatments (aOR 9.55, 95% CI 1.76-39.8).

Conclusions: While most AD clinical trials of systemic treatments report concomitant topical treatments, reporting practices for rescue topicals were less consistent and inadequate. A standardized approach to reporting topical therapy in AD trials is needed to enhance transparency and interpretability.