British Journal of Dermatology最新文献

Atopic dermatitis (AD) is the most common inflammatory skin condition and affects people of all ages. New therapies, including the monoclonal antibody therapy dupilumab, offer excellent efficacy. However, in clinical trials, and emphasized in real-world observations, an unexpected increased frequency of ocular adverse effects has become apparent. The effectiveness of dupilumab and the unpredictability of ocular adverse effects mean that clinicians need guidance on counselling patients prior to treatment and on managing them if adverse effects arise. The British Association of Dermatologists (BAD) and Royal College of Ophthalmologists collaborated on this consensus guidance on managing dupilumab-related ocular surface disorders (DROSD). A multidisciplinary group was formed of adult and paediatric dermatologists and ophthalmologists with expertise in DROSD, patient representatives and the BAD Clinical Standards Unit. A literature search was conducted and the results reviewed. All recommendations were reviewed, discussed and voted on. The recommendations pertain to dermatology and ophthalmology management, and apply to people of all ages, unless otherwise stated. Importantly, initiation of dupilumab for AD should not be delayed for most eye disorders except acute new problems (e.g. infections) or potentially severe conditions (e.g. a history of corneal transplant; ophthalmology advice should be sought first). There is insufficient evidence to recommend lubricant drops prophylactically. Dermatologists should assess eye complaints to diagnose DROSD; a severity grading system is provided. DROSD management differs slightly in those aged < 7 years, as ocular complications may affect neuro-ocular development. Therefore, irrespectively of DROSD severity, this population should be referred for ophthalmology advice. In those aged ≥ 7 years, dermatologists should feel confident to trial treatment and reserve ophthalmology advice for severe or nonresponding cases. Discussion about dupilumab withdrawal should be prompted by a significant impact on quality of life, threat to sight, or other complications. Although dupilumab is a highly effective agent for treating AD, the risk of ocular adverse effects should not inhibit clinicians or patients from using it, but clinicians should be aware of them. If a patient develops DROSD, there are clear pathways to assess severity and offer initial management. Where this is ineffective, dermatologists should assess the urgency and seek advice from or initiate referral to ophthalmology. While the evidence reviewed for these guidelines reflects the extensive literature on dupilumab, we believe our advice has relevance for ocular surface disorders in patients with AD treated with tralokinumab and lebrikizumab.

Background: Skin fibrosis is the typical pathological manifestation of systemic sclerosis (SSc) and localized scleroderma (LS); it has an unclear aetiology and few effective treatments. Although excessive collagen secretion by fibroblasts is the primary cause of skin fibrosis, evidence has suggested that vascular damage is the initiating event and that various cell types, including fibroblasts, work together to contribute to the pathogenesis of skin fibrosis.

Objectives: To explore the relationship between vascular endothelial cell lesions and immune cell infiltration, along with the interactions between various cell types within the fibrotic skin ecosystem.

Methods: Single-cell RNA sequencing was performed on skin biopsies from three healthy donors and seven patients with SSc. Additional data from three patients with localized scleroderma available in the Gene Expression Omnibus (GSE160536) were integrated by Harmony. CellChat (version 1.5.0) was used to analyse the cell communication network. A Transwell® assay and a bleomycin (BLM) mouse model were used to explore the role of atypical chemokine receptor 1 (ACKR1; 'Duffy antigen') in immune cell infiltration. Milo single-cell Western blot was used to show fibroblast subcluster activation.

Results: A total of 62 295 cells were obtained and subpopulations of stromal and immune cells identified. Interaction network analysis found that multiple chemokines secreted by macrophages, pericytes and proinflammatory fibroblasts could bind with ACKR1, which was highly expressed by endothelial cells in lesional skin. The Transwell® assay revealed that overexpression of ACKR1 in human umbilical vein endothelial cells facilitated leucocyte infiltration following treatment with interleukin-8. BLM mice showed enhanced ACKR1 expression, massive immune cell infiltration and skin fibrosis that was attenuated by ACKR1 inhibition. Furthermore, infiltrated macrophages expressing high levels of transforming growth factor (TGF)-β1 or platelet-derived growth factor B (PDGFB) could activate secreted frizzled-related protein 2 (SFRP2)/asporin (ASPN)+ fibroblasts to contribute to the excessive accumulation of extracellular matrix. It was also found that the SOX4-ASPN axis plays an important role in the TGF-β signalling cascade and the aetiology of skin fibrosis.

Conclusions: Our results reveal that high expression of ACKR1 by endothelial cells in fibrotic skin tissue promotes immune cell infiltration and that SFRP2/ASPN+ fibroblasts synergize to exacerbate skin fibrosis.

Background: Patient-reported outcome measures (PROMs) are crucial in assessing the impact of dermatological conditions on people's lives, but the existing dermatology-specific PROMs are not recommended for use, according to COSMIN. We developed the Patient-Reported Impact of Dermatological Diseases (PRIDD) measure in partnership with patients. It has strong evidence of content validity, structural validity, internal consistency, acceptability and feasibility.

Objectives: To test the remaining measurement properties of the PRIDD and establish the interpretability of scores against the COSMIN criteria, using classic and modern psychometric methods.

Methods: A global longitudinal study consisting of two online surveys administered 2-4 weeks apart was carried out. Adults (≥ 18 years of age) living with a dermatological condition were recruited via the International Alliance of Dermatology Patient Organizations' (GlobalSkin) membership network. Participants completed PRIDD, a demographics questionnaire and other related measures, including the Dermatology Life Quality Index. We tested the criterion validity, construct validity and responsiveness (Spearman's ρ, independent-samples t-tests and Anova); test-retest reliability [interclass correlation coefficient (ICC)]; measurement error [smallest detectable change or limits of agreement (LoA), distribution-based minimally important change (MIC)]; floor and ceiling effects (number of minimum and maximum scores and person-item location distribution maps), score bandings (κ coefficient of agreement) and the anchor-based MIC of the PRIDD.

Results: In total, 504 people with 35 dermatological conditions from 38 countries participated. Criterion validity (ρ = 0.79), construct validity (76% hypotheses met), test-retest validity (ICC = 0.93) and measurement error (LoA = 1.3 < MIC = 4.14) were sufficient. Floor and ceiling effects were in the acceptable range (< 15%). Score bandings were determined (κ = 0.47); however, the anchor-based MIC could not be calculated owing to an insufficient anchor.

Conclusions: PRIDD is a valid and reliable tool to evaluate the impact of dermatological disease on people's lives in research and clinical practice. It is the first dermatology-specific PROM to meet the COSMIN criteria. These results support the value of developing and validating PROMs with a patient-centred approach and using classic and modern psychometric methods. Further testing of responsiveness and MIC, cross-cultural translation, linguistic validation and global data collection are planned.

Background: Psoriatic disease (PsD) is closely associated with cardiovascular (CV) disease. The Life's Essential 8 (LE8) score is a new metric to assess CV health (CVH), where a higher score indicates better CVH. However, the longitudinal association between LE8 score and the risk of PsD remains uncertain.

Objectives: To investigate, in a cohort study, the association between LE8 score, genetic susceptibility and the risk of PsD.

Methods: This cohort study included 261 642 participants in the UK Biobank without PsD at baseline. LE8 comprises eight indicators: diet, physical activity, nicotine exposure, sleep health, body mass index, blood lipids, blood glucose and blood pressure. Cox proportional hazard models were used to examine the association between participants' LE8 scores, genetic risk of PsD and the risk of PsD. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated.

Results: During an average follow-up of 12.3 years, 1501 participants developed PsD. Compared with participants with low LE8 scores, the HRs of developing PsD for those with moderate and high LE8 scores were 0.51 (95% CI 0.43-0.59) and 0.34 (95% CI 0.27-0.42) after adjustments, respectively. Dose-response analysis revealed a linear negative association between continuous LE8 score and the risk of developing PsD (P < 0.001), with no evidence of nonlinear association detected. Genetic susceptibility to PsD did not modify this association (P-interaction = 0.63). Subgroup analyses revealed that women had a more pronounced beneficial association between LE8 scores and PsD risk (P-interaction = 0.02).

Conclusions: Our study suggests that a higher LE8 score, regardless of genetic risk, is associated with a lower risk of PsD, particularly in women. Consequently, maintaining good CVH status is recommended to prevent PsD and assess associated risks.

Background: Observational studies in cutaneous melanoma (CM) have indicated an inverse relationship between levels of 25-hydroxyvitamin D and Breslow thickness, in addition to a protective effect of high 25-hydroxyvitamin D levels on clinical outcome.

Objectives: To evaluate whether high-dose vitamin D supplementation in curatively resected CM reduces melanoma relapse.

Methods: In a prospective randomized double-blind placebo-controlled trial, 436 patients with resected CM stage IA to III (8th American Joint Committee on Cancer staging) were randomized. Among them, 218 received a placebo while 218 received monthly 100 000 IU cholecalciferol for a minimum of 6 months and a maximum of 42 months (treatment arm). Following randomization, patients were followed for a median of 52 months, with a maximum follow-up of 116 months. The primary endpoint was relapse-free survival. Secondary endpoints were melanoma-related mortality, overall survival, and the evolution of 25-hydroxyvitamin D serum levels over time.

Results: In our population (mean age 55 years, 54% female sex) vitamin D supplementation increased 25-hydroxyvitamin D serum levels after 6 months of supplementation in the treatment arm by a median 17 ng mL-1 [95% confidence interval (CI) 9-26] compared with 0 ng mL-1 (95% CI 6-8) in the placebo arm (P < 0.001, Wilcoxon test) and remained at a steady state during the whole treatment period. The estimated event rate for relapse-free survival at 72 months after inclusion was 26.51% in the vitamin D supplemented arm (95% CI 19.37-35.64) vs. 20.70% (95% CI 14.26-29.52) in the placebo arm (hazard ratio 1.27, 95% CI 0.79-2.03; P = 0.32). After adjusting for confounding factors (including baseline stage, body mass index, age, sex and baseline season), the hazard ratio was 1.20 (95% CI 0.74-1.94, P = 0.46). The number of deaths from progression of CM and nonmelanoma-related deaths was similar in both the vitamin D supplemented and placebo groups (deaths from progression of CM, n = 10 and n = 11, respectively; nonmelanoma-related deaths, n = 3 and n = 2, respectively). No major adverse events were observed during the study.

Conclusions: In patients with CM, monthly high-dose vitamin D supplementation was safe, resulted in a sustained increase in 25-hydroxyvitamin D levels during the treatment period, but did not improve relapse-free survival, melanoma-related death or overall survival.