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Follicular T helper cells in bullous pemphigoid: How polarization affects the pathophysiology of B cell-mediated autoimmune diseases. 大疱性类天疱疮中的滤泡 T 辅助细胞:极化如何影响 B 细胞介导的自身免疫性疾病的病理生理学?
IF 11 1区 医学 Q1 DERMATOLOGY Pub Date : 2024-10-18 DOI: 10.1093/bjd/ljae407
Farzan Solimani, Christian Möbs
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引用次数: 0
Cyphellophora ludoviensis: A new causative species of tinea nigra. Cyphellophora ludoviensis:黑天疱疮的一个新致病物种。
IF 11 1区 医学 Q1 DERMATOLOGY Pub Date : 2024-10-18 DOI: 10.1093/bjd/ljae390
ChangHyun Son, Sun Mun Jeong, Jang Hwan Jung, Do Ik Kwon, Seol Hwa Seong, Kee Suck Suh, Min Soo Jang
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引用次数: 0
Circular RNA circASH1L(4,5) protects microRNA-129-5p from target-directed microRNA degradation in human skin wound healing. 在人类皮肤伤口愈合过程中,环形 RNA circASH1L(4,5) 保护 microRNA-129-5p 免受目标定向 microRNA 降解。
IF 11 1区 医学 Q1 DERMATOLOGY Pub Date : 2024-10-18 DOI: 10.1093/bjd/ljae405
Qizhang Wang, Guanglin Niu, Zhuang Liu, Maria A Toma, Jennifer Geara, Xiaowei Bian, Letian Zhang, Minna Piipponen, Dongqing Li, Aoxue Wang, Pehr Sommar, Ning Xu Landén

Background: Skin wound healing involves a complex gene expression program that remains largely undiscovered in humans. Circular RNAs (circRNAs) and microRNAs (miRNAs) are key players in this process.

Objectives: To understand the functions and potential interactions of circRNAs and miRNAs in human skin wound healing.

Methods: CircRNA, linear RNA, and miRNA expression in human acute and chronic wounds were analyzed using RNA sequencing and qRT-PCR. The roles of circASH1L(4,5) and miR-129-5p were studied in human primary keratinocytes (proliferation and migration assays, microarray analysis) and ex vivo wound models (histological analysis). The interaction between circASH1L(4,5) and miR-129-5p was examined using luciferase reporter and RNA pull-down assays.

Results: We identified circASH1L(4,5) and its interaction with miR-129-5p, both of which increased during human skin wound healing. Unlike typical miRNA sponging, circASH1L enhanced miR-129 stability and silencing activity by protecting it from target-directed degradation triggered by NR6A1 mRNA. TGF-β signaling, crucial in wound healing, promoted circASH1L expression while suppressing NR6A1, thereby increasing miR-129 abundance at the post-transcriptional level. CircASH1L and miR-129 enhanced keratinocyte migration and proliferation, crucial for re-epithelialization of human wounds.

Conclusions: Our study uncovers a novel role for circRNAs as protectors of miRNAs and highlights the importance of regulated miRNA degradation in skin wound healing.

背景:皮肤伤口愈合涉及一个复杂的基因表达程序,而这一程序在人类身上大部分仍未被发现。环状 RNA(circRNA)和微 RNA(miRNA)是这一过程中的关键角色:了解 circRNAs 和 miRNAs 在人类皮肤伤口愈合中的功能和潜在相互作用:方法:使用 RNA 测序和 qRT-PCR 分析人急性和慢性伤口中的 circRNA、线性 RNA 和 miRNA 表达。研究了 circASH1L(4,5)和 miR-129-5p 在人类原代角质形成细胞(增殖和迁移试验、芯片分析)和体外伤口模型(组织学分析)中的作用。利用荧光素酶报告和 RNA 拉取实验检测了 circASH1L(4,5) 和 miR-129-5p 之间的相互作用:结果:我们发现了 circASH1L(4,5)及其与 miR-129-5p 之间的相互作用,两者在人体皮肤伤口愈合过程中均有所增加。与典型的 miRNA 海绵作用不同,circASH1L 通过保护 miR-129 免受 NR6A1 mRNA 触发的靶定向降解,增强了 miR-129 的稳定性和沉默活性。创伤愈合过程中至关重要的 TGF-β 信号促进了 circASH1L 的表达,同时抑制了 NR6A1,从而在转录后水平增加了 miR-129 的丰度。circASH1L和miR-129增强了角质形成细胞的迁移和增殖,这对人类伤口的再上皮化至关重要:我们的研究发现了circRNA作为miRNA保护因子的新作用,并强调了调控miRNA降解在皮肤伤口愈合中的重要性。
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引用次数: 0
Overtreatment of dysplastic naevi: results of a multiregional UK questionnaire study. 发育不良痣的过度治疗:英国多地区问卷调查结果。
IF 11 1区 医学 Q1 DERMATOLOGY Pub Date : 2024-10-18 DOI: 10.1093/bjd/ljae382
Fazleenah A Hussain, Arti Bakshi, Paul D Yesudian, Stuart N Cohen
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引用次数: 0
Secukinumab in adult patients with lichen planus: efficacy and safety results from the randomized placebo-controlled proof-of-concept PRELUDE study. 塞库单抗治疗成人扁平苔藓患者:随机、安慰剂对照、概念验证 PRELUDE 研究的疗效和安全性结果。
IF 11 1区 医学 Q1 DERMATOLOGY Pub Date : 2024-10-17 DOI: 10.1093/bjd/ljae181
Thierry Passeron, Maximilian Reinhardt, Benjamin Ehst, Jonathan Weiss, Jason Sluzevich, Michael Sticherling, Pascal Reygagne, Johannes Wohlrab, Michael Hertl, Nasim Fazel, Elisa Muscianisi, Heng Fan, Isabelle Hampele, Nicolò Compagno

Background: Patients with lichen planus (LP) refractory to available therapies often experience a high disease burden, representing a population with a clear unmet need for new treatments.

Objectives: To evaluate the efficacy and safety of secukinumab 300 mg over 32 weeks in adult patients with biopsy-proven cutaneous LP (CLP), mucosal LP (MLP) or lichen planopilaris (LPP) that is inadequately controlled by topical corticosteroids.

Methods: PRELUDE was a randomized double-blind placebo-controlled phase II proof-of-concept study that enrolled patients with CLP, MLP or LPP. Eligible patients were randomized to either secukinumab 300 mg every 4 weeks for 32 weeks (SECQ4W) or placebo for 16 weeks followed by secukinumab 300 mg every 2 weeks (SECQ2W) for 16 weeks. The primary endpoint was achievement of the newly designed Investigator's Global Assessment (IGA) score ≤ 2 at week 16.

Results: Overall, 111 patients were randomized (n = 37 each) to CLP, MLP and LPP cohorts. As the proof-of-concept criteria were not met for any of the three cohorts, the primary objective was not met. A numerically higher proportion of patients achieved IGA ≤ 2 response at week 16 with SECQ4W vs. placebo in the MLP {37.5% [95% credibility interval (Crl) 20.3-57.2] vs. 23.1% (95% Crl 6.5-49.2)} and LPP cohorts [37.5% (95% Crl 20.2-57.3) vs. 30.8% (95% Crl 10.8-57.6)]. In the LPP cohort, a sustained response for IGA ≤ 2 from week 16 to week 32 was achieved with SECQ4W (week 16, 37.5%; week 32, 45.8%), and a substantial improvement was observed in IGA ≤ 2 response in patients from this cohort who switched from placebo (week 16, 30.8%) to SECQ2W after week 16 (week 32, 63.6%). The safety profile was consistent with the known profile of secukinumab and showed no new or unexpected signals.

Conclusions: PRELUDE is the first randomized controlled basket trial evaluating interleukin (IL)-17A inhibition with secukinumab across three subtypes of LP. Secukinumab was well tolerated and safe, showing different response rates across the three subtypes, with numerical IGA improvements in MLP and LPP, and no response in CLP. The study raises the question of a differential role of IL-17A across LP subtypes. The novel IGA score showed significant correlation with both patient- and physician-reported outcome measurements.

背景:对现有疗法难治的扁平苔藓(LP)患者往往承受着沉重的疾病负担;这类患者对新疗法的需求显然尚未得到满足:目的:评估secukinumab 300毫克、持续32周对经活检证实患有皮肤扁平苔藓(CLP)、粘膜扁平苔藓(MLP)或扁平苔藓(LPP)、外用皮质类固醇激素控制不佳的成年患者的疗效和安全性:PRELUDE是一项随机、双盲、安慰剂对照的2期概念验证研究,招募了CLP、MLP或LPP患者。符合条件的患者被随机分配到secukinumab 300 mg,每4周一次,共32周(SECQ4W),或安慰剂16周,然后secukinumab 300 mg,每2周一次(SECQ2W),共16周。主要终点是在第16周时达到新设计的研究者总体评估(IGA)评分≤2分:共有 111 名患者被随机分配到 CLP、MLP 和 LPP 组别(各 37 人)。由于三个组别均未达到概念验证标准,因此未达到主要目标。在MLP队列(37.5% [95% 可信区间(Crl):20.3-57.2] vs. 23.1% [95% Crl:6.5-49.2])和LPP队列(37.5% [95% Crl:20.2-57.3] vs. 30.8% [95% Crl:10.8-57.6])中,SECQ4W与安慰剂相比,在第16周达到IGA≤2反应的患者比例更高。在LPP队列中,SECQ4W在第16周至第32周期间实现了IGA≤2的持续应答(第16周:37.5%;第32周:45.8%),在第16周后从安慰剂(第16周:30.8%)转为SECQ2W的该队列患者中观察到IGA≤2应答的大幅改善(第32周:63.6%)。安全性与secukinumab的已知特性一致,没有出现新的或意想不到的信号:PRELUDE是首个评估secukinumab对3种亚型LP的白细胞介素-17A抑制作用的随机对照篮子试验。赛库单抗耐受性良好且安全,在3种亚型中显示出不同的反应率,MLP和LPP的IGA数值有所改善,而CLP则无反应。该研究提出了白细胞介素-17A在不同LP亚型中的不同作用的问题。新的IGA评分与患者和医生报告的结果测量结果显示出明显的相关性:NCT04300296.
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引用次数: 0
Utilization and related harms of systemic glucocorticosteroids for atopic dermatitis: claims data analysis. 系统性糖皮质激素治疗特应性皮炎的使用情况及相关危害:索赔数据分析。
IF 11 1区 医学 Q1 DERMATOLOGY Pub Date : 2024-10-17 DOI: 10.1093/bjd/ljae250
Kristina Hagenström, Theresa Klinger, Katharina Müller, Charlotte Willers, Matthias Augustin

Background: Systemic glucocorticosteroids (SGCs) are used in the short-term treatment of atopic dermatitis (AD), but are not recommended for long-term use because they are associated with severe side-effects.

Objectives: This study aimed to characterize the utilization and potentially negative effects of SGC use for AD in German statutory health insurance (SHI) claims data.

Methods: Cross-sectional and longitudinal analysis of a large nationwide SHI dataset. SGC drug prescriptions and incidences of predefined comorbidities after drug initiation that were known to be potentially harmful side-effects were analysed. SGC use was quantified by (-definition 1) the number of quarters with at least one SGC prescription and (definition 2) the defined daily doses (DDD). Comparisons were adjusted for age, sex and morbidity.

Results: The AD prevalence was 4.07% in 2020 (4.12% women, 3.42% men). During this period 9.91% of people with AD were prescribed SGCs compared with 5.54% in people without AD (P < 0.01). Prescribing of SGCs was significantly higher in women (10.20% vs. 9.42% in men, P < 0.01) and in the elderly. AD and SGC prevalence varied regionally. In a 3-year follow-up period, 58% of people with AD receiving a SGC were prescribed SGCs in > one quarter and 15% in > six quarters. The odds of developing osteoporosis [odds ratio (OR) 3.90 -(definition 1) and 1.80 (definition 2)] and diabetes [OR 1.90 (definition 1) and 1.38 (definition 2)] were significantly higher in people with AD on SGCs, especially in the frequently prescribed group compared with the rarely prescribed group, regardless of quantified use.

Conclusions: A considerable number of people with AD in Germany are prescribed long-term SGCs. The onset of medical conditions known to be harmful effects of steroids was significantly more frequent in those who were frequently prescribed SGCs, indicating the need for optimized healthcare.

背景和目的:全身性糖皮质激素(SGCs)可用于特应性皮炎(AD)的短期治疗,但由于会产生严重的副作用,因此不建议长期使用。本研究旨在从德国法定医疗保险(SHI)理赔数据中了解特应性皮炎患者使用糖皮质激素的情况及其潜在的负面影响:患者和方法:对全国范围内的大型SHI数据集进行横截面和纵向分析。分析了SGC药物处方和用药后出现被称为潜在有害副作用的预定义合并症的情况。SGC药物的使用通过以下两个方面进行量化:1)至少有一个SGC处方的季度数;2)定义的每日剂量(DDD)。在进行比较时,对年龄、性别和发病率进行了调整:2020 年,注意力缺失症的发病率为 4.07%(女性为 4.12%,男性为 3.71%)。在此期间,9.91%的注意力缺失症患者被处方 SGCs,而非注意力缺失症患者的处方 SGCs 比例为 5.54%(p 1 季度和 15% > 6 季度)。无论量化使用情况如何,使用sGCS的AD患者患骨质疏松症(几率比3.95[方法1]和1.80[方法2])和糖尿病(几率比1.90[方法1]和1.38[方法2])的几率明显较高,尤其是在经常用药组与很少用药组之间:结论:在德国,有相当多的注意力缺失症患者长期服用 SGCs。结论:在德国,有相当多的注意力缺失症患者长期服用类固醇类药物,类固醇类药物的有害影响在 "经常处方 "类固醇类药物的患者中更为常见,这表明需要优化医疗保健。
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引用次数: 0
Advancing care in epidermolysis bullosa: insights from qualitative research. 推进牛皮癣护理:定性研究的启示。
IF 11 1区 医学 Q1 DERMATOLOGY Pub Date : 2024-10-17 DOI: 10.1093/bjd/ljae280
Marjolein Lugtenberg, Marlies Wakkee
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引用次数: 0
'Live long and prosper': living guidelines for immune-mediated inflammatory diseases. 健康长寿":免疫介导的炎症性疾病的生活指南。
IF 11 1区 医学 Q1 DERMATOLOGY Pub Date : 2024-10-17 DOI: 10.1093/bjd/ljae324
Zenas Z N Yiu, Emma McFarlane, Samuel L Whittle
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引用次数: 0
The impact of irritant challenge on the skin barrier and myeloid-resident immune cells in women who are postmenopausal is modulated by hormone replacement therapy. 激素替代疗法可调节刺激性挑战对绝经后妇女皮肤屏障和骨髓驻留免疫细胞的影响。
IF 11 1区 医学 Q1 DERMATOLOGY Pub Date : 2024-10-17 DOI: 10.1093/bjd/ljae226
Orsolya Kiss, Rajia Bahri, Rachel E B Watson, Chidera Chike, Abigail K Langton, Victoria L Newton, Mike Bell, Christopher E M Griffiths, Silvia Bulfone-Paus, Suzanne M Pilkington

Background: Sex hormone changes during menopausal transition contribute to declining skin health. However, how menopause and its treatment by hormone replacement therapy (HRT) impact the skin barrier and immune system is unclear.

Objectives: To examine how menopause and HRT affect the skin barrier and immune cell composition in postmenopausal women following irritant challenge.

Methods: Two cohorts of postmenopausal women were recruited to the study. The first cohort consisted of 10 untreated women [HRT-; mean (SEM) age 56.5 (1.6) years (range 48-63)] and the second was composed of 8 women receiving HRT [HRT+; mean (SEM) age 54.0 (2.1) years (range 48-63)]. Skin irritation was induced by applying topical sodium lauryl sulfate (SLS) 1.25% to occluded buttock skin for 48 h. Clinical assessment was conducted after 24 h, followed by biopsy of both SLS-challenged and unchallenged skin for analysis of skin barrier proteins and immune cell distribution using immunofluorescence.

Results: Clinically, there were no significant differences in skin irritant responses between those taking or not taking HRT (including increased skin redness and blood flow). In response to SLS challenge a significant increase in transepidermal water loss (P < 0.05), filaggrin deposition and cytokeratin 10 (K10)+ cell layers (P < 0.01) was observed in individuals receiving HRT compared with the HRT- group. Following SLS challenge in individuals taking HRT, a significant (P < 0.01) reduction in CD207+ cells in the epidermis was observed, accompanied by an increase of CD207+ cells in the dermis, indicative of migrating Langerhans cells (LCs). Significantly fewer migrating LCs were found in those who were not receiving HRT (P < 0.01). Furthermore, the numbers of dermal dendritic cells (DCs), macrophages, and CD11c+CD206- and CD68+CD206- subsets were found to be significantly (P < 0.05) higher in those taking HRT following SLS challenge.

Conclusions: Individuals receiving HRT displayed enhanced skin barrier response to SLS challenge with thicker filaggrin and increased K10+ epidermal cell layers. Following challenge, HRT users exhibited elevated LC, inflammatory DC and macrophage counts in the dermis. These may render skin both more prone to inflammation and more capable of resolving it, while also promoting skin repair.

背景:绝经过渡期的性激素变化会导致皮肤健康状况下降。然而,更年期及其激素替代疗法(HRT)如何影响皮肤屏障和免疫系统尚不清楚。因此,我们研究了绝经和激素替代疗法如何影响绝经后妇女在接受刺激物挑战后的皮肤屏障和免疫细胞组成:研究招募了两组绝经后妇女,一组未接受治疗(HRT-;n = 10;平均年龄 56.5 岁 [范围 48-63 岁]),另一组接受 HRT(n = 8;平均年龄 54 岁 [范围 48-63 岁])。在闭塞的臀部皮肤上局部涂抹 1.25% 的十二烷基硫酸钠(SLS),持续 48 小时,诱发皮肤过敏。24 小时后进行临床评估,然后对受 SLS 刺激和未受刺激的皮肤进行活组织检查,用免疫荧光法分析皮肤屏障蛋白和免疫细胞分布:在临床上,服用或未服用 HRT(包括皮肤发红和血流量增加)的人的皮肤刺激反应没有明显差异。在应对 SLS 挑战时,经表皮失水率(pConclusion)显著增加:接受 HRT 的人对 SLS 挑战的皮肤屏障反应增强,丝胶蛋白变厚,角蛋白-10 阳性表皮细胞层增加。接受 SLS 挑战后,HRT 使用者的真皮层中 LCs、炎性 DCs 和巨噬细胞的数量增加。这可能会使皮肤更容易发炎,也更有能力消除炎症,同时促进皮肤修复。
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引用次数: 0
Epidermal growth factor receptor/mitogen-activated kinase inhibitor treatment induces a distinct inflammatory hair follicle response that includes collapse of immune privilege. 表皮生长因子受体/MEK 抑制剂疗法会诱发一种独特的炎症性毛囊反应,其中包括免疫特权的崩溃。
IF 11 1区 医学 Q1 DERMATOLOGY Pub Date : 2024-10-17 DOI: 10.1093/bjd/ljae243
David Rutkowski, Rachel Scholey, John Davies, Derek Pye, Fiona Blackhall, Richard B Warren, Francisco Jimenez, Christopher E M Griffiths, Ralf Paus

Background: Inhibitors of epidermal growth factor receptor (EGFRi) or mitogen-activated kinase (MEKi) induce a folliculitis in 75-90% of patients, the pathobiology of which remains insufficiently understood.

Objectives: To characterize changes in the skin immune status and global transcriptional profile of patients treated with EGFRi; to investigate whether EGFRi affects the hair follicle's (HF) immune privilege (IP); and to identify early proinflammatory signals induced by EGFRi/MEKi in human scalp HFs ex vivo.

Methods: Scalp biopsies were taken from patients exhibiting folliculitis treated long term with EGFRi ('chronic EGFRi' group, n = 9) vs. healthy scalp skin (n = 9) and patients prior to commencing EGFRi treatment and after 2 weeks of EGFRi therapy ('acute EGFRi' group, n = 5). Healthy organ-cultured scalp HFs were exposed to an EGFRi (erlotinib, n = 5) or a MEKi (cobimetinib, n = 5). Samples were assessed by quantitative immunohistomorphometry, RNA sequencing (RNAseq) and in situ hybridization.

Results: The 'chronic EGFRi' group showed CD8+ T-cell infiltration of the bulge alongside a partial collapse of the HF's IP, evidenced by upregulated major histocompatibility complex (MHC) class I, β2-microglobulin (B2 M) and MHC class II, and decreased transforming growth factor-β1 protein expression. Healthy HFs treated with EGFRi/MEKi ex vivo also showed partial HF IP collapse and increased transcription of human leucocyte antigen (HLA)-A, HLA-DR and B2 M transcripts. RNAseq analysis showed increased transcription of chemokines (CXCL1, CXCL13, CCL18, CCL3, CCL7) and interleukin (IL)-26 in biopsies from the 'chronic EGFRi' cohort, as well as increased IL-33 and decreased IL-37 expression in HF biopsies from the 'acute EGFRi' group and in organ-cultured HFs.

Conclusions: The data show that EGFRi/MEKi compromise the physiological IP of human scalp HFs and suggest that future clinical management of EGFRi/MEKi-induced folliculitis requires HF IP protection and inhibition of IL-33.

目的:表皮生长因子受体(EGFRi)或丝裂原活化蛋白激酶(MEKi)抑制剂在 75-90% 的患者中会诱发毛囊炎,但对其病理生物学仍缺乏充分了解。目的:(1)描述表皮生长因子受体(EGFRi)治疗患者的皮肤免疫状态和全局转录特征的变化(2)探究表皮生长因子受体(EGFRi)是否会影响毛囊(HF)的免疫特权(IP)(3)确定表皮生长因子受体(EGFRi)/MEKi在体外人类头皮HF中诱导的早期促炎信号:头皮活检取自长期接受表皮生长因子受体(EGFRi)治疗的毛囊炎患者(慢性-EGFRi,n=9)与正常头皮皮肤(n=9),以及开始接受EGFRi治疗前和接受EGFRi治疗两周后的患者(急性-EGFRi,n=5)。健康器官培养的头皮高频暴露于表皮生长因子受体(EGFRi)(厄洛替尼)或MEKi(Cobimetinib)(各5名患者)。样本通过定量免疫组织形态学、RNAseq和原位杂交进行评估:慢性-EGFRi队列显示CD8+ T细胞浸润隆起,同时HF的IP部分塌陷,表现为MHC I类、ß2-微球蛋白和MHC II类上调以及TGF-ß1蛋白表达减少。用表皮生长因子受体i/MEKi体内外治疗的健康高频也显示出高频IP的部分崩溃和HLA-A、HLA-DR、ß2-微球蛋白转录本的增加。RNAseq分析显示,慢性-EGFRi活检组织中趋化因子(CXCL1、CXCL13、CCL18、CCL3、CCL7)和IL-26的转录增加,急性-EGFRi活检组织和器官培养的HF中IL-33的转录增加,IL-37的转录减少:这些数据表明,表皮生长因子受体(EGFRi)/表皮生长因子受体(MEKi)会损害人类头皮毛囊炎的生理性 IP,并表明未来临床治疗表皮生长因子受体(EGFRi)/表皮生长因子受体(MEKi)诱导的毛囊炎需要保护毛囊炎 IP 和抑制 IL-33。
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引用次数: 0
期刊
British Journal of Dermatology
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