Search

Background: Acne vulgaris (AV) is the eighth most common nonfatal disease globally. Previous work identified an association between AV and increased filaggrin (FLG) protein expression in the follicular epidermis, but further work did not find a clear link between loss-of-function (LoF) FLG gene mutations and protection from AV., Objectives: To explore any association between AV and FLG LoF mutations in a cohort of genotyped patients of Bangladeshi ancestry with atopic eczema (AE) in East London., Methods: A retrospective notes review was performed on 245 patients who had been genotyped for FLG LoF mutations and undergone -clinical assessment. A χ2-test or Fisher's exact test was used to determine differences in AV history between FLG LoF genotype groups., Results: We found a significant reduction in history of AV in patients with AE with FLG LoF mutations (19 of 82) relative to those without FLG mutations (47 of 129) (23% vs. 36.4%; P = 0.02). We showed a nonsignificant reduction in AV diagnosis in patients with impaired barrier function (measured by transepidermal water loss) and palmar hyperlinearity. We found that patients with severe AE were less likely to have a history of AV only if they had an existing FLG LoF mutation (P = 0.02)., Conclusions: In the context of AE, our work suggests that FLG LoF mutations protect patients from developing AV., Competing Interests: Conflicts of interest The authors declare no conflicts of interest., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Association of Dermatologists.)

Pachyonychia congenita (PC) is an autosomal dominant genodermatosis characterized by a triad of chronic severe plantar pain, focal palmoplantar keratoderma and hypertrophic nail dystrophy. Plantar pain can be debilitating and have a profound impact on quality of life. Current therapeutic options for pain in PC are limited to lifestyle adjustment and mechanical techniques, with a small subgroup of patients benefiting from oral retinoids. This review investigates the pathogenesis of pain in PC and provides a summary of the current and future therapeutic options., Competing Interests: Conflicts of interest E.O’T. has received funding from Palvella Therapeutics (consultancy, clinical trial), Timber Pharmaceuticals (consultancy), Unilever (research), the LEO Foundation (research) and Kamari Pharma (research grant, consultancy and clinical trial). All funding is to the university/hospital. M.D.B. held a position funded by the Chan Zuckerberg Initiative and is now a Medical Research Council clinical training fellow. R.L.M. held a position funded by Palvella Therapeutics to work on a pachyonychia congenita clinical trial. All funding goes to the university/hospital., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Association of Dermatologists.)

Atopic dermatitis (AD) is a chronic, inflammatory skin condition which affects over 200 million people worldwide, with patients commonly presenting with dry, itchy and sore skin. The challenge in finding optimal treatment for AD stems from the heterogenous nature of the disease and its multifaceted aetiology: skin barrier dysfunction, immune system dysregulation, genetic factors, environmental factors and alterations in skin microorganisms. Traditional treatments for AD such as corticosteroids, calcineurin inhibitors and immunosuppressants have several limitations such as reoccurrence of symptoms when discontinued, lack of targeted action and risk of adverse effects. The aim of this literature review was to explore and summarise the role of aryl hydrocarbon receptor (AHR) agonists (namely Tapinarof) as potential future therapy for AD. AHR agonists hope to overcome the limitations of traditional AD therapies and exert their therapeutic value by maintaining integrity of the skin barrier, defending against oxidative stress, modulating immune activity and inflammation and restoring a healthy skin microbiome. Tapinarof, a topical AHR agonist, is showing promising results and is currently in phase 3 trials (ADORING 3). For Tapinarof to be integrated into the AD treatment pathway, further research must be conducted on its efficacy, durability, potential remittive effect and safety across different AD subtypes in a large, diverse patient population. In addition, Tapinarof's cost-effectiveness compared to its topical counterparts needs to be considered and multidisciplinary collaboration is required between researchers, clinicians and policy makers., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Association of Dermatologists.)

Human prenatal skin is populated by innate immune cells, including macrophages, but whether they act solely in immunity or have additional functions in morphogenesis is unclear. Here we assembled a comprehensive multi-omics reference atlas of prenatal human skin (7-17 post-conception weeks), combining single-cell and spatial transcriptomics data, to characterize the microanatomical tissue niches of the skin. This atlas revealed that crosstalk between non-immune and immune cells underpins the formation of hair follicles, is implicated in scarless wound healing and is crucial for skin angiogenesis. We systematically compared a hair-bearing skin organoid (SkO) model derived from human embryonic stem cells and induced pluripotent stem cells to prenatal and adult skin 1 . The SkO model closely recapitulated in vivo skin epidermal and dermal cell types during hair follicle development and expression of genes implicated in the pathogenesis of genetic hair and skin disorders. However, the SkO model lacked immune cells and had markedly reduced endothelial cell heterogeneity and quantity. Our in vivo prenatal skin cell atlas indicated that macrophages and macrophage-derived growth factors have a role in driving endothelial development. Indeed, vascular network remodelling was enhanced following transfer of autologous macrophages derived from induced pluripotent stem cells into SkO cultures. Innate immune cells are therefore key players in skin morphogenesis beyond their conventional role in immunity, a function they achieve through crosstalk with non-immune cells., Competing Interests: Competing interests: J.L. and K.R.K., with the Indiana University Research and Technology Corporation, have a patent relating to the methodology and composition of SkOs (PCT/US2016/058174). K.R.K. is a consultant for StemCell Technologies. All other authors declare no competing interests., (© 2024. The Author(s).)

Objectives: To explore the demographic and clinical profile of erosive lichen planus (ELP) across multiple ethnicities within a single cohort, deepening our understanding of disease severity, progression and outcomes., Methods: A longitudinal retrospective cohort study of ELP patients in the ethnically diverse population of East London was carried out, profiling ELP ( n = 57) against the milder reticular lichen planus (RLP) ( n = 35)., Results: A higher prevalence of ELP was observed in white populations compared to other ethnicities. Affected females were no more likely than males to develop ELP. There was an increased time to diagnosis for ELP patients (median ELP: 452 days, RLP: 312 days), spending longer in primary care before onward referral, in particular when referred by their general medical practitioner (GP) (median dentist 313 days, GP: 606 days). Depression was more likely to occur alongside ELP. Being an ex-smoker is a risk factor for ELP while being a current smoker is associated with RLP. A higher proportion of patients with ELP were missing teeth and had periodontal disease. Multisite involvement was more common in ELP, (ELP: 68% RLP: 11.43%). 55% of ELP cases developed scarring and were less likely to respond to first line medications, requiring systemic immunosuppression. The duration of follow up was increased in the ELP who were reviewed for almost twice as long as RLP patients (ELP 71 months, RLP 35 months)., Conclusion: ELP takes longer to diagnose, requires prolonged tertiary care and is more resistant to treatment, when compared across multiple ethnicities. These patients have increased medical and oral health needs and are at greater risk of scarring than the reticular form. A greater education amongst primary carers on its presentation, as well as a greater understanding of the cellular and molecular mechanisms driving ELP are required to improve diagnostics and identify novel therapeutic approaches., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Macken, Senusi, O’Toole, Caley, Rognoni and Fortune.)

Competing Interests: Conflicts of interest J.M. is Editor-in-Chief of the BJD; E.A.O’T. is on the BJD’s Editorial Advisory Board. The other authors declare no conflicts of interest.

Varicella-zoster virus (VZV) is the etiological agent of chickenpox and shingles, diseases characterised by epidermal virus replication in skin and mucosa and the formation of blisters. We have previously shown that VZV infection has a profound effect on keratinocyte differentiation, altering the normal pattern of epidermal gene expression. In particular, VZV infection reduces expression of suprabasal keratins 1 and 10 and desmosomal proteins, disrupting epidermal structure to promote expression of a blistering phenotype. Here, we extend these findings to show that VZV infection upregulates the expression of keratin 15 (KRT15), a marker expressed by basal epidermal keratinocytes and hair follicles stem cells. We demonstrate that KRT15 is essential for VZV replication in the skin, since downregulation of KRT15 inhibits VZV replication in keratinocytes, while KRT15 exogenous overexpression supports viral replication. Importantly, our data show that VZV upregulation of KRT15 depends on the expression of the VZV immediate early gene ORF62. ORF62 is the only regulatory gene that is mutated in the live attenuated VZV vaccine and contains four of the five fixed mutations present in the VZV Oka vaccine. Our data indicate that the mutated vaccine ORF62 is not capable of upregulating KRT15, suggesting that this may contribute to the vaccine attenuation in skin. Taken together our data present a novel association between VZV and KRT15, which may open a new therapeutic window for a topical targeting of VZV replication in the skin via modulation of KRT15., (© 2024. The Author(s).)

Postnatal growth failure is often attributed to dysregulated somatotropin action, however marked genetic and phenotypic heterogeneity exist. We report five patients from three families who present with short stature, immune dysfunction, atopic eczema and gastrointestinal pathology associated with recessive variants in QSOX2. QSOX2 encodes a nuclear membrane protein linked to disulphide isomerase and oxidoreductase activity. Loss of QSOX2 disrupts Growth hormone-mediated STAT5B nuclear translocation despite enhanced Growth hormone-induced STAT5B phosphorylation. Moreover, patient-derived dermal fibroblasts demonstrate Growth hormone-induced mitochondriopathy and reduced mitochondrial membrane potential. Located at the nuclear membrane, QSOX2 acts as a gatekeeper for regulating stabilisation and import of phosphorylated-STAT5B. Altogether, QSOX2 deficiency modulates human growth by impairing Growth hormone-STAT5B downstream activities and mitochondrial dynamics, which contribute to multi-system dysfunction. Furthermore, our work suggests that therapeutic recombinant insulin-like growth factor-1 may circumvent the Growth hormone-STAT5B dysregulation induced by pathological QSOX2 variants and potentially alleviate organ specific disease., (© 2024. The Author(s).)

Pityriasis rubra pilaris (PRP) is a rare skin disease which manifests as a psoriasiform dermatosis and palmoplantar keratoderma and has significant clinical-histopathological overlap with psoriasis. Recently, several case reports have demonstrated successful treatment of PRP with anti-IL7A and anti-IL12/anti-IL23 monoclonal antibodies. We report a case of atypical juvenile PRP definitively diagnosed during adulthood with presence of CARD14 mutation. This case demonstrates a dramatic improvement with ustekinumab and highlights the role of genetic testing in chronic disease of diagnostic uncertainty., Competing Interests: RMC: Position funded by Palvella Therapeutics to work on a clinical trial. All unrelated to this work and all funding goes to the university. EOT: Research funding: Kamari Pharma, Unilever. Consultancy: Azitra Inc, Palvella Therapeutics and Kamari Pharma; Speaker: Almirall. All unrelated to this work and all funding goes to the university., (© 2024 The Authors. Skin Health and Disease published by John Wiley & Sons Ltd on behalf of British Association of Dermatologists.)

Pachyonychia congenita (PC) is a dominantly inherited genetic disorder of cornification. PC stands out among other genodermatoses because despite its rarity, it has been the focus of a very large number of pioneering translational research efforts over the past 2 decades, mostly driven by a patient support organization, the Pachyonychia Congenita Project. These efforts have laid the ground for innovative strategies that may broadly impact approaches to the management of other inherited cutaneous and noncutaneous diseases. This article outlines current avenues of research in PC, expected outcomes, and potential hurdles., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Atopic eczema is a common, chronic, inflammatory skin condition with considerable heterogeneity. South Asian people living in the UK frequently have low serum vitamin D3 (25(OH)D 3 ), and those with atopic disease can present with severe eczema. The association between vitamin D deficiency and eczema severity, and the role of vitamin D supplementation in atopic eczema is inconsistent, and under-researched in people with Asian ancestry., Objectives: This cross-sectional study investigates the association between serum 25(OH)D 3 and eczema severity in a cohort of South Asian children and young adults living in London., Methods: Eligible participants were Bangladeshi children and young adults aged 0-30 years with eczema, living in London and participating in the Tower Hamlets Eczema Assessment study. Data was collected via parent/patient self-reporting, clinical history and examination, and hospital databases. 25(OH)D 3 levels were documented retrospectively, if available, from hospital databases. Eczema severity was classified by Eczema Area and Severity Index (EASI) score less than or greater than 10 (clear-mild vs. moderate-severe). Multivariate logistic regression was used to adjust for confounding factors., Results: 681 participants were included in analyses. 25(OH)D 3 results were available for 49.6% (338/681), 84.3% of which had deficient or insufficient lowest 25(OH)D 3 . Lowest 25(OH)D 3 was inversely correlated with EASI score (Spearman's rank R 2  = -0.24, p  < 0.001). 26.1% (178/681) had EASI >10 and a lower median lowest and nearest 25(OH)D 3 . After adjustment for confounding EASI > 10 was significantly associated with a lowest 25(OH)D 3  < 25 (OR 3.21, 95%CI 1.35, 8.60), use of mild-moderate potency topical steroid on the face and neck (OR 3.11, 95%CI 1.86, 5.31), calcineurin inhibitor on the face and neck (OR 2.79, 95% CI 1.26, 6.10) and potent - very potent topical steroid on the face and neck (OR2.23, 95%CI 1.02, 4.77) and body (OR 2.11, 95%CI 1.18, 3.87)., Discussion: Vitamin D plays a role in modulation of proteins required for skin barrier function and regulation of the innate immune system, suggesting 25(OH)D 3 deficiency contributes to skin inflammation. This study demonstrates a relationship between 25(OH)D 3 deficiency and worse eczema severity in a cohort of South Asian children and young adults., Competing Interests: Rebecca L. McCarthy: Position funded by Palvella Therapeutics to work on a clinical trial. Unrelated to this work and all funding goes to the university. Edel A. O'Toole: Research funding: Kamari Pharma, Unilever. Consultancy: Azitra Inc, Palvella Therapeutics and Kamari Pharma; Speaker: Almirall. All unrelated to this work and all funding goes to the university., (© 2024 The Authors. Skin Health and Disease published by John Wiley & Sons Ltd on behalf of British Association of Dermatologists.)

Pachyonychia Congenita Project (PC Project) is an international patient advocacy organization dedicated to patients who suffer from pachyonychia congenita (PC). This condition is a painful and debilitating skin disorder caused by a mutation in one of five keratin genes: KRT6A, KRT6B, KRT6C, KRT16,or KRT17. Through two primary programs, namely the International Pachyonychia Congenita Consortium (IPCC) and the International Pachyonychia Congenita Research Registry (IPCRR), PC Project provides comprehensive patient support and diagnostics while uniting patients, researchers, physicians, and industry partners on a global level to advance research and drug development for meaningful treatments and, ultimately, a cure for PC.

Competing Interests: Conflicts of interest R.L.McC. has held a position funded by Palvella Therapeutics to work on a clinical trial (all unrelated to this work with all funding going to the university. D.G. has been a speaker for Lilly and La Roche-Posay (none applicable to this work). M.T. has been a speaker for AbbVie, Almirall, Eucerin, Janssen and Sanofi (none applicable to this work). E.O’T. has received research funding from Kamari Pharma and Unilever; consultancy fees from Azitra, Palvella Therapeutics and Kamari Pharma; and speaker’s fees from Almirall (all unrelated to this work with all funding going to the university). M.S. declares no conflicts of interest.

Recessive X-linked ichthyosis (RXLI), a genetic disorder caused by deletion or point mutations of the steroid sulfatase ( STS ) gene, is the second most common form of ichthyosis. It is a disorder of keratinocyte cholesterol sulfate retention and the mechanism of extracutaneous phenotypes such as corneal opacities and attention deficit hyperactivity disorder are poorly understood. To understand the pathomechanisms of RXLI, the transcriptome of differentiated primary keratinocytes with STS knockdown was sequenced. The results were validated in a stable knockdown model of STS, to confirm STS specificity, and in RXLI skin. The results show that there was significantly reduced expression of genes related to epidermal differentiation and lipid metabolism, including ceramide and sphingolipid synthesis. In addition, there was significant downregulation of aldehyde dehydrogenase family members and the oxytocin receptor which have been linked to corneal transparency and behavioural disorders respectively, both of which are extracutaneous phenotypes of RXLI. These data provide a greater understanding of the causative mechanisms of RXLI's cutaneous phenotype, and show that the keratinocyte transcriptome and lipidomics can give novel insights into the phenotype of patients with RXLI., Competing Interests: EO has had grant funding from Palvella Therapeutics and Kamari Pharma. She has consulted for Palvella Therapeutics, Kamari Pharma and Azitra Inc. She has had PhD studentships co-funded with GSK and Unilever. She has been a speaker for Almirall. All money goes to the university. MD was employed by Senzo Health Limited. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 McGeoghan, Camera, Maiellaro, Menon, Huang, Dewan, Ziaj, Caley, Donaldson, Enright and O’Toole.)

Background: Hyperlinear palms are described as a feature of loss-of-function (LoF) variants in filaggrin (FLG)., Objectives: To explore the phenotype of participants (age < 31 years) with atopic eczema of Bangladeshi ancestry from East London and investigate which factors best associate with LoF FLG variants., Methods: A cross-sectional study with participants recruited between May 2018 and December 2020. Patterns of palmar linearity were categorized and modelled with the Eczema Area and Severity Index (EASI), transepidermal water loss (TEWL), skin hydration (SH) and LoF FLG variants., Results: There were 506 complete cases available. Five palm patterns were noted. The 'prominent diamond' pattern associated best with EASI [marginal effects (ME) 2.53, 95% confidence interval (CI) 1.74-3.67], SH (ME 0.85, 95% CI 0.78-0.96) and TEWL (ME 1.32, 95% CI 1.11-1.62). Using five palm patterns had some ability to discriminate LoF FLG variants [area under the receiver operator characteristic (AUROC) 76.32%, 95% CI 71.91-80.73], improving to 77.99% (73.70-82.28) with the addition of SH. In subgroup analysis with only fine perpendicular/prominent diamond patterns the AUROC was 89.11% (95% CI 84.02-94.19)., Conclusions: This was a single-centre study design with humans classifying clinical patterns. The stability of temperature and humidity was not guaranteed across TEWL and SH measurements despite using a climate-controlled room. Palm patterns associate with EASI and TEWL. The fine perpendicular/prominent diamond patterns are markers to detect the absence/presence of LoF FLG variants, respectively., Competing Interests: Conflicts of interest E.A.O’T. has received research funding paid to the university from Kamari Pharma and Unilever, consulting fees paid to the university from Azitra Inc., Kamari Pharma, Palvella Therapeutics and Timber Pharma unrelated to this work. All other authors have no conflicts of interest to declare., (© The Author(s) 2023. Published by Oxford University Press on behalf of British Association of Dermatologists.)

Sphingosine 1-phosphate lyase (SGPL1) insufficiency (SPLIS) is a syndrome which presents with adrenal insufficiency, steroid-resistant nephrotic syndrome, hypothyroidism, neurological disease, and ichthyosis. Where a skin phenotype is reported, 94% had abnormalities such as ichthyosis, acanthosis, and hyperpigmentation. To elucidate the disease mechanism and the role SGPL1 plays in the skin barrier we established clustered regularly interspaced short palindromic repeats-Cas9 SGPL1 KO and a lentiviral-induced SGPL1 overexpression (OE) in telomerase reverse-transcriptase immortalised human keratinocytes (N/TERT-1) and thereafter organotypic skin equivalents. Loss of SGPL1 caused an accumulation of S1P, sphingosine, and ceramides, while its overexpression caused a reduction of these species. RNAseq analysis showed perturbations in sphingolipid pathway genes, particularly in SGPL1&#95;KO, and our gene set enrichment analysis revealed polar opposite differential gene expression between SGPL1&#95;KO and &#95;OE in keratinocyte differentiation and Ca 2+ signaling genesets. SGPL1&#95;KO upregulated differentiation markers, while SGPL1&#95;OE upregulated basal and proliferative markers. The advanced differentiation of SGPL1&#95;KO was confirmed by 3D organotypic models that also presented with a thickened and retained stratum corneum and a breakdown of E-cadherin junctions. We conclude that SPLIS associated ichthyosis is a multifaceted disease caused possibly by sphingolipid imbalance and excessive S1P signaling, leading to increased differentiation and an imbalance of the lipid lamellae throughout the epidermis., Competing Interests: Conflict of interest The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Atopic eczema (AE) is a chronic relapsing, pruritic disease that greatly affects the child and family's quality of life (QoL). It is usually common and severe among children of Bangladeshi ethnicity., Objectives: This is a cross-sectional quantitative study in patients with AE of Bangladeshi origin, which aims to analyse different components of the family, children and adult quality-of-life indices and their relationship to patient age, sex, eczema severity and distribution, other allergic associations, parental education and socioeconomic level., Methods: Children and young adults of Bangladeshi origin aged 0-30 years, clinically diagnosed with AE were recruited as part of the Tower Hamlets Eczema Assessment project, a clinical phenotyping study of AE in the Bangladeshi population living in East London. Questionnaires completed by children/parents included the Family Dermatology Life Quality Index (FDLQI), Infant's Dermatology Quality of Life (IDQOL) and the Children's Dermatology Life Quality Index (CDLQI). Young adults completed the Dermatology Life Quality Index (DLQI). The disease severity was assessed objectively using the Eczema Area Severity Index (EASI). Patients and parents who did not read or speak English were aided by Bengali/Sylheti-speaking research assistants., Results: Overall, 460 Bangladeshi children and 98 adults with AE were recruited. Burden of care, extra housework and emotional distress were the highest affected domains in parental QoL, while itching and sleep were the highest for children. Significant factors influencing FDLQI score were EASI [marginal effect (ME) 1.01, 95% confidence interval (CI) 1.00-1.03; P = 0.004], age (ME 0.98, 95% CI 0.97-0.99; P = 0.004), extensor eczema distribution (ME 1.25, 95% CI 1.03-1.52; P = 0.023), parental English fluency (ME 1.29, 95% CI 1.10-1.52; P = 0.002) and atopic comorbidities (ME 1.10, 95% CI 1.04-1.17; P = 0.001). Parental socioeconomic class was a nonsignificant factor. IDQOL/CDLQI was influenced significantly by the child's age (ME 0.99, 95% CI 0.97-1.00, P = 0.023), 'nonclear' eczema distribution clusters especially the 'severe extensive' cluster (ME 1.46, 95% CI 1.15-1.84; P = 0.002) and nonsignificantly by EASI and parental English literacy and socioeconomic levels. DLQI was affected significantly by nonclear eczema distribution groups especially 'severe extensive' (ME 2.49, 95% 1.76-3.53; P < 0.001) and nonsignificantly by patient age, and female sex., Conclusions: AE is a chronic disease where many external factors other than disease severity affect QoL of patients and their families, -especially in under-represented minority groups who face different linguistic and cultural barriers., Competing Interests: Conflicts of interest E.O.T. - research funding to university from Kamari Pharma and Unilever, consulting fees to university from Palvella Therapeutics, Azitra Inc, Timber Pharma and Kamari Pharma unrelated to this work. The other authors declare they have no conflicts of interest., (© The Author(s) 2022. Published by Oxford University Press on behalf of British Association of Dermatologists.)

Competing Interests: Conflicts of interest: the authors declare they have no conflicts of interest.

Competing Interests: Conflicts of interest Professor O’Toole has received funding for the university from Palvella Therapeutics (consultancy), Timber Pharma (consultancy), and Kamari Pharma (research grant and consultancy). Dr Hansen has received support from Palvella as a principal investigator for a clinical study in pachyonychia. Drs Tan, Steele and Thomas and Ms Schwartz have no conflicts of interest to declare.

Objectives: The gingiva heals at an accelerated rate with reduced scarring when compared to skin. Potential well-studied factors include immune cell number, angiogenesis disparities and fibroblast gene expression. Differential keratinocyte gene expression, however, remains relatively understudied. This study explored the contrasting healing efficiencies of gingival and skin keratinocytes, alongside their differential gene expression patterns., Methods: 3D organotypic culture models of human gingiva and skin were developed using temporarily immortalised primary keratinocytes. Models were wounded for visualisation of re-epithelialisation and analysis of keratinocyte migration to close the wound gap. Concurrently, differentially expressed genes between primary gingival and skin keratinocytes were identified, validated, and functionally assessed., Results: Characterisation of the 3D cultures of gingiva and skin showed differentiation markers that recapitulated organisation of the corresponding in vivo tissue. Upon wounding, gingival models displayed a significantly higher efficiency in re-epithelialisation and stratification versus skin, repopulating the wound gap within 24 hours. This difference was likely due to distinct patterns of migration, with gingival cells demonstrating a form of sheet migration, in contrast to skin, where the leading edge was typically 1-2 cells thick. A candidate approach was used to identify several genes that were differentially expressed between gingival and skin keratinocytes. Knockdown of PITX1 resulted in reduced migration capacity of gingival cells., Conclusion: Gingival keratinocytes retain in vivo superior wound healing capabilities in in vitro 2D and 3D environments. Intrinsic gene expression differences could result in gingival cells being 'primed' for healing and play a role in faster wound resolution., Clinical Significance Statement: The successful development of organotypic models, that recapitulate re-epithelialisation, will underpin further studies to analyse the oral response to wound stimuli, and potential therapeutic interventions, in an in vitro environment., Competing Interests: Conflict of Interest Statement The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Pruritus is a hallmark of atopic dermatitis (AD), which affects disease severity and patient quality of life. In AD uncontrolled with first-line topical therapies or in moderate to severe AD, systemic therapies are used; however, there is a paucity of head-to-head trials comparing the effectiveness of these therapies. The aim of this study was to compare the effectiveness of systemic therapies in relieving pruritus in moderate to severe AD in adults, using a meta-analysis. The PubMed, EMBASE, Medline and CINAHL databases were searched from inception up to 31 May 2020 for randomized, placebo-controlled trials investigating the effectiveness of systemic therapies on pruritus with moderate to severe AD in patients aged ≥ 16 years. In total, 26 studies (n = 5190 participants) were identified. Compared with placebo, there was a large and statistically significant (P < 0.001 for all) reduction in pruritus [standard mean difference (SMD); 95% CI] with dupilumab every 2 weeks (-0.88; -1.13 to -0.63), dupilumab every 2 weeks plus topical corticosteroids (-0.77; -0.91 to -0.62), dupilumab once weekly (-0.99; -1.29 to -0.68), dupilumab once weekly plus topical corticosteroids (-0.70; -0.81 to -0.59). There was also a large and statistically significant reduction with ciclosporin (-1.30; -2.34 to -0.26; P = 0.01) and a large, although not statistically significant reduction with azathioprine (-0.85; -2.07 to 0.35). There was a small reduction with both mepolizumab (-0.27; -0.89 to 0.35) and interferon-γ (-0.31; -0.75 to 0.12). Of the investigational drugs, nemolizumab 2.0 mg/kg was the most effective (-8.13; -9.31 to -6.94). The majority of systemic therapies were superior to placebo in reducing pruritus. In particular, the dupilumab studies consistently showed large improvements in pruritus, while nemolizumab showed the strongest antipruritic effects. However, future head-to-head trials are required for conclusive evidence., (© 2021 British Association of Dermatologists.)

Atopic eczema is a common and complex disease. Missing genetic hereditability and increasing prevalence in industrializing nations point toward an environmental driver. We investigated the temporal association of weather and pollution parameters with eczema severity. This cross-sectional clinical study was performed between May 2018 and March 2020 and is part of the Tower Hamlets Eczema Assessment. All participants had a diagnosis of eczema, lived in East London, were of Bangladeshi ethnicity, and were aged <31 years. The primary outcome was the probability of having an Eczema Area and Severity Index score > 10 after previous ambient exposure to commonly studied meteorological variables and pollutants. There were 430 participants in the groups with Eczema Area and Severity Index ≤ 10 and 149 in those with Eczema Area and Severity Index > 10. Using logistic generalized additive models and a model selection process, we found that tropospheric ozone averaged over the preceding 270 days was strongly associated with eczema severity alongside the exposure to fine particles with diameters of 2.5 μm or less (fine particulate matter) averaged over the preceding 120 days. In our models and analyses, fine particulate matter appeared to largely act in a supporting role to ozone. We show that long-term exposure to ground-level ozone at high levels has the strongest association with eczema severity., (Crown Copyright © 2021 Published by Elsevier Inc. on behalf of the Society for Investigative Dermatology.)

Background: Maintaining adequate oxygen delivery (DO 2 ) after major surgery is associated with minimising organ dysfunction. Skin is particularly vulnerable to reduced DO 2 . We tested the hypothesis that reduced perioperative DO 2 fuels inflammation in metabolically compromised skin after major surgery., Methods: Participants undergoing elective oesophagectomy were randomised immediately after surgery to standard of care or haemodynamic therapy to achieve their individualised preoperative DO 2 . Abdominal punch skin biopsies were snap-frozen before and 48 h after surgery. On-line two-dimensional liquid chromatography and ultra-high-definition label-free mass spectrometry was used to characterise the skin proteome. The primary outcome was proteomic changes compared between normal (≥preoperative value before induction of anaesthesia) and low DO 2 (2 after oesophagectomy. Failure to maintain preoperative DO 2 was associated with upregulation of proteins counteracting oxidative stress. Normal DO 2 after surgery was associated with pathways involving leucocyte recruitment and upregulation of an antimicrobial peptidoglycan recognition protein. Immunohistochemistry (n=6 patients) and immunoblots after liver resection (n=12 patients) supported the proteomic findings., Conclusions: Proteomic profiles in serial skin biopsies identified organ-protective mechanisms associated with normal DO 2 after major surgery., Clinical Trial Registration: ISRCTN76894700., Competing Interests: Declarations of interest GLA is an Editor of British Journal of Anaesthesia; and declares consultancy work for GlaxoSmithKline, unrelated to this work., (Copyright © 2021 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.)

Recent meta-analyses of Janus kinase (JAK) inhibitors in alopecia areata (AA) have excluded trial registries and may thus be subject to publication bias. This study assessed the potential for evidence selection bias and provides an overview of JAK inhibitor trials in AA. A broad search strategy of ClinicalTrials.gov was performed for AA. We also recorded whether results were published on PubMed. There were 26 trials identified, of which 9 were ongoing (mostly oral JAK inhibitors: 8 studies; 89%). Of completed/terminated trials, 4/17 (24%) had terminated prematurely, citing 'inefficacy/futility' or 'sponsor decision'. These were all topical JAK inhibitor trials (4/8, 50% termination rate), with a 0% termination rate (0/9) for oral JAK inhibitor trials. We conclude that topical JAK inhibitors may be less efficacious than has been apparent in the literature to date, with 50% of trials having terminated due to inefficacy/futility or sponsor decision and only one topical JAK inhibitor trial ongoing., (© 2021 British Association of Dermatologists.)

Tape strips have been used widely in dermatology research as a minimally invasive method to sample the epidermis, avoiding the need for skin biopsies. Most research has focused on epidermal pathology, such as atopic eczema, but there is increasing research into the use of tape strips in other dermatoses, such as skin cancer, and the microbiome. This review summarizes the technique of tape stripping, and discusses which dermatoses have been studied by tape stripping and alternative minimally invasive sampling methods. We review the number of tape strips needed from each patient and the components of the epidermis that can be obtained by tape stripping. With a focus on protein and RNA extraction, we address the techniques used to process tape strips. There is no optimal protocol to extract protein, as this depends on the abundance of the protein studied, its level of expression in the epidermis and its solubility. Many variables can alter the amount of protein obtained from tape strips, which must be standardized to ensure consistency between samples. No study has compared different RNA extraction techniques, but our own experience is that RNA yield is optimized by using 20 tape strips and the use of a cell scraper., (© 2020 The Authors. British Journal of Dermatology published by John Wiley & Sons Ltd on behalf of British Association of Dermatologists.)

Background: Cutaneous squamous cell carcinoma (cSCC) is a common cancer that invades the dermis through the basement membrane. The role of the basement membrane in poorly differentiated cSCC is not well understood., Objectives: To study the effect that loss of the laminin subunit alpha-3 (α3) chain from the tumour microenvironment has on tumour invasion and inflammatory cell recruitment., Methods: We examined the role of the basement membrane proteins laminin subunits α3, β3 and γ2 in SCC invasion and inflammatory cell recruitment using immunohistochemistry, short hairpin RNA knockdown, RNA-Seq, mouse xenograft models and patient tumour samples., Results: Analysis of SCC tumours and cell lines using antibodies specific to laminin chains α3, β3 and γ2 identified a link between poorly differentiated SCC and reduced expression of laminin α3 but not the other laminin subunits investigated. Knockdown of laminin α3 increased tumour invasion both in vitro and in vivo. Western blot and immunohistochemical staining identified increased phosphorylated myosin light chain with loss of laminin α3. Inhibition of ROCK (rho-associated protein kinase) but not Rac1 significantly reduced the invasive potential of laminin α3 knockdown cells. Knockdown of laminin subunits α3 and γ2 increased monocyte recruitment to the tumour microenvironment. However, only the loss of laminin α3 correlated with increased tumour-associated macrophages both in xenografted tumours and in patient tumour samples., Conclusions: These data provide evidence that loss of the laminin α3 chain in cSCC has an effect on both the epithelial and immune components of cSCC, resulting in an aggressive tumour microenvironment., (© 2020 The Authors. British Journal of Dermatology published by John Wiley & Sons Ltd on behalf of British Association of Dermatologists.)

Periostin, an extracellular matrix macromolecule implicated in tumorigenesis, serves as a prognostic marker for many cancer types. However, there are no data on periostin expression in cutaneous squamous cell carcinoma (cSCC). This study examined periostin expression in patients with cSCC and explored its clincopathological relationship and prognosis. Using immunohistochemistry and ImageJ analysis, we compared periostin expression in 95 cSCCs across a spectrum of cSCC aggressiveness: cSCC in situ (SCCIS) (n = 25), low-risk cSCC (LR-cSCC) (n = 26), high-risk cSCC (HR-cSCC) (n = 38), and cSCC in recessive dystrophic epidermolysis bullosa patients (RDEB cSCC) (n = 6). Immunohistochemistry demonstrated periostin expression within the intra-tumoral stroma but not within tumor cells. Periostin levels significantly (P < 0.001) increased from SCCIS, LR-cSCC, HR-cSCC to RDEB SCC. The stroma of most of the cSCCs we evaluated contained cancer-associated fibroblasts with a myofibroblastic (α -SMA-positive) phenotype. Co-localization of periostin with α-SMA, evidence of fibroblast periostin expression, and absence of keratinocyte or tumor cell periostin expression suggest that, in cSCC, periostin is a product of the peritumoral microenvironment and not the tumor cells themselves. Our data indicate that fibroblast periostin expression is highly correlated with the aggressiveness of cSCC, and may thereby provide a molecular marker that will be useful for subtyping and diagnosing cSCCs according to their biological nature., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Photoageing describes complex cutaneous changes which occur following chronic exposure to solar ultraviolet radiation (UVR). Amongst White Northern Europeans, facial photoageing appears as distinct clinical phenotypes: 'hypertrophic' photoageing (HP) and 'atrophic' photoageing (AP). Deep, coarse wrinkles predominate in individuals with HP, whereas those with AP have relatively smooth, unwrinkled skin with pronounced telangiectasia. AP individuals have an increased propensity for developing keratinocyte cancers., Objectives: To investigate whether histological differences underlie these distinct phenotypes of facial photoageing., Methods: Facial skin biopsies were obtained from participants with AP (10 M, 10 F; mean age: 78.7 years) or HP (10 M, 10 F; mean age: 74.5 years) and were assessed histologically and by immunohistochemistry., Results: Demographic characterization revealed 95% of AP subjects, as compared to 35% with HP, were Fitzpatrick skin type I/II; of these, 50% had a history of one or more keratinocyte cancers. There was no history of keratinocyte cancers in the HP cohort. Analysis of UVR-induced mitochondrial DNA damage confirmed that all volunteers had received similar lifetime cumulative doses of sun exposure. Histologically, male AP had a significantly thicker epidermis than did AP females or those of either sex with HP. HP facial skin exhibited severe solar elastosis, whereas in AP facial skin, solar elastosis was apparent only in females. Loss of papillary dermal fibrillin-rich microfibrils occurred in all HP and AP female subjects, but not in AP males. Furthermore, male AP had a significant reduction in collagen VII at the dermal-epidermal junction than did AP females or those of either sex with HP., Conclusions: This study provides further evidence that AP and HP represent distinct clinical and histological entities. Knowledge of these two phenotypes is clinically relevant due to the increased prevalence of keratinocyte cancers in those - particularly males - with the AP phenotype., (© 2020 The Authors. Journal of the European Academy of Dermatology and Venereology published by John Wiley & Sons Ltd on behalf of European Academy of Dermatology and Venereology.)

Background: No specific or curative therapy exists for hereditary palmoplantar keratoderma (hPPK), which can profoundly alter patient quality of life, leading sometimes to severe functional impairment and pain. The rarity and the aetiological diversity of this group of disorders can explain the difficulty in comparing the efficacy of available treatments., Objectives: To review the different treatments tried in patients with hPPK since 2008, their efficacy and safety, with an evaluation of the various therapeutic modalities that can be used to treat hPPK., Methods: We undertook a comprehensive review of the literature data published since 2008., Results: Only a few case series and individual case reports were identified. Topical (emollients, keratolytics, retinoids, steroids) and systemic treatments (mostly different retinoids), often combined, are used to relieve symptoms. Oral retinoids appear to be the most efficient treatment, but not in all PPK forms, and with variable tolerance. New targeted treatments, according to the specific mechanisms of hPPK, appear promising for the future., Conclusions: More studies using robust methodology and involving larger cohorts of well-characterized patients (phenotype-genotype) are necessary and should be prioritized by structured networks, such as the European Network for Rare Skin Diseases (ERN-Skin), with the aim of better management of patients with rare skin diseases., (© 2020 British Association of Dermatologists.)

The skin confers biophysical and immunological protection through a complex cellular network established early in embryonic development. We profiled the transcriptomes of more than 500,000 single cells from developing human fetal skin, healthy adult skin, and adult skin with atopic dermatitis and psoriasis. We leveraged these datasets to compare cell states across development, homeostasis, and disease. Our analysis revealed an enrichment of innate immune cells in skin during the first trimester and clonal expansion of disease-associated lymphocytes in atopic dermatitis and psoriasis. We uncovered and validated in situ a reemergence of prenatal vascular endothelial cell and macrophage cellular programs in atopic dermatitis and psoriasis lesional skin. These data illustrate the dynamism of cutaneous immunity and provide opportunities for targeting pathological developmental programs in inflammatory skin diseases., (Copyright © 2021, American Association for the Advancement of Science.)