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Epidermolysis bullosa (EB) encompasses a heterogeneous group of inherited skin fragility disorders, with mutations in genes encoding the basement membrane zone (BMZ) proteins that normally ensure dermal-epidermal integrity. Of the four main EB types, recessive dystrophic EB (RDEB), especially the severe variant, represents one of the most debilitating clinical entities, with recurrent mucocutaneous blistering and ulceration leading to chronic wounds, infections, inflammation, scarring and ultimately cutaneous squamous cell carcinoma, which leads to premature death. Improved understanding of the molecular genetics of EB over the past three decades and advances in biotechnology have led to rapid progress in developing gene and cell-based regenerative therapies for EB. In particular, RDEB is at the vanguard of advances in human clinical trials of advanced therapeutics. Furthermore, the past decade has witnessed the emergence of a real collective, global effort involving academia and industry, supported by international EB patient organizations such as the Dystrophic Epidermolysis Bullosa Research Association (DEBRA), among others, to develop clinically relevant and marketable targeted therapeutics for EB. Thus, there is an increasing need for the practising dermatologist to become familiar with the concept of gene therapy, fundamental differences between various approaches, and their human applications. This review explains the principles of different approaches of gene therapy, summarizes its journey, and discusses its current and future impact in RDEB.

Background The content validity (appropriateness and acceptability) of patient-reported outcome (PRO) measures for scalp hair loss, eyebrow loss, eyelash loss, nail damage and eye irritation has been demonstrated in adults with alopecia areata (AA) but not adolescents. Objective To explore the content validity of the suite of AA PRO measures and accompanying photoguides in an adolescent sample. Methods Semi-structured, 90-minute, combined concept elicitation and cognitive interviews were conducted face-to-face with adolescents who experienced ≥50% AA-related scalp hair loss. Transcripts underwent thematic and framework analysis. Results Eleven adolescents (age 12-17 years, 55% female, 45% non-Caucasian/white) diagnosed with AA for 5.9 years (mean) participated. Participants had 69.6% scalp hair (mean) and current eyebrow (82%), eyelash loss (82%) and/or nail involvement (36%). Adolescents reported scalp, eyebrow and eyelash hair loss as their top three most bothersome signs/symptoms. Despite mostly accepting their AA, impacts related to visible areas of hair loss were prominent. Participants demonstrated good understanding and appropriate use of the PRO measures, and advocated including hair loss percentages alongside descriptive categories in the Scalp Hair Assessment PRO™. Results confirmed treatment success thresholds established with adults: achievement of ≤20% scalp hair loss, no/minimal eyebrow and eyelash loss, no/a little nail damage and eye irritation (PRO categories 0 or 1). Conclusions The Scalp Hair Assessment PRO™, PRO Measure for Eyebrows™, PRO Measure for Eyelashes™, PRO Measure for Nail Appearance™ and PRO Measure for Eye Irritation™ and accompanying photoguides are fit-for-purpose self-reported measures of AA signs/symptoms that are impactful to adolescents with AA.

Dear Editor, Growing evidence suggests that SARS‐CoV‐2 vaccination is associated with a variety of cutaneous reactions, also including autoimmune‐mediated conditions such as autoimmune blistering diseases such as bullous pemphigoid (BP).1,2 We report new‐onset BP in two patients following the first SARS‐CoV‐2 vaccination.

Summary Background Permanent chemotherapy-induced alopecia (pCIA), for which preventive interventions remain limited, can manifest with scarring. While the underlying pathomechanisms of pCIA are unclear, depletion of epithelial hair follicle (HF) stem cells (eHFSCs) is likely to play a role. Objectives To explore the hypothesis that, besides apoptosis, eHFSCs undergo pathological epithelial–mesenchymal transition (EMT) in pCIA, thus explaining the scarring phenotype. Furthermore, we tested whether a peroxisome proliferator-activated receptor (PPAR)-γ modulator could prevent pCIA-associated pathomechanisms. Methods Organ-cultured human scalp HFs were treated with the cyclophosphamide metabolite 4-hydroperoxycyclophosphamide (4-HC). Additionally, HFs were pretreated with the agonistic PPAR-γ modulator N-acetyl-GED-0507-34-Levo (NAGED), which has previously been shown to promote K15 expression and antagonize EMT in eHFSCs. Results In accordance with anticipated hair bulb cytotoxicity, dystrophy and catagen induction, 4-HC promoted apoptosis along with increased p53 expression, DNA damage and pathological EMT in keratin 15+ (K15) eHFSCs, as evidenced by decreased E-cadherin expression and the appearance of fibronectin+ and vimentin+ cells in the hair bulge. Pretreatment with NAGED protected against 4-HC-induced hair bulb cytotoxicity/dystrophy, and apoptosis, p53 upregulation and EMT in the bulge, thereby significantly preventing depletion of K15+ human eHFSCs ex vivo. Conclusions Since a key cyclophosphamide metabolite alone suffices to damage and deplete human scalp eHFSCs by promoting apoptosis, DNA damage and EMT ex vivo, strategies to prevent pCIA need to target these pathomechanisms. Given the ability of NAGED to prevent chemotherapy-induced eHFSCs damage ex vivo, our study introduces the stimulation of PPAR-γ signalling as a novel intervention strategy for the prevention of pCIA.

WNTs (Wingless-related integration sites) are secreted glycoproteins that are involved in signalling pathways critical to organ development and tissue regeneration. Of the 19 known WNT ligands, one member of this family, WNT10A, appears to have specific relevance to skin, its appendages and teeth. This review focuses on how variants in the WNT10A gene have been associated with various ectodermal disorders and how such changes may have clinical relevance to dermatologists and dentists. Germline mutations in WNT10A underlie several forms of autosomal recessive ectodermal dysplasia in which heterozygous carriers may also display some lesser ectodermal anomalies. Within the general population, multiple heterozygous variants in WNT10A can cause skin, hair, sweat gland or dental alterations, also known as ectodermal derivative impairments. WNT10A variants have also been implicated in hair thickness, male androgenetic alopecia, hair curl, acne vulgaris, lipodystrophy, keloids, wound healing, tooth size, tooth agenesis, hypodontia, taurodontism and oral clefting. Beyond dermatology and dentistry, WNT10A abnormalities have also been identified in kidney fibrosis, keratoconus, certain malignancies (particularly gastrointestinal) and neuropathic pain pathways. In this review, we detail how WNT10A is implicated as a key physiological and pathological contributor to syndromic and nonsyndromic disorders, as well as population variants, affecting the skin and teeth, and document all reported mutations in WNT10A with genotype-phenotype correlation.

Background Melanism is more frequent in animals living in polluted areas at urban-industrial sites. Given that a growing part of the human population is exposed to elevated air pollution levels, we wondered if environmental pollutants might affect melanogenesis in human skin likewise. Epidemiological studies in Caucasians and East Asians indeed showed that exposure to traffic-related air pollutants such as Diesel Exhaust Particles (DEP) is associated with more clinical signs of hyperpigmentation. Mechanistic evidence linking DEP exposure with pigmentation, however, has been elusive. Objectives to develop an ex vivo skin model allowing topical repetitive application of ambient relevant DEP and proof-of-concept in humans. Methods Measurement of skin pigmentation, melanin and pigmentation associated gene expression and evaluation of oxidative stress. Results Repetitive exposure of ex vivo skin to DEP at non-toxic concentrations increased pigmentation. This increase was visible by the naked eye, time-dependent, associated with an increase in melanin content and transcription of genes involved in melanin de novo synthesis. In healthy subjects (n=76) repetitive topical application of DEP at non-toxic concentrations increased skin pigmentation similarly. DEP-induced pigmentation was mediated by an oxidative stress response, because after DEP application (i) epidermal antioxidants were depleted, (ii) lipid peroxidation and oxidative DNA damage were enhanced, and (iii) in a vehicle-controlled, double-blinded, clinical study DEP-induced pigmentation was prevented by topical application of an antioxidant mixture. Conclusion Similar to solar radiation, air pollutants cause skin tanning. Since eumelanin is an antioxidant, we propose that this response serves to protect human skin against air pollution-induced oxidative stress.

Anthropogenic climate change affects our environment through higher temperatures, poorer air quality, polluted waters, and increased extreme weather events. These changes in our environment negatively influence the health of the population.1 The integument is not spared by climate change. Higher temperatures, decreased ozone protection, increased airborne pollutants, and decreased ultraviolet (UV) protection can cause flares of atopic dermatitis, pemphigus, lupus, and other inflammatory diseases, and increase rates of skin cancer.2.

Pemphigoid is a heterogeneous group of rare and chronic autoimmune subepidermal bullous diseases, characterized by circulating autoantibodies against structural proteins in the hemidesmosomes. Long-term therapy with systemic oral prednisone and immunosuppressants are often required and associated with severe adverse reactions.

Background Pemphigus is a severe bullous autoimmune skin disease. Pemphigus foliaceus (PF) is characterized by antidesmoglein (Dsg) 1 IgG causing epidermal blistering; mucosal pemphigus vulgaris (mPV) by anti‐Dsg3 IgG inducing erosions in the mucosa; and mucocutaneous pemphigus vulgaris (PV) by affecting both, with autoantibodies targeting Dsg1 and Dsg3. Objectives To characterize the Ca\(^{2+}\) flux pathway and delineate its importance in pemphigus pathogenesis and clinical phenotypes caused by different antibody profiles. Methods Immunoprecipitation, Ca\(^{2+}\) flux analysis, Western blotting, immunofluorescence staining, dissociation assays and a human skin ex vivo model were used. Results PV IgG and PF IgG, but neither Dsg3‐specific monoclonal antibody (AK23) nor mPV IgG, caused Ca\(^{2+}\) influx in primary human keratinocytes. Phosphatidylinositol 4‐kinase α interacts with Dsg1 but not with Dsg3. Its downstream target – phospholipase‐C‐γ1 (PLC) – was activated by PV IgG and PF IgG but not AK23 or mPV IgG. PLC releases inositol 1,4,5‐trisphosphate (IP3) causing IP3 receptor (IP3R) activation and Ca2+ flux from the endoplasmic reticulum into the cytosol, which stimulates Ca2+ release‐activated channels (CRAC)‐mediated Ca\(^{2+}\) influx. Inhibitors against PLC, IP3R and CRAC effectively blocked PV IgG and PF IgG‐induced Ca\(^{2+}\) influx; ameliorated alterations of Dsg1 and Dsg3 localization, and reorganization of keratin and actin filaments; and inhibited loss of cell adhesion in vitro. Finally, inhibiting PLC or IP3R was protective against PV IgG‐induced blister formation and redistribution of Dsg1 and Dsg3 in human skin ex vivo. Conclusions Ca2+‐mediated signalling is important for epidermal blistering and dependent on the autoantibody profile, which indicates different roles for signalling complexes organized by Dsg1 and Dsg3. Interfering with PLC and Ca\(^{2+}\) signalling may be a promising approach to treat epidermal manifestations of pemphigus.

Porokeratosis is an autosomal dominant skin disorder characterized by annular or circular skin lesions surrounded by a hyperkeratotic rim called "cornoid lamella".1 Clinical subtypes of porokeratosis have been classified mostly based on age at onset, and the distribution and size of skin lesions.1 It has been demonstrated that most patients with porokeratosis have a heterozygous germline mutation in genes that encode enzymes of the mevalonate pathway, MVK, MVD, PMVK, or FDPS, in both familial and sporadic cases.

Background Human skin, which is constantly exposed to solar ultraviolet radiation (UVR), has a unique ability to respond by increasing its pigmentation in a protective process driven by melanogenesis in human epidermal melanocytes (HEMs). However, the molecular mechanisms used by HEMs to detect and respond to UVR remain unclear. Objectives To investigate the function and potential mechanism of opsin 5 (OPN5), a photoreceptor responsive to UVR wavelengths, in melanogenesis in HEMs. Methods Melanin content in HEMs was determined using the NaOH method, and activity of tyrosinase (TYR) (a key enzyme in melanin synthesis) was determined by the l-DOPA method. OPN5 expression in UVR-treated vs. untreated HEMs and explant tissues was detected by reverse-transcription quantitative polymerase chain reaction (RT-qPCR), Western blotting and immunofluorescence. Short interfering RNA-mediated OPN5 knockdown and a lentivirus OPN5 overexpression model were used to examine their respective effects on TYR, tyrosinase-related protein 1 (TRP1), TRP2 and microphthalmia-associated transcription factor (MITF) expression, under UVR. Changes in expression of TYR, TRP1 and TRP2 caused by changes in OPN5 expression level were detected by RT-qPCR and Western blot. Furthermore, changes in signalling pathway proteins were assayed. Results We found that OPN5 is the key sensor in HEMs responsible for UVR-induced melanogenesis. OPN5-induced melanogenesis required Ca2+ -dependent G protein-coupled receptor- and protein kinase C signal transduction, thus contributing to the UVR-induced MITF response to mediate downstream cellular effects, and providing evidence of OPN5 function in mammalian phototransduction. Remarkably, OPN5 activation was necessary for UVR-induced increase in cellular melanin and has an inherent function in melanocyte melanogenesis. Conclusions Our results provide insight into the molecular mechanisms of UVR sensing and phototransduction in melanocytes, and may reveal molecular targets for preventing pigmentation or pigment diseases.

Epidermal necrolysis (EN, including Stevens-Johnson syndrome and toxic epidermal necrolysis (TEN)) is mostly induced by drugs. Prevalence of lupus erythematosus (LE) is higher in EN than in general population (1.2 to 2%).1,2 Furthermore, flares of LE may present as EN (TEN-like LE).3-5 We aimed to describe EN in patients with clinical or biological LE to better characterize the relation between both diseases.

Classification of facial and truncal segmental vitiligo and its clinical courses including recurrence rate and patterns: a retrospective review of 956 patients

BACKGROUND Chronic wounds, a common morbidity in recessive dystrophic epidermolysis bullosa (RDEB), lack definitive therapies. OBJECTIVES To assess allogeneic epidermal skin grafts in terms of wound healing and durability over time. METHODS In a prospective, open-label clinical trial for postallogeneic haematopoietic cell transplantation (post-alloHCT) patients with RDEB, up to nine chronic wounds per patient were grafted over 1 year. Epidermal grafts measuring 5 cm2 were obtained from related alloHCT donors in the outpatient setting using the CELLUTOMETM Epidermal Harvesting System. Wounds were photographed and symptom inventories completed at baseline and 6, 12 and 52 weeks after grafting. The trial was registered at ClinicalTrials.gov (NCT02670837). RESULTS Between August 2016 and January 2019, eight patients with RDEB received a total of 35 epidermal allografts at a median of 1157 days (range 548-2884) post-alloHCT. The median (interquartile range) percentage reductions in wound surface area were 75% (52-94), 95% (72-100) and 100% (97-100) at 6, 12 and 52 weeks postgraft, respectively, each significantly reduced from baseline (P

BACKGROUND Peeling skin syndrome type 1 (PSS1) is a rare and severe autosomal recessive form of congenital ichthyosis. Patients are affected by pronounced erythroderma accompanied by pruritus and superficial generalized peeling of the skin. The disease is caused by nonsense mutations or complete deletion of the CDSN gene encoding for corneodesmosin (CDSN). PSS1 severely impairs quality of life and therapeutic approaches are totally unsatisfactory. OBJECTIVES The objective of this study was to develop the first steps towards a specific protein replacement therapy for CDSN deficiency. Using this approach, we aimed to restore the lack of CDSN and improve cell-cell cohesion in the transition area of the stratum granulosum (SG) to the stratum corneum. METHODS Human CDSN was recombinantly expressed in Escherichia coli. A liposome-based carrier system, prepared with a cationic lipopeptide to mediate the transport to the outer membrane of keratinocytes, was developed. This formulation was chosen for CDSN delivery into the skin. The liposomal carrier system was characterized with respect to size, stability and toxicity. Furthermore, the interaction with primary keratinocytes and human epidermal equivalents was investigated. RESULTS The liposomes showed an accumulation at the membranes of keratinocytes. CDSN-deficient epidermal equivalents that were treated with liposomal encapsulated CDSN demonstrated presence of CDSN in the SG. Finally, the penetration assay and histological examinations revealed an improved epidermal integrity for CDSN-deficient epidermal equivalents, if they were treated with liposomal encapsulated CDSN. CONCLUSIONS This study presents the first preclinical in vitro experiments for a future specific protein replacement therapy for patients affected by PSS1.

Background Loose anagen hair is a rare form of impaired hair anchorage in which anagen hairs that lack inner and outer root sheaths can be gently and painlessly plucked from the scalp. This condition usually occurs in children and is often self-limiting. A genetic basis for the disorder has been suggested but not proven. A better understanding the aetiology of loose anagen hair may improve prevention and treatment strategies. Objectives To identify a possible genetic basis of loose anagen hair using next-generation DNA sequencing and functional analysis of variants identified. Methods In this case study, whole-exome sequencing analysis of a pedigree with one affected individual with features of loose anagen hair was performed. Results The patient was found to be compound heterozygous for two single-nucleotide substitutions in TKFC resulting in the following missense mutations: c.574G> C (p.Gly192Arg) and c.682C> T (p.Arg228Trp). Structural analysis of human TKFC showed that both mutations are located near the active site cavity. Kinetic assays of recombinant proteins bearing either of these amino acid substitutions showed almost no dihydroxyacetone kinase or D-glyceraldehyde kinase activity, and FMN cyclase activity reduced to just 10% of wildtype catalytic activity. Conclusions TKFC missense mutations may predispose to the development of loose anagen hairs. Identification of this new biochemical pathobiology expands the metabolic and genetic basis of hypotrichosis.

Summary Background Valid patient‐reported outcome (PRO) measures are required to evaluate alopecia areata (AA) treatments. Objectives To develop a content‐valid and clinically meaningful PRO measure to assess AA scalp hair loss with scores comparable with the five‐response‐level Alopecia Areata Investigator Global Assessment (AA‐IGA™). Methods A draft PRO measure was developed based on input from 10 clinical experts in AA. The PRO measure was cognitively debriefed, modified and finalized through two rounds of qualitative semistructured interviews with patients with AA who had experienced ≥ 50% scalp hair loss. Data were thematically analysed. Results Adults (round 1: n = 25; round 2: n = 15) and adolescents aged 15–17 years (round 1: n = 5) in North America participated. All patients named scalp hair loss as a key AA sign or symptom. Patients demonstrated the ability to self‐report their current amount of scalp hair using percentages. In round 1 not all patients interpreted the measurement concept consistently; therefore, the PRO was modified to clarify the measurement concept to improve usability. Following modifications, patients in round 2 responded without difficulty to the PRO measure. Patients confirmed that they could use the five‐level response scale to rate their scalp hair loss: no missing hair, 0%; limited, 1–20%; moderate, 21–49%; large, 50–94%; nearly all or all, 95–100%. Almost all patients deemed hair regrowth resulting in ≤ 20% scalp hair loss a treatment success. Conclusions The Scalp Hair Assessment PRO™ is a content‐valid, clinically meaningful assessment of distinct gradations of scalp hair loss for evaluating AA treatment for patients with ≥ 50% hair loss at baseline., What is already known about this topic? Assessing patient‐reported outcomes is critical in patient‐focused drug development.The patient perspective on their own signs, symptoms and unmet needs provides a key clinical trial data source for evaluating treatment outcomes.Clinically meaningful and content‐valid patient‐reported outcome (PRO) measures are required to collect these data in alopecia areata (AA) clinical trials. What does this study add? This study developed a content‐valid PRO measure for patients with AA to self‐report the status of their scalp hair loss.This novel PRO measure allows scalp hair loss to be characterized into clinically meaningful gradations across the range of 0–100% missing scalp hair. What are the clinical implications of this work? The Scalp Hair Assessment PRO™ provides a new clinical outcome assessment of AA scalp hair loss for use in both clinical trials to evaluate the efficacy of novel treatments and in clinical practice to obtain a patient‐centred perspective on the key sign and symptom of AA.With corresponding response options to the newly developed Alopecia Areata Investigator Global Assessment (AA‐IGA™), clinician and patient assessments are comparable to elucidate any perceived differences between respondents. Linked Comment: Rencz. Br J Dermatol 2020; 183:986–987.

Author(s): Wyrwich, KW; Kitchen, H; Knight, S; Aldhouse, NVJ; Macey, J; Nunes, FP; Dutronc, Y; Mesinkovska, N; Ko, JM; King, BA | Abstract: BackgroundContent-valid and clinically meaningful instruments are required to evaluate outcomes of therapeutic interventions in alopecia areata (AA).ObjectivesTo develop an Investigator's Global Assessment (IGA) to interpret treatment response in AA treatment studies.MethodsQualitative interviews were conducted in the USA with expert dermatologists and with patients with AA who had experienced ≥ 50% scalp-hair loss. Thematic data analysis identified critical outcomes and evaluated the content validity of the new IGA.ResultsExpert clinicians (n = 10) judged AA treatment success by the amount of scalp-hair growth (median 80% scalp hair). Adult (n = 25) and adolescent (n = 5) patients participated. Scalp-hair loss was the most bothersome AA sign/symptom for most patients. Perceived treatment success - short of 100% scalp hair - was the presence of ~ 70-90% scalp hair (median 80%). Using additional clinician and patient insights, the Alopecia Areata Investigator Global Assessment (AA-IGA™) was developed. This clinician-reported outcome assessment is an ordinal, static measure comprising five severity categories of scalp-hair loss. Nearly all clinicians and patients in this study agreed that, for patients with ≥ 50% scalp-hair loss, successful treatment would be hair regrowth resulting in ≤ 20% scalp-hair loss.ConclusionsWe recommend using the Severity of Alopecia Tool to assess the extent (0-100%) of scalp-hair loss. The AA-IGA is a robust ordinal measure providing distinct and clinically meaningful gradations of scalp-hair loss that reflects patients' and expert clinicians' perspectives and treatment expectations. What is already known about this topic? The Severity of Alopecia Tool is widely used to assess the extent of scalp-hair loss in patients with alopecia areata. Guidelines define treatment success as a 50% improvement in scalp hair, and clinical trials have used dynamic thresholds of 50% and 90%. However, there is no clinical consensus on these endpoints, and patient perspectives on treatment success are unknown. What does this study add? Through qualitative interviews with 10 expert dermatologists and 30 patients with alopecia areata who had experienced ≥ 50% scalp-hair loss, we developed the Alopecia Areata Investigator Global Assessment (AA-IGA™) to measure five clinically meaningful gradations of alopecia areata scalp-hair loss that reflects patients' and clinicians' perspectives and expectations of treatment success in alopecia areata treatment studies. What are the clinical implications of this work? The AA-IGA is a robust ordinal measure that can inform clinical evaluation of alopecia areata treatment outcomes. The AA-IGA can be used to determine clinically meaningful treatment success for alopecia areata, with success defined by patients and clinicians as reaching ≤ 20% scalp-hair loss. Linked Comment: Blome. Br J Dermatol 2020; 183:609.

Background: Our understanding of the pathogenesis underlying keloid scar formation is still very limited, and the morphological distinction between hypertrophic and keloid scars remains difficult. Objectives: To test whether hypertrophic and keloid scars may reflect an inability to progress from immaturity to the desired mature normotrophic scar phenotype. Methods: Using whole-biopsy imaging and an objectively quantifiable way to analyse immunoreactivity, we have compared the immunohistopathological profiles of young immature scars with mature normotrophic scars, hypertrophic scars, and keloids with their surrounding-normal-skin. Results: Abnormal scars (hypertrophic scars and keloids) maintain the immature scar phenotype, characterized by a CD34− (tumour biomarker) and α-smooth muscle actin (α-SMA)+ (myofibroblast) dermal region. This is in contrast to normal skin, surrounding-normal-skin and mature normotrophic scars that were CD34+/ α-SMA−. Immature, hypertrophic and keloid scars showed abnormal epidermal differentiation (involucrin), but only hypertrophic scars and keloids showed increased epidermal thickness. Immature scars did show increased epidermal and dermal proliferation (Ki67), which was absent from abnormal scars, where mesenchymal hypercellularity (vimentin) and senescence (p16) were predominant. Keloidal collagen and α-SMA were previously considered to distinguish between hypertrophic scars and keloids. However, α-SMA staining was present in both abnormal scar types, while keloidal collagen was present mostly in keloids. There were no obvious signs of heterogeneity within keloid scars, and the surrounding-normal-skin resembled normal skin. Conclusions: Both abnormal scar types showed a unique CD34−/α-SMA+/p16+ scar phenotype, but the differences between hypertrophic scars and keloids observed in this study were of a gradient rather than absolute nature. This suggests that scar progression to the mature normal scar phenotype is, for as yet unknown reasons, hindered in hypertrophic and keloid scars. What's already known about this topic?. Hypertrophic and keloid scars both have sustained epidermal barrier dysfunction, suggesting the persistence of an immature scar phenotype. Morphological distinction between hypertrophic and keloid scars remains a topic of debate, although α-smooth muscle actin (α-SMA) and keloidal collagen have been considered distinguishing features of hypertrophic and keloid scars, respectively. It has been suggested that keloids are not simply homogeneous growths, as heterogeneity within keloid scars and possible involvement of the surrounding-normal-skin have been reported. What does this study add?. An extensive whole-biopsy imaging and quantifiable immunohistochemical assessment of immature, mature normal, hypertrophic and keloid scars, including normal skin surrounding keloids. Hypertrophic and keloid scars maintain dermal characteristics of immature scars, rather than transitioning into the normal mature phenotype. Differences between hypertrophic and keloid scars were of a gradient rather than absolute nature, with keloids showing the more extreme phenotype. There was no obvious heterogeneity within keloids, and the normal skin surrounding keloids resembled normal skin. What is the translational message?. Keloids remain primarily a clinical diagnosis. A raised scar with the CD34−/α-SMA+/p16+ phenotype with strong immunoreactivity for p16 and significant amounts of keloidal collagen, together with a thickened and strongly abnormal involucrin-stained epidermis, would sway the diagnosis towards keloid scars. A hypertrophic scar seems more likely when the CD34−/α-SMA+/p16+ phenotype shows very strong presence of α-SMA+ in large dermal nodules, with lesser p16 staining and absent or negligible keloidal collagen.

Background Total-body skin examination (TBSE) by dermatologists detects incidental skin cancers, but there is insufficient evidence for screening guidelines. As a result, the decision to perform screening TBSE in patients presenting for a focused visit is left to the dermatologist's discretion. Objectives To model the financial and time tradeoffs of risk-stratified skin cancer screening by dermatologists in patients presenting with unrelated focused complaints. Methods We performed an economic evaluation incorporating data from a previously published prospective multicentre international study in addition to US demographic data on age and skin phototype (SPT). Results The mean number needed to examine (NNE) for all US adults was 105 at an additional cost of $3796 per skin cancer detected when performing TBSE on a patient who presents for a focused exam. The NNE consistently decreased with increasing age and lighter SPT for every age and SPT screening threshold. The cost per person screened increased with higher age and lighter SPT owing to the higher likelihood of incurring diagnostic biopsies. The additional face-to-face time required per skin cancer detected by performing TBSE in patients who present for a focused visit was 4·5 h for all adults. We used a diverse cohort of international patients that did not include Americans and because of a low event rate, we combined detection of melanoma and nonmelanoma skin cancer. Conclusions Incidental skin cancers are detected by screening TBSE and its value can be enhanced through consideration of patients' age and SPT, which are established and readily identifiable skin cancer risk factors. What is already known about this topic? Risk stratification of asymptomatic individuals using age and skin phototype (SPT) can enhance the value of total-body skin examination when performed in the clinic by a dermatologist. What does this study add? For every age and SPT screening threshold, the number needed to examine to identify one skin cancer consistently decreased with increasing age and lighter SPT. When deciding to perform a screening skin examination in patients presenting with a focused complaint, dermatologists may wish to consider a patient's risk using age and SPT to enhance the yield of this intervention. Linked Comment: Ferris. Br J Dermatol 2020; 183:417-418.

BACKGROUND Vitiligo is a chronic inflammatory skin disorder characterized by the loss of melanocytes. While a T helper cell (Th)1/cytotoxic T cell (Tc)1-skewed immune response is now well demonstrated in vitiligo, recent data suggest that the T-cell component could be more complex, involving different combinatorial T-cell subsets. OBJECTIVES To analyse the phenotype and function of circulating CD4+ and CD8+ memory T-cell subsets in patients with stable and active vitiligo, in comparison with patients with psoriasis and healthy controls. METHODS This is a monocentric, prospective, descriptive and exploratory study. Multiparametric flow cytometry analyses were performed to evaluate the surface expression of homing and T-cell-subset markers together with intracellular cytokine production in peripheral blood mononuclear cells from 60 patients with vitiligo, 25 patients with psoriasis and 28 healthy donors. RESULTS Vitiligo peripheral blood circulating effector and central memory T cells expressed similar proportions of skin-homing markers. Decrease in the frequencies of circulating CD4+ and CD8+ Th1/Tc1, Th17/Tc17, and Th1/Th17 or Tc1/Tc17 effector memory T-cell subsets were observed in patients with vitiligo compared with healthy donors. Similar observations were made in psoriasis. In contrast, vitiligo circulating T cells showed a similar capacity for proinflammatory cytokine production compared with those in psoriasis and healthy controls. CONCLUSIONS The decreased frequencies of circulating Th1/Tc1, Th17/Tc17 and Th1/Th17-Tc1/Tc17 cells suggest a possible migration of these T-cell subsets into the skin of patients with vitiligo. These could be targeted to prevent flares of the disease. What is already known about this topic? Vitiligo is a chronic inflammatory skin disorder associated with the loss of melanocytes. Vitiligo is characterized by a T helper cell (Th)1/cytotoxic T cell (Tc)1-skewed immune response in the skin. What does this study add? A thorough analysis of the phenotype and function of circulating memory T cells suggests the migration of Th1/Tc1, Th17/Tc17 and Th1/Th17-Tc1/Tc17 cell subsets in the skin. What is the translational message? A better understanding of the different immune T-cell subsets involved in vitiligo could lead to better therapeutic options. Linked Comment: Matos. Br J Dermatol 2020; 183:803.

Background Frontal fibrosing alopecia (FFA) is traditionally regarded as a variant of lichen planopilaris (LPP) based on histological features. Distinct clinical presentation, demographics and epidemiology suggest that differing pathogenic factors determine the final phenotype. Objectives To map the hair follicle immune system in LPP and FFA by systematically comparing key inflammatory markers in defined hair follicle compartments. Methods Lesional scalp biopsies from LPP and FFA and healthy controls were stained with the following immunohistochemical markers: CD1a and CD209, CD4, CD8, CD56, CD68, CD123, CXCR3, forkhead box (FOX)P3, mast cell tryptase and cKit. Macrophage polarization was explored using CD206, CD163, CD86, receptor for advanced glycation end products (RAGE), interleukin (IL)-4 and IL-13 on paired lesional and nonlesional LPP and FFA samples. Results Increased numbers of CD8+ , CXCR3+ and FOXP3+ T cells and CD68+ macrophages were identified in the distal hair follicle epithelium and perifollicular mesenchyme in both LPP and FFA compared with controls. In both LPP and FFA, total and degranulated mast cells and CD123+ plasmacytoid dendritic cells were increased in the perifollicular mesenchyme adjacent to the bulge and infundibulum, whereas numbers of CD1a+ and CD209+ dendritic cells were significantly reduced in the infundibulum connective tissue sheath. However, only with CD68 staining was a significant difference between LPP and FFA identified, with greater numbers of CD68+ cells in LPP samples. Furthermore, the identified macrophage polarization markers downregulated CD86 and upregulated CD163 and IL-4 expression in lesional LPP compared with FFA samples. Conclusions This comparative immunopathological analysis is the first to profile systematically the hair follicle immune system in LPP and FFA. Our analysis highlights a potential role of macrophages in disease pathobiology and suggests that macrophage polarization may differ between LPP and FFA, allowing microscopic differentiation. Linked Comment: Kinoshita-Ise. Br J Dermatol 2020; 183:419-420.

The increasing prevalence of atopic dermatitis (AD) parallels a global rise in industrialization and urban living over recent decades. This shift in lifestyle is accompanied by greater cutaneous exposure to environmental pollutants during the course of daily activities. The objectives of this review are to highlight the effects of airborne pollution on epidermal barrier function, examine evidence on the relationship between pollutants and AD, synthesize a proposed mechanism for pollution-induced exacerbation of AD, and identify potential methods for the reduction and prevention of pollutant-induced skin damage. The literature review was done by searching the PubMed, Embase and Google Scholar databases. Inclusion criteria were in vitro and animal studies, clinical trials and case series. Non-English-language publications, review articles and case reports were excluded. Pollutants induce cutaneous oxidative stress and have been shown to damage skin barrier integrity by altering transepidermal water loss, inflammatory signalling, stratum corneum pH and the skin microbiome. AD represents a state of inherent barrier dysfunction, and both long- and short-term pollutant exposure have been linked to exacerbation of AD symptoms and increased AD rates in population studies. Airborne pollutants have a detrimental effect on skin barrier integrity and AD symptoms, and appear to pose a multifaceted threat in AD through several parallel mechanisms, including oxidative damage, barrier dysfunction, immune stimulation and propagation of the itch-scratch cycle. Future research is needed to elucidate specific mechanisms of pollution-induced epidermal barrier dysfunction and to identify efficacious methods of skin barrier repair and protection against pollutant-driven damage.

Lung transplant recipients are at high risk of skin cancer, but precise annual incidence rates of treated skin cancers per patient are unknown.To perform a prospective assessment of the total burden of histologically confirmed squamous cell carcinoma (SCC) and basal cell carcinoma (BCC) and associated factors in lung transplant recipients.A population-based cohort of 125 Queensland lung transplant recipients aged 18 years and over, recruited between 2013 and 2015, were followed to the end of 2016. All underwent dermatological skin examinations at baseline and annually thereafter and patients self-reported all interim treated skin cancers, which were verified against pathology databases. Standard skin cancer risk factors were obtained via questionnaire, and details of medications were acquired from hospital records.During a median follow-up time of 1·7 years, 29 (23%) and 30 (24%) lung transplant recipients with a median duration of immunosuppression of 3·3 years developed SCC and BCC, respectively. The general population age-standardized incidence rates of SCC and BCC were 201 and 171 per 1000 person-years, respectively (based on first primary SCC or BCC during follow-up); however, on accounting for multiple primary tumours, corresponding incidence rates were 447 and 281 per 1000 person-years. Risk of multiple SCCs increased around sixfold in those aged ≥ 60 years and in those with previous skin cancer, and increased around threefold in those treated with the antifungal medication voriconazole. Multiple BCC risk rose threefold from age 60 years and tenfold for patients with previous skin cancer.Lung transplant recipients have very high incidence of multiple primary skin cancers. Close surveillance and assiduous prevention measures are essential. Linked Comment: Proby and Harwood. Br J Dermatol 2020; 183:416-417.

BACKGROUND Hypotrichosis simplex of the scalp (HSS) is characterized by progressive loss of scalp hair that results in almost complete baldness at a young age. HSS is often caused by dominant nonsense mutations in CDSN encoding corneodesmosin, leading to the formation of an amyloid-like material, which interferes with normal hair follicle cycle. OBJECTIVES As gentamicin has been shown to mediate ribosomal read-through, we aimed to ascertain its therapeutic efficacy in a small series of patients carrying a recurrent mutation in CDSN . METHODS We used a green fluorescence reporter assay system, confocal microscopy and Western blot analysis to ascertain in vitro the ability of gentamicin to induce translational read-through across a causative CDSN mutation. RESULTS Using a reporter assay, we initially showed that gentamicin induces read-through activity across an HSS-causing nonsense mutation. Gentamicin was further shown to rescue corneodesmosin translation in primary keratinocytes obtained from a patient with HSS. To validate the in vitro data, we conducted a pilot clinical trial where the scalp of four patients was treated topically with gentamicin for 6 months, demonstrating significant improvement as ascertained by the Severity of Alopecia Tool score. CONCLUSIONS Our findings indicate that topical gentamicin should be considered as a potential therapeutic modality in HSS. What's already known about this topic? Hypotrichosis simplex of the scalp (HSS) is caused by nonsense mutations in CDSN encoding corneodesmosin. The mutant corneodesmosin has been hypothesized to be toxic to the hair follicles, leading to hypotrichosis. Disorders caused by nonsense mutations are amenable to ribosomal read-through using gentamicin. What does this study add? Gentamicin enhanced read-through activity and promoted full-length corneodesmosin synthesis in primary keratinocytes derived from patients carrying a nonsense mutation in CDSN. Topical treatment with gentamicin was found to rescue the hypotrichosis phenotype partially in four patients with HSS. What is the translational message? Topical gentamicin should be considered as a potential treatment for HSS.

Mucous membrane pemphigoid (MMP) is a heterogeneous group of subepidermal autoimmune bullous skin disease (AIBD), which affects mainly various mucous membranes and occasionally skin.1-3 Although oral mucosa is most commonly affected, ocular, nasal, pharyngeal, laryngeal, esophageal and genital mucosae are also involved.2.

CD30, also known as tumor necrosis factor receptor 8 (TNF-R 8), was primarily called Ki-1 and is a cell surface molecule which has first been described from a group of pathologists from Kiel in 1982.1 CD30 can be targeted with the drug brentuximab-vedotin (BV), which is approved for relapsed or refractory CD30+ cutaneous T-cell lymphoma (CTCL) including primary cutaneous anaplastic large cell lymphoma and CD30+ mycosis fungoides and Sezary syndrome.

Wnt signalling is one of the most fundamental molecular pathways for modulating the human hair cycle and is essential for maintaining hair growth1 . We recently identified that the Wnt antagonist, secreted frizzled related protein 1 (SFRP1), prematurely induces catagen in microdissected human scalp hair follicles (HFs) ex vivo1 . SFRP1 is inhibited by the potent hypertrichosis inducing immunosuppressant, cyclosporine A (CsA)2 , and the specific SFRP1 antagonist, WAY-316606, both of which prevent spontaneous catagen development1 .

primary cutaneous anaplastic lymphomas (pcALCL) commonly present as solitary or grouped skin lesions and have a 5-year specific survival greater than 91% (1-3). One study showed that, in cases of extracutaneous extension, 5-year overall survival is 41% (4). At diagnosis some patients have skin and locoregional node involvement but their prognosis is as favorable as that of patients with lesions limited to the skin (1).

Background: Given that unwanted hair growth (hirsutism, hypertrichosis) can cause major psychological distress, new pharmacological treatment strategies with safe and effective hair growth inhibitors that do not destroy the hair follicle (HF) and its stem cells need to be developed. Objectives: To establish if osteopontin-derived fragments may modulate human hair growth given that human HFs express the multifunctional, immunomodulatory glycoprotein, osteopontin. Methods: Our hypothesis was tested ex vivo and in vivo by using a newly generated, toxicologically well-characterized, modified osteopontin-derived peptide (FOL-005), which binds to the HF. Results: In organ-cultured human HFs and scalp skin, and in human scalp skin xenotransplants onto SCID mice, FOL-005 treatment (60 nmol L−1 to 3 μmol L−1) significantly promoted premature catagen development without reducing the number of keratin 15-positive HF stem cells or showing signs of drug toxicity. Genome-wide DNA microarray, quantitative reverse-transcriptase polymerase chain reaction and immunohistochemistry revealed decreased expression of the hair growth promoter, fibroblast growth factor-7 (FGF7) by FOL-005, while cotreatment of HFs with recombinant FGF7 partially abrogated FOL-005-induced catagen promotion. Conclusions: With caveats in mind, our study identifies this osteopontin-derived peptide as an effective, novel inhibitory principle for human hair growth ex vivo and in vivo, which deserves systematic clinical testing in hirsutism and hypertrichosis. What's already known about this topic?. The treatment of unwanted hair growth (hypertrichosis, hirsutism) lacks pharmacological intervention, with only few and often unsatisfactory treatments available. Osteopontin is prominently expressed in human HFs and has been reported to be elevated during catagen in the murine hair cycle. What does this study add?. We tested the effects on hair growth of a novel, osteopontin-derived fragment (FOL-005) ex vivo and in vivo. In human hair follicles, high-dose FOL-005 significantly reduces hair growth both ex vivo and in vivo. What is the translational message?. High-dose FOL-005 may provide a new therapeutic opportunity as a treatment for unwanted hair growth.

Background A subset of patients with bullous pemphigoid (BP) show deposition of IgE in the basement membrane zone (BMZ), yet the relationship between BMZ IgE and the clinical presentation of BP remains unclear. Objectives To investigate the relationship between IgE deposition, IgE levels in serum, and disease severity in patients with BP. Methods We investigated IgE autoantibodies in 53 patients with BP by direct immunofluorescence (DIF), indirect immunofluorescence and enzyme-linked immunosorbent assay. Results Of 53 patients with BP, 23 (43%) had IgE deposition, 10 (19%) of whom were IgE+ and 13 (25%) IgE± according to DIF analyses. Erosion/blister (E/B) Bullous Pemphigoid Disease Area Index (BPDAI) scores were significantly higher in IgE+ patients than in IgE- patients (n = 15), while no significant differences were found for urticaria/erythema BPDAI scores. IgE+ and IgE± patients took longer to reduce their E/B BPDAI score by 75% after systemic corticosteroid treatment. BP180-IgE levels were significantly higher among IgE+ patients than IgE± or IgE- patients (n = 10). Total IgE levels in the serum and blood eosinophil counts did not differ between IgE+, IgE± and IgE- patients. A significant correlation was detected between BP180-IgG and BP180-IgE, but not between BPDAI scores and any of BP180-IgG, BP180-IgE or blood eosinophil count. Conclusions IgE deposition in the BMZ is associated with higher E/B BPDAI scores and longer treatment periods. We conclude that IgE binding in the BMZ may contribute to BP pathogenesis by promoting blister formation. What's already known about this topic? BP180-IgE autoantibodies have an important role in the pathogenesis of bullous pemphigoid (BP). A subset of patients with BP display deposition of IgE within the basement membrane zone (BMZ) of skin tissue. What does this study add? Patients with in vivo IgE deposition in the BMZ displayed higher erosion/blister Bullous Pemphigoid Disease Area Index (BPDAI) scores, while urticaria/erythema BPDAI scores were not significantly different. Patients with in vivo IgE deposition in the BMZ took longer to reduce their erosion/blister BPDAI score by 75% after systemic corticosteroid treatment. BP180-specific IgE levels in serum were higher among patients with linear IgE deposition in the BMZ than in those with granular or no IgE deposition.

Autosomal recessive epidermolytic ichthyosis is a rare skin condition associated with KRT10 loss-of-function mutations. It presents with severe life-threatening clinical manifestations. Here we describe a case of autosomal recessive epidermolytic ichthyosis with an unusually mild, spontaneously improving phenotype. Erythroderma and superficial blistering were present at birth, but the skin recovered and remained almost intact at the age of 1 year. Mild scaling on the neck and skin fragility manifesting as superficial erosions after scratching were the only clinical features as the child grew. As a cause, previously unreported compound heterozygous KRT10 pathogenic variants were found: a nonsense mutation leads to mRNA decay, while the other synonymous variant induces a leaky splice site, explaining the residual keratin 10 expression and mild clinical phenotype. What's already known about this topic? Autosomal recessive epidermolytic ichthyosis is a rare skin condition caused by loss-of-function KRT10 mutations. The clinical phenotype is severe with superficial skin blistering, scaling and hyperkeratosis. What does this study add? Here we extend the mutational and phenotypic spectrum of autosomal recessive epidermolytic ichthyosis. Our case presented with erythroderma and superficial blistering at birth, but the skin recovered and was almost intact at the age of 1 year. The only disease manifestations were mild scaling on the neck and skin fragility appearing as superficial erosions after scratching. The causative factors were found to be one nonsense mutation in KRT10 that leads to mRNA decay, and one synonymous variant that affects the donor splice site of exon 3. We hypothesize that this leaky splice site explains the residual keratin 10 expression and self-improving clinical phenotype.

Background While studies report a lower incidence of skin cancer in white patients with vitiligo compared with controls, the skin cancer incidence in Asian patients with vitiligo is unknown. Objectives To quantify the incidence of melanoma and nonmelanoma skin cancer (NMSC) in Korean patients with vitiligo and compare it with matched nonvitiligo controls. Methods A retrospective matched cohort study was performed with 131 245 incident vitiligo cases and 2 624 900 age- and sex-matched (1 : 20) controls at index date, who were selected from the Korean National Health Insurance database between January 2005 and December 2017. Stratified Cox proportional hazards regression (stratified by sex, birth year and index year) was used to calculate the hazard ratio (HR) of skin cancer in patients with vitiligo. Results Patients with vitiligo were followed up for a mean duration of 6·34 years compared with a follow-up period of 6·27 years for matched controls. Ultraviolet (UV) treatment-adjusted HR for melanoma in patients with vitiligo was 3·32 [95% confidence interval (CI) 2·29-4·81] and 1·29 (95% CI 1·06-1·56) for NMSC. The HRs for melanoma and NMSC in the vitiligo population without a history of UV treatment were 3·37 (95% CI 2·32-4·90) and 1·35 (95% CI 1·11-1·64), respectively. Conclusions In contrast to white patients with vitiligo, the risk of skin cancer was increased in the Korean vitiligo population. However, it is noteworthy that the skin cancer incidence in Korean patients with vitiligo was lower than that of their white counterparts. Owing to possible ethnic differences in the susceptibility to skin cancer, skin cancer surveillance in the vitiligo population may be adjusted for race. What's already known about this topic? Prior studies have reported a lower incidence of melanoma and nonmelanoma skin cancer (NMSC) in white patients with vitiligo compared with nonvitiligo controls. The skin cancer incidence in Asian patients with vitiligo is unknown. What does this study add? In contrast to white patients, the risk of both melanoma and NMSC was increased in Korean patients with vitiligo compared with controls. Owing to possible ethnic differences in susceptibility to skin cancer, skin cancer surveillance in the vitiligo population should be adjusted for race.

Background: Our understanding of the pathogenesis underlying keloid scar formation is still very limited, and the morphological distinction between hypertrophic and keloid scars remains difficult. Objectives: To test whether hypertrophic and keloid scars may reflect an inability to progress from immaturity to the desired mature normotrophic scar phenotype. Methods: Using whole-biopsy imaging and an objectively quantifiable way to analyse immunoreactivity, we have compared the immunohistopathological profiles of young immature scars with mature normotrophic scars, hypertrophic scars, and keloids with their surrounding-normal-skin. Results: Abnormal scars (hypertrophic scars and keloids) maintain the immature scar phenotype, characterized by a CD34− (tumour biomarker) and α-smooth muscle actin (α-SMA)+ (myofibroblast) dermal region. This is in contrast to normal skin, surrounding-normal-skin and mature normotrophic scars that were CD34+/ α-SMA−. Immature, hypertrophic and keloid scars showed abnormal epidermal differentiation (involucrin), but only hypertrophic scars and keloids showed increased epidermal thickness. Immature scars did show increased epidermal and dermal proliferation (Ki67), which was absent from abnormal scars, where mesenchymal hypercellularity (vimentin) and senescence (p16) were predominant. Keloidal collagen and α-SMA were previously considered to distinguish between hypertrophic scars and keloids. However, α-SMA staining was present in both abnormal scar types, while keloidal collagen was present mostly in keloids. There were no obvious signs of heterogeneity within keloid scars, and the surrounding-normal-skin resembled normal skin. Conclusions: Both abnormal scar types showed a unique CD34−/α-SMA+/p16+ scar phenotype, but the differences between hypertrophic scars and keloids observed in this study were of a gradient rather than absolute nature. This suggests that scar progression to the mature normal scar phenotype is, for as yet unknown reasons, hindered in hypertrophic and keloid scars. What's already known about this topic?. Hypertrophic and keloid scars both have sustained epidermal barrier dysfunction, suggesting the persistence of an immature scar phenotype. Morphological distinction between hypertrophic and keloid scars remains a topic of debate, although α-smooth muscle actin (α-SMA) and keloidal collagen have been considered distinguishing features of hypertrophic and keloid scars, respectively. It has been suggested that keloids are not simply homogeneous growths, as heterogeneity within keloid scars and possible involvement of the surrounding-normal-skin have been reported. What does this study add?. An extensive whole-biopsy imaging and quantifiable immunohistochemical assessment of immature, mature normal, hypertrophic and keloid scars, including normal skin surrounding keloids. Hypertrophic and keloid scars maintain dermal characteristics of immature scars, rather than transitioning into the normal mature phenotype. Differences between hypertrophic and keloid scars were of a gradient rather than absolute nature, with keloids showing the more extreme phenotype. There was no obvious heterogeneity within keloids, and the normal skin surrounding keloids resembled normal skin. What is the translational message?. Keloids remain primarily a clinical diagnosis. A raised scar with the CD34−/α-SMA+/p16+ phenotype with strong immunoreactivity for p16 and significant amounts of keloidal collagen, together with a thickened and strongly abnormal involucrin-stained epidermis, would sway the diagnosis towards keloid scars. A hypertrophic scar seems more likely when the CD34−/α-SMA+/p16+ phenotype shows very strong presence of α-SMA+ in large dermal nodules, with lesser p16 staining and absent or negligible keloidal collagen.

Background Chronic pruritus is a distressing symptom associated with various dermatological conditions and systemic diseases. Current treatment options are often inadequate, resulting in impaired quality of life for many patients. An understanding of the underlying mechanisms of itch across pruritic conditions is important for development of effective, targeted treatments for chronic pruritus. Objectives To provide an overview of the pathogenesis of chronic pruritus, focusing on the role of substance P (SP) and neurokinin 1 receptor (NK1 R) in itch signalling, and to describe data supporting NK1 R antagonism as a potential strategy for the treatment of chronic pruritus. Methods A PubMed search was conducted to determine what data were available that investigated the role of SP and NK1 R in itch signalling. Results SP is a neuropeptide that is a mediator of itch signalling. One of the target receptors for SP is NK1 R, which is expressed in the central nervous system and on multiple cell types involved in the initiation and transmission of itch. Studies demonstrating that SP and NK1 R are overexpressed across multiple chronic itch-inducing conditions and that NK1 R antagonism disrupts itch signalling and reduces itch provide a rationale for targeting this pathway as a potential treatment of chronic pruritus across multiple diseases. Conclusions A large and growing body of evidence, including recent phase II clinical studies of NK1 R antagonists, demonstrate that SP and NK1 R play an important role in itch signalling. Additional studies are ongoing to further evaluate the use of NK1 R antagonists for the treatment of chronic pruritus. What's already known about this topic? Chronic pruritus has a significant impact on quality of life. Current treatment options for chronic pruritus are inadequate. Substance P (SP) and neurokinin 1 receptor (NK1 R) have been shown to play a role in itch signalling, and may be a rational target for addressing chronic pruritus. NK1 R antagonists are being evaluated as potential treatment for chronic pruritus. What does this study add? This review provides a compilation of the most up-to-date data elucidating the role of SP and NK1 R in itch signalling, which supports targeting this pathway as a potential treatment of chronic pruritus. NK1 R antagonism disrupts itch signalling and reduces itch. A summary of the latest data on NK1 R antagonists in the treatment of pruritus is provided.

BACKGROUND Extensive exposure to solar ultraviolet radiation (UVR) is the main risk factor for keratinocyte carcinoma (KC), making outdoor workers, including farmers, a high-risk population for KC. The use of sun protection is crucial for KC prevention but is not typically implemented by outdoor workers during their daily tasks. OBJECTIVES To explore the attitudes of Bavarian farmers regarding sun-protective measures in their daily work and to understand perceived barriers and unmet needs. METHODS Farmers were recruited through the Bavarian Farmers Association in Bavaria, Southern Germany. Qualitative semi structured interviews were conducted with participants between December 2017 and March 2018. Interviews were recorded, transcribed verbatim and analysed using qualitative content analysis. RESULTS Twenty farmers (11 women, nine men; nine aged 18-30 years, 11 aged \textgreater 60 years) participated. Knowledge and awareness of UVR exposure and KC, perceived individual barriers to implementing sun-protective measures, individual experiences and farm life-specific circumstances emerged as key areas influencing the perspectives of farmers regarding the primary prevention of KC. Female farmers tended to take a more positive stance on sun protection, whereas male farmers showed a lower overall interest. CONCLUSIONS Knowledge and awareness of KC and UVR exposure is very limited in Bavarian farmers with serious perceived barriers due to the demands of daily agricultural work. Further qualitative studies are needed to identify intervention options that can increase skin cancer awareness and that can successfully overcome real barriers to implementing sun protection.

Background Nonsteroidal anti-inflammatory drugs (NSAIDs) have been postulated as chemopreventive agents for basal cell carcinoma (BCC) and squamous cell carcinoma (SCC), but findings from observational studies have been inconsistent, and clinical trial data are scant. Objectives To examine the association between aspirin and NSAID (nonaspirin) use and the risk of BCC and SCC in a large cohort specifically designed for skin cancer outcomes. Methods We used data from the QSkin Study, a prospective cohort of 43 764 residents of Queensland, Australia (34 630 were included in this study and 23 581 were used in our primary analyses). We used Cox proportional hazards models to estimate the hazard ratios (HRs) between self-reported aspirin and NSAID use 1 year prior to study baseline and the first histologically confirmed BCC or SCC for high-risk (history of skin cancer excisions or more than five actinic lesions treated) and average-to-low-risk participants (no history of skin cancer excision and at most five actinic lesions treated). Results After a median of 3 years of follow-up, 3421 participants developed BCC and 1470 SCC (2288 BCC and 932 SCC with complete covariate information). Among the high-risk group (1826 BCC and 796 SCC), compared with never use, frequent (at least weekly) NSAID use was associated with reduced risk of BCC (HR 0·84, 95% confidence interval 0·71-0.99) but not SCC. Aspirin use was associated with reduced risk of SCC (HR 0·77, 95% confidence interval 0·64-0·93) only among infrequent (less than weekly) users and was not associated with BCC. We observed no association between NSAID or aspirin use and the risk of BCC or SCC among average-to-low-risk participants. Conclusions While some weakly inverse associations were observed between prior use of aspirin or NSAIDs and skin cancer, the inconsistent patterns of associations do not provide convincing evidence that these medications reduce subsequent skin cancer risk. Further data on doses, duration and long-term follow-up may help us to comprehend the cumulative dose effect.

Background The epidermal barrier functions to limit skin infection and inflammation by inhibiting irritant and immunogen invasion. Abundant evidence suggests that psychological stress stemming from crowding, isolation, nicotine smoking, insomnia, mental arithmetic tasks, physical pain, real-life stressors (examinations and marital strain) and lack of positive personality traits may impart both acute and chronic epidermal dysfunction. Objectives To review the relationship between stress and epidermal barrier dysfunction. Methods A review of the PubMed and Embase databases was conducted to identify all English-language case-control, cross-sectional and randomized control trials that have reported the effect of stress on epidermal barrier function. The authors' conclusions are based on the available evidence from 21 studies that met the inclusion and exclusion criteria. Results Psychological stressors upregulate the hypothalamic-pituitary-adrenal axis to stimulate local and systemic stress hormone production. This ultimately leads to aberrant barrier dysfunction, characterized by decreased epidermal lipid and structural protein production, decreased stratum corneum hydration and increased transepidermal water loss. Conclusions This evidence-based review explores the adverse effects of psychological stressors on epidermal barrier function. Future investigations using more real-life stressors are needed to elucidate further their impact on skin physiology and identify practical stress-relieving therapies that minimize and restore epidermal barrier dysfunction, particularly in at-risk populations. What's already known about this topic? The literature reports the negative effect of stress on prolonged wound healing. Less is known about the relationship between stress and epidermal barrier dysfunction, a chronic, superficial wound involving the upper epidermal layers. What does this study add? Psychological stressors impact epidermal barrier function by activating the hypothalamic-pituitary-adrenal axis to stimulate local and systemic stress hormone production. Stress hormones negatively affect the epidermal barrier by decreasing epidermal lipids and structural proteins, decreasing stratum corneum hydration and increasing transepidermal water loss. Identification of such stressors can promote stress-avoidance and stress-reduction behaviours that protect epidermal barrier function and prevent certain dermatological conditions.

Background: Atopic dermatitis (AD) affects children of all skin types. Most research has focused on light skin types. Studies investigating biomarkers in people with AD with dark skin types are lacking. Objectives: To explore skin barrier and immune response biomarkers in stratum corneum (SC) tape strips from children with AD with different skin types. Methods: Tape strips were collected from lesional and nonlesional forearm skin of 53 children with AD and 50 controls. We analysed 28 immunomodulatory mediators, and natural moisturizing factors (NMF) and corneocyte morphology. Results: Interleukin (IL)-1β, IL-18, C-X-C motif chemokine (CXCL) 8 (CXCL8), C-C motif chemokine ligand (CCL) 22 (CCL22), CCL17, CXCL10 and CCL2 were significantly higher (P

BACKGROUND Sun protection factor (SPF) is assessed with sunscreen applied at 2 mg cm-2 . People typically apply around 0·8 mg cm-2 and use sunscreen daily for holidays. Such use results in erythema, which is a risk factor for skin cancer. OBJECTIVES To determine (i) whether typical sunscreen use resulted in erythema, epidermal DNA damage and photoimmunosuppression during a sunny holiday, (ii) whether optimal sunscreen use inhibited erythema and (iii) whether erythema is a biomarker for photoimmunosuppression in a laboratory study. METHODS Holidaymakers (n = 22) spent a week in Tenerife (very high ultraviolet index) using their own sunscreens without instruction (typical sunscreen use). Others (n = 40) were given SPF 15 sunscreens with instructions on how to achieve the labelled SPF (sunscreen intervention). Personal ultraviolet radiation (UVR) exposure was monitored electronically as the standard erythemal dose (SED) and erythema was quantified. Epidermal cyclobutane pyrimidine dimers (CPDs) were determined by immunostaining, and immunosuppression was assessed by contact hypersensitivity (CHS) response. RESULTS There was no difference between personal UVR exposure in the typical sunscreen use and sunscreen intervention groups (P = 0·08). The former had daily erythema on five UVR-exposed body sites, increased CPDs (P < 0·001) and complete CHS suppression (20 of 22). In comparison, erythema was virtually absent (P < 0·001) when sunscreens were used at ≥ 2 mg cm-2 . A laboratory study showed that 3 SED from three very different spectra suppressed CHS by around ~50%. CONCLUSIONS Optimal sunscreen use prevents erythema during a sunny holiday. Erythema predicts suppression of CHS (implying a shared action spectrum). Given that erythema and CPDs share action spectra, the data strongly suggest that optimal sunscreen use will also reduce CPD formation and UVR-induced immunosuppression.

Background The skin is the first organ that manifests changes in response to zinc deficiency. However, the molecular mechanism underlying how zinc is involved in skin homeostasis, especially its epigenetic regulation, is largely unknown. Objectives In this study we demonstrate the importance of zinc levels and the zinc transporter ZIP10 in the epigenetic maintenance of human epidermal homeostasis. Methods Adult human skin, including skin appendages, were stained with anti-ZIP10 antibody. Histone acetyltransferase (HAT) activity was assessed after treating human keratinocytes with ZIP10 small interfering (si)RNAs or the zinc chelator TPEN. ZIP10- or HAT-regulated genes were analysed based on limma bioinformatics analysis for keratinocytes treated with ZIP10 siRNAs or a HAT inhibitor, or using a public database for transcription factors. A reconstituted human skin model was used to validate the role of ZIP10 in epidermal differentiation and the functional association between ZIP10 and HAT. Results ZIP10 is predominantly expressed in the interfollicular epidermis, epidermal appendages and hair follicles. ZIP10 depletion resulted in epidermal malformations in a reconstituted human skin model via downregulation of the activity of the epigenetic enzyme HAT. This decreased HAT activity, resulting from either ZIP10 depletion or treatment with the zinc chelator TPEN, was readily restored by zinc supplementation. Through bioinformatics analysis for gene sets regulated by knockdown of SLC39A10 (encoding ZIP10) and HAT inhibition, we demonstrated that ZIP10 and HATs were closely linked with the regulation of genes related to epidermal homeostasis, particularly filaggrin and metallothionein. Conclusions Our study suggests that ZIP10-mediated zinc distribution is crucial for epidermal homeostasis via HATs. Therefore, zinc-dependent epigenetic regulation could provide alternatives to maintaining healthy skin or alleviating disorders with skin barrier defects.

The outermost layer of skin, the epidermis has evolved to provide a physical barrier of protection from harmful substances and invasion of pathogens. The skin barrier consists in part of highly glycosylated proteins called mucins and the epithelium. Epidermal homeostasis is maintained by the proliferation and differentiation of its basal layer keratinocytes that migrate to the superficial layer of the epidermis, and through its regulated inter-cellular communication with the pigment producing cells, the melanocytes. Science Foundation Ireland Update citation details during checkdate report - ROR

We read with interest the classification of cutaneous manifestations in Coronavirus disease 19 (COVID-19) by C Galvan Casas et al (1) In particular, vesicular eruptions are characterized as monomorphic vesicles, involving the trunk, happening early in the course of the disease, and occasionally preceding other symptoms(1-3) However, investigations to exclude other causes of widespread vesicular eruption, in particular, varicella, were absent In our clinical experience to date, we have had four patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection presenting with vesicular eruptions, which were subsequently confirmed to be true varicella with microbiological and serological investigations

Background To prevent infections that arise from the skin surface it is necessary to decolonize human skin prior to any proposed treatment or surgical intervention. Photodynamic inactivation of bacteria (PIB) uses cationic photosensitizers that attach to the surface of bacteria, generate reactive oxygen species on light irradiation and thereby kill bacteria via oxidative mechanisms. Objectives To evaluate the potential and the safety of PIB for decolonization of bacteria from skin. Methods PIB with the new photosensitizer SAPYR [2-((4-pyridinyl)methyl)-1H-phenalen-1-one chloride] was initially tested against different bacterial species in vitro. Then, ex vivo porcine skin samples were used as a model for decolonization of different bacteria species. The numbers of viable bacteria were quantified and the mitochondrial activity of skin cells was histologically analysed (using nitroblue tetrazolium chloride, NBTC). The same procedure was performed for human skin and meticillin-resistant Staphylococcus aureus (MRSA). Results The in vitro studies showed a 5 log(10) reduction of all tested bacterial species. On ex vivo porcine skin samples, PIB reduced the viability of all tested bacterial species by at least 3 log(10) steps. On human skin samples ex vivo, PIB reduced the number of viable MRSA by maximal 4 center dot 4 log(10) steps (1000 mu mol L-1 SAPYR, incubation time 10 min, 60 J cm(-2)). NBTC staining showed normal mitochondrial activity in skin cells after all PIB modalities. Conclusions The results of this study show that PIB can effectively and safely kill bacteria like MRSA on the skin surface and might have the potential of skin decolonization in vivo.

Summary Background Generalized severe epidermolysis bullosa simplex (EBS‐gen sev) is a genetic blistering skin disease in which autosomal dominant mutations in either the keratin KRT5 or KRT14 genes lead to impaired function of the intermediate filament cytoskeleton in the basal epidermis. Here we present an ex vivo RNA trans‐splicing‐based therapeutic approach to correct the phenotype. Objectives To correct a mutation within exon 1 of the KRT14 gene, using a 5′‐trans‐splicing approach, where any mutation within the first seven exons could be replaced by a single therapeutic molecule. Methods A therapeutic RNA trans‐splicing molecule containing wild‐type exons 1–7 was stably transduced into an EBS patient‐derived keratinocyte line. Trans‐splicing was confirmed via reverse‐transcriptase polymerase chain reaction, Western blotting and immunofluorescence microscopy. Skin equivalents generated from corrected keratinocytes were grafted onto nude mice and analysed about 8 weeks post‐transplantation for regular epidermal stratification, trans‐splicing‐induced green fluorescent protein expression and blistering. Results Transplanted skin equivalents generated from trans‐splicing‐corrected patient keratinocytes showed a stable and blister‐free epidermis. KRT14 correction disrupted EBS‐gen sev‐associated proinflammatory signalling, as shown at the mRNA and protein levels. Disruption of the pathogenic feedback loop in addition to overall downregulation of KRT14 expression highlighted the effect of KRT14 correction on the EBS pathomechanism. Conclusions Our data demonstrate that trans‐splicing‐mediated mRNA therapy is an effective method for the correction of dominantly inherited KRT14 mutations at the transcriptional level. This results in the rescue of the EBS‐gen sev phenotype and stabilization of the epidermis in a xenograft mouse model., What's already known about this topic? RTM163, described in this study, was previously used in a transient in vitro transfection system, where the ability to correct KRT14 at the mRNA level was demonstrated. What does this study add? In this study, we stably transduced RTM163 in a second patient‐derived keratinocyte line.Successful trans‐splicing was confirmed in this cell line.The expression of disease‐related marker genes, which are characteristically deregulated in epidermolysis bullosa simplex, were analysed.For the first time this study showed that RNA trans‐splicing molecule‐transduced patient keratinocytes can differentiate into a phenotypically normal and blister‐free epidermis in a xenograft mouse model. What is the translational message? This study shows the feasibility of using spliceosome‐mediated RNA trans‐splicing to generate a stable and blister‐free epidermis in vivo.Combined with pre‐existing ex vivo gene therapeutic methods, this might be a valid option for future treatments of dominantly inherited genodermatoses. Linked Comment: Bremer and van den Akker. Br J Dermatol 2019; 180:17–19.

BACKGROUND There is no cure or firm clinical recommendations for the treatment of vitiligo. One of the main issues is the heterogeneity of outcome measures used in randomized controlled trials for vitiligo. OBJECTIVES To define successful repigmentation from the patients' point of view and to propose how and when repigmentation should be evaluated in clinical trials in vitiligo. METHODS We conducted three workshops with patients with vitiligo and their parents or caregivers. Workshop 1 was held at World Vitiligo Day (Detroit, MI), workshop 2 at the University of Texas Southwestern Medical Center and workshop 3 at the Vitiligo and Pigmentation Institute of Southern California, University of California. RESULTS Seventy-three participants were recruited. Consensus on the following questions was achieved unanimously: (i) the definition of 'successful repigmentation' was 80-100% of repigmentation of a target lesion and (ii) both an objective and a subjective scale to measure repigmentation should be used. CONCLUSIONS This was the largest patients' outcomes workshop. We followed the guidance from the CSG-COUSIN and the Vitiligo Global Issues Consensus Group. Our recommendations to use percentage of repigmentation quartiles (0-25%, 26-50%, 51-79%, 80-100%) and the Vitiligo Noticeability Scale are based on the best available current evidence. A limitation of the research is that the workshops were conducted only in the U.S.A., due to pre-existing organisational support and the availability of funding.

Background Transepidermal water loss (TEWL) is one of the most important skin barrier characteristics. Higher TEWL is usually associated with skin barrier impairments, and lower TEWL with healthy skin. Objectives To update an existing systematic review and meta-analysis to provide TEWL reference values for healthy skin in adults. Methods The databases MEDLINE and Embase and other sources were searched. This update includes studies identified by two combined searches that cover the period from 1947 to 13 April 2017. Primary empirical observational and interventional studies in healthy adults providing quantitative estimates of TEWL measurements including measures of spread, such as SDs, with clear reporting of skin areas and age were included. Data were extracted per skin area and statistically pooled. Results After full-text assessment, the results of 45 studies were included additionally to the existing meta-analysis. TEWL estimates were identified for 86 skin areas in 212 studies. The lowest TEWL of 2·3 g m-2 h-1 (95% confidence interval 1·9-2·7) was reported for breast skin and the highest TEWL of 44·0 g m-2 h-1 (95% confidence interval 39·8-48·2) for the axilla. Sample sizes ranged from four (forehead middle left middle) to 4013 (mid volar right forearm). The clinical relevance of the difference between TEWL estimates for different measurement devices seems to be minimal. TEWL in elderly patients was either similar to or lower than values in the younger group. Conclusions Reference estimates are useful for clinical study planning and interpretation of results. TEWL is highly dependent on skin area, and our results further support the symmetry between right and left measuring sites. TEWL in elderly people seems to be generally similar or decreased compared with younger individuals, but available evidence is limited. Reporting of TEWL should be improved: mean and spread parameters should always be reported in future studies.

Background Patients with atopic dermatitis (AD) often report that stress aggravates their itch. However, no study has investigated if and how acute stress influences itch sensation and scratching behaviour in these patients. Objectives We evaluated the impact of acute stress on experimentally induced cowhage itch perception and scratching behaviour in 16 healthy subjects and 15 patients with AD. Methods The Trier Social Stress Test (TSST) was used to induce acute stress. The itch sensation, provoked by applying cowhage to the forearms, and off-site scratching behaviour (not directed at the cowhage application site) were compared before and after performing the TSST or the control condition (watching a video of landscape scenes). Results In patients with AD, stress induced by TSST caused a significant reduction of cowhage-evoked itch but significantly increased off-site scratching behaviour. Such changes in itch perception and scratching behaviour were not observed in healthy controls. In addition, a significant positive correlation was noted between stress induced by TSST and clinical severity of eczema. Conclusions We speculate that psychological stress increases spontaneous scratching in patients with AD, which may enhance the vicious cycle of itching and scratching, resulting in aggravation of the skin eczema. These results provide new insights on the mechanism of acute stress-related exacerbation of itch in patients with AD.

Background Adiponectin is an adipocyte-derived cytokine that circulates as a full-length protein and a fragment containing the globular domain of adiponectin (gAd). A recent study has reported the antimelanogenic effects of full-length adiponectin. Objectives To examine the involvement of gAd in melanogenesis and its mechanisms of action. Methods The effects of gAd on melanogenesis and its mechanisms of action were investigated in human epidermal melanocytes and reconstructed epidermis, including melanin content, cellular tyrosinase activity, cyclic adenosine monophosphate (cAMP) production and protein kinase A (PKA) activity, expression and phosphorylation of signalling molecules. Results Exogenous gAd increased melanin content, and the mRNA levels of microphthalmia-associated transcription factor (MITF) and its downstream genes TRP1, but not TRP2, were increased by gAd. However, cAMP production and PKA activity were not affected by gAd. Moreover, attempts to elucidate the underlying mechanism behind the gAd-mediated effect revealed that gAd could regulate melanogenesis by upregulating MITF through phosphorylation of the cAMP response element-binding protein (CREB). In addition, upregulation of MITF was mediated by activation of adenosine monophosphate-activated protein kinase (AMPK)-p38 mitogen-activated protein kinase (MAPK) signalling. Taken together, these findings indicate that promotion of melanogenesis by gAd occurs through increased expression of MITF, which is mediated by activation of the AMPK-p38 MAPK-CREB pathway. Conclusions These findings suggest that gAd contributes to epidermal homeostasis via its effect on melanocyte biology, and products of adipose tissue could affect epidermal biology.

Background Photoageing is attributed to continuous sunlight or artificial ultraviolet exposure and manifests as clinical and histological changes in skin. Epigenetic changes have been found to be involved in the pathogenesis of photoageing. However, the underlying mechanisms are unclear. Objectives To analyse histone modification patterns in sun-exposed and nonexposed skin, and to identify the abnormally histone-modified genes related to photoageing. Methods Skin biopsies were collected from both the outer forearm (sun-exposed area) and the buttock (sun-protected area) in 20 healthy middle-aged female volunteers. Global histone H3/H4 acetylation and H3K4/H3K9 methylation statuses were assessed by enzyme-linked immunosorbent assay. Expression levels of histone acetyltransferases and histone deacetylases were measured by reverse-transcriptase quantitative polymerase chain reaction (qPCR) and Western blot. Chromatin immunoprecipitation combined with DNA microarray (ChIP-chip) assay with anti-acetyl-histone H3 antibody in a sun-exposed pool (combining six sun-exposed skin samples) and a nonexposed pool (combining six nonexposed skin samples) was conducted to explore the abnormally acetylated histone H3 genes related to photoageing; ChIP-qPCR was then used to verify the results of ChIP-chip. Results We observed higher global histone H3 acetylation levels increased EP300 and decreased HDAC1 and SIRT1 expression in sun-exposed skin compared with matched nonexposed skin. Furthermore, the ChIP-chip assay showed that 227 genes displayed significant hyperacetylation of histone H3, and 81 genes displayed significant hypoacetylation of histone H3 between the two groups. Histone H3 acetylation levels on the promoters of PDCD5, ITIH5, MMP1 and AHR were positively correlated with the mRNA expression of the corresponding gene. Conclusions Chronic sun exposure-induced histone H3 hyperacetylation may play a critical role in the pathogenesis of skin photoageing.