Atopic dermatitis microbiomes stratify into ecologic dermotypes enabling microbial virulence and disease severity.

BACKGROUND: Atopic dermatitis (AD) is a common skin disease affecting up to 20% of the global population, with significant clinical heterogeneity and limited information about molecular subtypes and actionable biomarkers. Although alterations in the skin microbiome have been described in subjects with AD during progression to flare state, the prognostic value of baseline microbiome configurations has not been explored. OBJECTIVE: Our aim was to identify microbial signatures on AD skin that are predictive of disease fate. METHODS: Nonlesional skin of patients with AD and healthy control subjects were sampled at 2 time points separated by at least 4 weeks. Using whole metagenome analysis of skin microbiomes of patients with AD and control subjects (n = 49 and 189 samples), we identified distinct microbiome configurations (dermotypes A and B). Blood was collected for immunophenotyping, and skin surface samples were analyzed for correlations with natural moisturizing factors and antimicrobial peptides. RESULTS: Dermotypes were robust and validated across 2 additional cohorts (63 individuals), with strong enrichment of subjects with AD in dermotype B. Dermotype B was characterized by reduced microbial richness, depletion of Cutibacterium acnes, Dermacoccus and Methylobacterium species, individual-specific outlier abundance of Staphylococcus species (eg, S epidermidis, S capitis, S aureus), and enrichment in metabolic pathways (eg, branched chain amino acids and arginine biosynthesis) and virulence genes (eg, ß-toxin, δ-toxin) that defined a pathogenic ecology. Skin surface and circulating host biomarkers exhibited a distinct microbial-associated signature that was further reflected in more severe itching, frequent flares, and increased disease severity in patients harboring the dermotype B microbiome. CONCLUSION: We report distinct clusters of microbial profiles that delineate the role of microbiome configurations in AD heterogeneity, highlight a mechanism for ongoing inflammation, and provide prognostic utility toward microbiome-based disease stratification.

Belinostat resolves skin barrier defects in atopic dermatitis by targeting the dysregulated miR-335:SOX6 axis.

BACKGROUND: Atopic dermatitis (AD) is a common chronic inflammatory skin disease. Skin barrier defects contribute to disease initiation and development; however, underlying mechanisms remain elusive. OBJECTIVE: To understand the underlying cause of barrier defect, we investigated aberrant expression of specific microRNAs (miRNAs) in AD. Delineating the molecular mechanism of dysregulated miRNA network, we focused on identification of specific drugs that can modulate miRNA expression and repair the defective barrier in AD. METHODS: A screen for differentially expressed miRNAs between healthy skin and AD lesional skin resulted in the identification of miR-335 as the most consistently downregulated miRNA in AD. Using in silico prediction combined with experimental validation, we characterized downstream miR-335 targets and elucidated the molecular pathways by which this microRNA maintains epidermal homeostasis in healthy skin. RESULTS: miR-335 was identified as a potent inducer of keratinocyte differentiation; it exerts this effect by directly repressing SOX6. By recruiting SMARCA complex components, SOX6 suppresses epidermal differentiation and epigenetically silences critical genes involved in keratinocyte differentiation. In AD lesional skin, miR-335 expression is aberrantly lost. SOX6 is abnormally expressed throughout the epidermis, where it impairs skin barrier development. We demonstrate that miR-335 is epigenetically regulated by histone deacetylases; a screen for suitable histone deacetylase inhibitors identified belinostat as a candidate drug that can restore epidermal miR-335 expression and rescue the defective skin barrier in AD. CONCLUSION: Belinostat is of clinical significance not only as a candidate drug for AD treatment, but also as a potential means of stopping the atopic march and further progression of this systemic allergic disease.

Cost-effectiveness study of pediatric atopic dermatitis in Asia: atopiclair vs. regular emollient (AD-ATOP).

BACKGROUND: Atopic dermatitis (AD) is a highly prevalent, chronic relapsing condition in childhood with significant financial burden and impact on the quality of life of patients and caregivers. Proactive maintenance treatment with moisturizing agents is the mainstay AD therapy. OBJECTIVES: The aim of this study was to assess the cost-effectiveness of a non-steroidal barrier cream (Atopiclair), compared to regular emollient in pediatric patients with mild-to-moderate AD. METHODS: A Markov decision model was developed to evaluate the cost-effectiveness of Atopiclair versus regular emollient in 12 Asia-Pacific countries, grouped by income categories based on gross domestic product (GDP) per capita. Data was obtained from structured literature review, expert opinion, fee schedules, and findings from a 2012 survey of 12 Asia-Pacific countries. Analysis was performed a societal perspective. RESULTS: In the base case analysis, Atopiclair was cost-effective against regular emollient, with USD786, USD499, and USD289 in cost savings per year for high, middle, and low-income countries, respectively. Sensitivity analyses showed that Atopiclair remained cost-effective versus regular emollient. CONCLUSIONS: Modelling analysis showed that Atopiclair is a cost-effective treatment compared to regular emollient for mild-to-moderate pediatric AD in the countries included in the study.

A prospective study on the use of teledermatology in psychiatric patients with chronic skin diseases.

BACKGROUND: To compare the use of live interactive teledermatology versus conventional face-to-face consultation in long-term, institutionalised psychiatric patients with chronic skin diseases. METHODS: All institutionalised psychiatric patients at the Institute of Mental Health with follow-up appointments at the National Skin Centre were assessed for eligibility and invited to participate. Recruited patients were first seen by a dermatologist via videoconferencing, and then by another dermatologist in person, within 1 week. Clinical outcome measures were then assessed by a third independent dermatologist. The following outcome measures were assessed for each paired patient visit: inter-physician clinical assessment, diagnosis, management plan, adverse events and total patient turnaround time (PTAT) for each consultation. RESULTS: There were a total of 13 patients (mean age, 64.6 years; range 44-80) with 27 patient visits. All were male patients with chronic schizophrenia. The predominant skin condition was chronic eczema and its variants (62%), followed by cutaneous amyloidosis (23%) and psoriasis (15%). The level of complete and partial agreement between the teledermatology and face-to-face consultation was 100% for history-taking and physical examination and 96% for the investigations, diagnosis, management plan and the treatment prescribed. The PTAT for teledermatology was 23 min, compared to 240 min for face-to-face consultations. No adverse events were reported. CONCLUSION: Teledermatology was as effective as face-to-face consultation and reduced the PTAT by 90%, resulting in increased patient convenience, operational efficiency and reduced manpower need. Our study supports the safe and cost-effective use of teledermatology for the follow-up of chronic skin conditions in psychiatric patients.

Atopic dirty neck or acquired atopic hyperpigmentation? An epidemiological and clinical study from the National Skin Centre in Singapore.

BACKGROUND: 'Atopic dirty neck' is a poorly understood acquired hyperpigmentation in patients with atopic dermatitis (AD). OBJECTIVE: To report a single-centre experience with synthesis of this entity's features. METHODS: All patients with AD with dirty neck seen over a 5-month period at the National Skin Centre were invited to participate. RESULTS: Out of 544 AD patients examined, 78 (14.3%) had acquired pigmentation of the neck. The majority had moderate-to-severe underlying eczema. Histopathology showed increased epidermal melanin and dermal melanophages, a thickened basement membrane and a dense superficial perivascular infiltrate. CONCLUSION: Acquired atopic hyperpigmentation has a high prevalence, particularly in adolescent Asian males. Clinico-pathological correlation suggests it results from both frictional melanosis and post-inflammatory hyperpigmentation. The rippled appearance and the onset in adolescence are probably due to accentuation of the juxta-clavicular beaded lines. Optimal control of eczema may improve and potentially prevent the development, which is of importance considering the psychosocial impact of the condition.

Pediatric mycosis fungoides in Singapore: a series of 46 children.

Few studies have evaluated Asian children with mycosis fungoides (MF). We report a series of patients from a tertiary dermatologic institution in Singapore. A retrospective review was performed of patients younger than 16 years old diagnosed with MF between 2000 and 2008 at the National Skin Centre, Singapore. Forty-six patients were identified. At initial presentation, a provisional diagnosis of MF was made in 19 patients (41.3%), pityriasis lichenoides chronica (PLC) in 11 (23.9%) and postinflammatory hypopigmentation due to eczema or other causes in 11 (23.9%). After skin biopsy, the hypopigmented variant of MF was diagnosed in 42 patients (91.3%). There was one case each of PLC-like MF, pigmented purpuric dermatosis-like MF, classic MF, and solitary MF. Pityriasis lichenoides coexisted in three cases (6.5%). All except one patient presented with the early patch-plaque stage of disease (stage IA/B). The disease did not progress in any of our patients after a mean follow-up of 71.0 ± 52.5 months. Twenty-seven patients (58.7%) had complete disease clearance after a mean duration of 27.1 ± 28.1 months; 15 (49.7%) of 32 patients who received narrowband ultraviolet B treatment had complete clearance within an average of 8.9 ± 5.3 months, but 7 patients relapsed within 14.9 ± 14.8 months. One patient with solitary MF failed multiple treatment modalities before eventually achieving disease clearance with photodynamic therapy. Hypopigmented MF is the most common MF variant in Asian children. The diagnostic difficulty is in differentiating this from PLC, which may coexist with MF. Long-term prognosis is generally favorable.

A retrospective review of the therapeutic response with remission in patients with newly diagnosed bullous pemphigoid.

We reviewed the clinical characteristics and therapeutic response in cases of newly diagnosed bullous pemphigoid at the National Skin Centre between June 2009 and December 2010. Most (76%, n = 68/90) achieved clinical remission within 6 months of commencement of therapy. Oral mucosal involvement was identified as a risk factor associated with a prolonged duration of treatment beyond 6 months.

Chronic leg ulcers in adult patients with rheumatological diseases - a 7-year retrospective review.

Chronic leg ulcers in patients with rheumatological diseases can cause significant morbidity. We performed a retrospective case review to describe the epidemiology, clinical features and outcome of chronic leg ulcers in this group of patients. Twenty-nine patients with underlying rheumatological conditions, such as, rheumatoid arthritis (15 patients), systemic lupus erythematosus (8 patients), overlap syndromes (3 patients), systemic sclerosis (1 patient) and ankylosing spondylitis (1 patient) were included. The ulcers were mostly located around the ankle (55·2%) and calves (37·9%). The predominant aetiology of the ulcers, in decreasing order of frequency, was venous disease, multifactorial, vasculitis or vasculopathy, infective, pyoderma gangrenosum, ischaemic microangiopathy and iatrogenic. Treatment modalities included aggressive wound bed preparation, compression therapy (17 patients), changes in immunosuppressive therapy (15 patients), hyperbaric oxygen therapy (4 patients) and cellular skin grafting (2 patients). Management of chronic leg ulcers in rheumatological patients is challenging and the importance of careful clinicopathological correlation and treatment of the underlying cause cannot be overemphasised.

A synergistic capture strategy for enhanced detection and elimination of bacteria.

Despite the advanced detection and sterilization techniques available today, the sensitive diagnosis and complete elimination of bacterial infections remain a significant challenge. A strategy is reported for efficient bacterial capture (ca. 90%) based on the synergistic effect of the nanotopography and surface chemistry of the substrate on bacterial attachment and adhesion. The outstanding bacterial-capture capability of the functionalized nanostructured substrate enables rapid and highly sensitive bacterial detection down to trace concentrations of pathogenic bacteria (10 colony-forming units mL(-1)). In addition, this synergistic biocapture substrate can be used for efficient bacterial elimination and shows great potential for clinical antibacterial applications.

Similarities and Differences in the Perception of Atopic Dermatitis Burden Between Patients, Caregivers, and Independent Physicians (AD-GAP Survey).

INTRODUCTION: Atopic dermatitis (AD)-a chronic inflammatory skin disease characterized by intense itching-can have a detrimental impact on quality of life (QoL). We report results of a quantitative assessment of pediatric patient, caregiver, and physician perceptions of AD burden in children and adolescents. METHODS: Pediatric patients (aged 6-11 [children] or 12-17 [adolescents] years) with moderate-to-severe AD, their caregivers, and independent physicians were recruited in 13 countries. Caregivers and their children/adolescents completed an online survey about the impact of AD on 16 key items of patient QoL. Physicians completed surveys on their patients aged 6-11 and 12-17 years. Best-worst scaling was used to rank the importance of the QoL items. RESULTS: Overall, 1447 children/adolescents with moderate-to-severe AD (aged 6-11 years: 701; 12-17 years: 746), 1447 caregivers, and 1092 physicians participated. Patients and caregivers in both age groups ranked disturbed sleep as the most important QoL item, followed by feeling ashamed because of AD. Independent physicians ranked feeling ashamed because of AD as the most important QoL item for both age groups, followed by disturbed sleep for those aged 6-11 years and being singled out for those aged 12-17 years. The relative importance of the 16 QoL items to patients was strongly aligned between patients in both age groups and their caregivers, but somewhat less so between patients and physicians. Between-country differences were more apparent in physician- versus patient-/caregiver-reported results. CONCLUSION: The most burdensome QoL items were impact of AD on sleep and feeling ashamed. Caregivers and physicians correctly identified the QoL items most burdensome to patients. However, patient and caregiver perceptions were generally more closely aligned than patient and physician perceptions. Between-country differences in perceptions (particularly for physicians) were observed, probably due to multifactorial reasons, necessitating further evaluation. Video Abstract (MP4 42,877 kb) INFOGRAPHIC.

Epidemiology of adult patients with atopic dermatitis in AWARE 1: A second international survey.

Background: There are gaps in our understanding of the epidemiology of atopic dermatitis (AD) in adults. Objective: To evaluate the prevalence and severity of AD in adults from countries/regions within Asia, Eurasia, Latin America, Middle East, and Russia. Methods: This international, web-based survey was performed in Argentina, Brazil, China, Colombia, Egypt, Hong Kong, Israel, Malaysia, Mexico, Russia, Kingdom of Saudi Arabia (KSA), Singapore, Taiwan, Thailand, Turkey, and United Arab Emirates. Questionnaires were sent to adult members of online respondent panels for determination of AD and assessment of severity. A diagnosis of AD required respondents to meet the modified United Kingdom (UK) Working Party criteria and to self-report they had a physician diagnosis of AD. Severity of AD was determined using Patient-Oriented Scoring of Atopic Dermatitis (PO-SCORAD), Patient-Oriented Eczema Measure (POEM), and Patient Global Assessment (PGA). Results: Among respondents by country/region the prevalence of AD ranged from 3.4% in Israel to 33.7% in Thailand. The prevalence was generally higher in females versus males. Severity varied by scale, although regardless of scale the proportion of respondents with mild and moderate disease was higher than severe disease. PGA consistently resulted in the lowest proportion of severe AD (range 2.4% China - 10.8% Turkey) relative to PO-SCORAD (range 13.4% China - 41.6% KSA) and POEM (range 5.1% China - 16.6% Israel). Conclusions: This survey highlights the importance of AD in adults, with high prevalence and high morbidity among respondents and emphasizes that AD is not just a disease of childhood-there is disease persistence and chronicity in adults.

Physician Perception of Disease Severity and Treatment Outcomes for Children and Adolescents with Atopic Dermatitis in Emerging Economies.

INTRODUCTION: Pediatric atopic dermatitis (AD) leads to a considerable reduction in quality of life for patients and their families. Therapeutic options for pediatric patients with moderate-to-severe disease are limited and treatment is challenging. As little is understood about physician perceptions of pediatric AD in countries with emerging healthcare, we conducted a questionnaire-based study to identify treatment patterns and gaps. METHODS: Physicians treating children (aged 6-11 years) and adolescents (aged 12-17 years) with AD in 11 emerging economy countries were interviewed regarding their beliefs and behaviors relating to the disease. Physicians gave an initial assessment of patient disease severity and control, which was then compared with patient records and pre-specified criteria to assess concordance and discordance between physician perception and recorded patient presentation. RESULTS: A total of 574 physicians completed the study, with an assessment of 1719 patients. Only 51% of patients whose disease criteria matched 'severe disease' to pre-specified criteria and SCORing Atopic Dermatitis scores (SCORAD) were also initially identified by physicians as having severe disease. Patients with moderate-to-severe disease experienced flares for an average of 263 days in the preceding year. Ninety and 74% of patients experienced chronic flares and unpredictable flares, respectively. Control of flares could only be achieved within 7 days in 14% (n = 153) of patients. Most physicians listed elimination of skin symptoms as their primary treatment goal, and for moderate and severe cases, 59% and 33% of physicians reported that they were able to achieve this respectively. Nearly 24% and 40% of physicians were slightly dissatisfied with the treatment options for moderate disease and severe disease and severe disease, respectively. CONCLUSIONS: AD severity of children (aged 6-11 years) and adolescents (aged 12-17 years) appears to be underestimated by physicians in emerging economy countries. Practical, easy-to-use, and validated objective measures for assessment of disease severity and control, as well as effective use of novel therapies, are essential to ensure that patients are appropriately managed.

Atopic dermatitis (AD) is a common childhood disease that occurs in up to 30% of individuals under 18 years of age. Although most forms are mild, more severe disease forms of AD including symptoms such as pruritus, xerosis, lichenification, and excoriation of the skin can cause significant problems, such as lack of sleep, lack of productivity, poor self-image, and mental health disorders among patients. It also places a burden on patients' families, which affects home, school, and work life. In children with moderate-to-severe disease, treatment options are limited especially since doctors may not be keen to prescribe high-dose treatments to children such as potent and super-potent topical corticoid steroids and progress to systemic therapies. Relatively little is understood about how doctors determine whether the disease is mild, moderate, or severe and what they consider to be the best treatment options for patients. Therefore, we conducted a series of interviews with doctors in 11 countries with emerging healthcare to better understand their beliefs and behaviors about treating childhood AD. Our results indicated that doctors tended to underestimate the severity of a patient's disease. Additionally, 59% of doctors felt that they were able to successfully eliminate itching and skin syndrome frequently (that is, in 70% or more of their patients) in patients with moderate disease and 33% of doctors for their patients with severe disease. These results suggest that there are many unmet needs in the treatment of children and adolescents with AD in emerging economies, whose treatment could be further optimized. Improving how doctors measure the severity of a patient's disease should help them select the most appropriate and effective treatments for their patients.

Angiopoietin-like 4 interacts with matrix proteins to modulate wound healing.

A dynamic cell-matrix interaction is crucial for a rapid cellular response to changes in the environment. Appropriate cell behavior in response to the changing wound environment is required for efficient wound closure. However, the way in which wound keratinocytes modify the wound environment to coordinate with such cellular responses remains less studied. We demonstrated that angiopoietin-like 4 (ANGPTL4) produced by wound keratinocytes coordinates cell-matrix communication. ANGPTL4 interacts with vitronectin and fibronectin in the wound bed, delaying their proteolytic degradation by metalloproteinases. This interaction does not interfere with integrin-matrix protein recognition and directly affects cell-matrix communication by altering the availability of intact matrix proteins. These interactions stimulate integrin- focal adhesion kinase, 14-3-3, and PKC-mediated signaling pathways essential for effective wound healing. The deficiency of ANGPTL4 in mice delays wound re-epithelialization. Further analysis revealed that cell migration was impaired in the ANGPTL4-deficient keratinocytes. Altogether, the findings provide molecular insight into a novel control of wound healing via ANGPTL4-dependent regulation of cell-matrix communication. Given the known role of ANGPTL4 in glucose and lipid homeostasis, it is a prime therapeutic candidate for the treatment of diabetic wounds. It also underscores the importance of cell-matrix communication during angiogenesis and cancer metastasis.

Angiopoietin-like 4 interacts with integrins beta1 and beta5 to modulate keratinocyte migration.

Adipose tissue secretes adipocytokines for energy homeostasis, but recent evidence indicates that some adipocytokines also have a profound local impact on wound healing. Upon skin injury, keratinocytes use various signaling molecules to promote reepithelialization for efficient wound closure. In this study, we identify a novel function of adipocytokine angiopoietin-like 4 (ANGPTL4) in keratinocytes during wound healing through the control of both integrin-mediated signaling and internalization. Using two different in vivo models based on topical immuno-neutralization of ANGPTL4 as well as ablation of the ANGPTL4 gene, we show that ANGPTL4-deficient mice exhibit delayed wound reepithelialization with impaired keratinocyte migration. Human keratinocytes in which endogenous ANGPTL4 expression was suppressed by either siRNA or a neutralizing antibody show impaired migration associated with diminished integrin-mediated signaling. Importantly, we identify integrins ß1 and ß5, but not ß3, as novel binding partners of ANGPTL4. ANGPTL4-bound integrin ß1 activated the FAK-Src-PAK1 signaling pathway, which is important for cell migration. The findings presented herein reveal an unpredicted role of ANGPTL4 during wound healing and demonstrate how ANGPTL4 stimulates intracellular signaling mechanisms to coordinate cellular behavior. Our findings provide insight into a novel cell migration control mechanism and underscore the physiological importance of the modulation of integrin activity in cancer metastasis.

Fas-ligand staining in non-drug- and drug-induced maculopapular rashes.

BACKGROUND: Morphologically and histopathologically, drug- and non-drug-induced maculopapular rashes can be almost indistinguishable. It has been postulated that Fas-ligand (Fas-L) is involved in the pathogenesis of drug rashes but not in the genesis of rashes, such as viral exanthems, that are not induced by medications. AIM: This study sought to determine if epidermal Fas-L is a distinguishing feature in the pathology of drug and non-drug maculopapular rashes. METHODS: Archived skin biopsies of patients with a confirmed diagnosis of drug or non-drug maculopapular rashes (n = 10 each) and positive and negative controls were retrieved for immunohistochemical staining for Fas-L. The proportion of Fas-L-positive skin biopsies were compared. The presence of tissue eosinophilia was also evaluated. RESULTS: Ten percent of non-drug-induced rashes were Fas-L positive compared to 50% of drug rashes (p = 0.05). Twenty percent of non-drug exanthems had moderate tissue eosinophilia, while 60% from drug rashes had moderate to dense tissue eosinophilia (p = 0.17). CONCLUSION: There is a trend toward Fas-L being more prevalent in the epidermis of drug maculopapular rashes, although this did not reach statistical significance. This is possibly because of the small sample size.

Use of complementary and alternative medicine among dermatology outpatients in Singapore.

BACKGROUND/OBJECTIVES: Although the prevalence of complementary and alternative medicine (CAM) use has been studied among general and specific disease populations, little is known on the use of CAM among Asian dermatology patients. This study assesses prevalence, demographics, disease determinants, expectations and reasons for CAM use among patients visiting a major referral dermatology centre in Singapore. METHODS: A descriptive cross-sectional study of 855 dermatology outpatients was done. Consecutive sampling using interviewer-administered questionnaires collected information on patient demographics, dermatological condition, prevalence, reasons and expectations of CAM use. Patient-perceived disease severity was measured via the Dermatological Life Quality Index (DLQI). Dermatologists completed Patient Data Forms, detailing diagnosis, diagnosis date and CAM use. RESULTS: The prevalence of CAM use was 25.7%. Patients who were higher educated, held white collar occupations, had longer disease duration, higher DLQI scores or were suffering from psoriasis or eczema were more likely to have used CAM. More than 60% of patients expected dermatologists to provide at least basic CAM advice and 75% were willing to declare their CAM use. Forty percent of dermatologists accurately knew their patients' current CAM use. CONCLUSIONS: Prevalence of CAM use in dermatology patients was high. Many doctors were unaware of patients' CAM use despite most patients being willing to declare it. Patients generally expected dermatologists to provide CAM advice. Dermatologists should make a concerted effort to identify likely CAM users and consider openly discussing CAM use with them.

Mixed Individual-Aggregate Data on All-Cause Mortality in Bullous Pemphigoid: A Meta-analysis.

Importance: The 1-year standardized mortality ratio (SMR) of bullous pemphigoid (BP) has been reported as 2.15 to 7.56 and lower in the US than in Europe. Objective: To estimate the worldwide 1-year SMR of BP. Data Sources: PubMed, Embase, Cochrane Library, Google Scholar, Lissa, and gray literature (eg, medRxiv) were screened for studies of BP published from inception to June 10, 2020, with review of reference lists. Study Selection: Retrospective and prospective studies reporting 1-year all-cause mortality rate in patients with BP and providing age statistics (eg, mean [SD]). Data Extraction and Synthesis: Two reviewers independently extracted the data. The 1-year SMR was computed in studies reporting 1-year mortality by combining information on age obtained from studies with aggregate data and individual data. Risk of representativity, misclassification, and attrition bias were assessed by a custom tool. Main Outcomes and Measures: The primary end point was the worldwide 1-year SMR. Secondary analysis included comparison of 1-year SMRs between continents in a meta-regression. Results: Three studies were performed in the US (n = 260), 1 in South America (n = 45), 16 in Asia (n = 1903), and 36 in Europe (n = 10 132) for a total of 56 unique studies and 12 340 unique patients included in the meta-analysis (mean [SD] age, 77.3 [12.7] years; 55.9% women). The mean (SD) patient age in the United States was 75.6 (13.7) years; in Asia, 73.8 (13.6) years; and in Europe, 78.1 (12.3) years. The worldwide 1-year SMR was estimated at 2.93 (95% CI, 2.59-3.28; I2 = 85.6%) for all 56 studies. The 1-year SMR in the US was 2.40 (95% CI, 0.89-3.90; I2 = 86.3%) for 3 studies; in Asia, 3.53 (95% CI, 2.85-4.20; I2 = 86.3%) for 16 studies; and in Europe, 2.77 (95% CI, 2.35-3.19; I2 = 86.3%) for 36 studies. After adjustment on the expected 1-year mortality rate, the European 1-year SMR did not differ significantly from the 1-year SMR in the United States (-0.48 vs Europe; 95% CI, -2.09 to 1.14; P = .56) and Asia (0.51 vs Europe; 95% CI, -0.56 to 1.58; P = .35). Risk of attrition bias was high (>10% censorship) in 16 studies (28.6%), low in 16 (28.6%), and unclear in 24 (42.9%). Only 4 studies (7.1%) had a sampling method guaranteeing the representativity of BP cases in a population. Conclusions and Relevance: Although heterogeneity was high and overall quality of follow-up was poor, this meta-analysis confirms the high mortality rate among patients with BP.

Single-cell analysis of human skin identifies CD14+ type 3 dendritic cells co-producing IL1B and IL23A in psoriasis.

Inflammatory skin diseases including atopic dermatitis (AD) and psoriasis (PSO) are underpinned by dendritic cell (DC)-mediated T cell responses. Currently, the heterogeneous human cutaneous DC population is incompletely characterized, and its contribution to these diseases remains unclear. Here, we performed index-sorted single-cell flow cytometry and RNA sequencing of lesional and nonlesional AD and PSO skin to identify macrophages and all DC subsets, including the newly described mature LAMP3+BIRC3+ DCs enriched in immunoregulatory molecules (mregDC) and CD14+ DC3. By integrating our indexed data with published skin datasets, we generated a myeloid cell universe of DC and macrophage subsets in healthy and diseased skin. Importantly, we found that CD14+ DC3s increased in PSO lesional skin and co-produced IL1B and IL23A, which are pathological in PSO. Our study comprehensively describes the molecular characteristics of macrophages and DC subsets in AD and PSO at single-cell resolution, and identifies CD14+ DC3s as potential promoters of inflammation in PSO.

Regulation of cell proliferation and migration by TAK1 via transcriptional control of von Hippel-Lindau tumor suppressor.

Skin maintenance and healing after wounding requires complex epithelial-mesenchymal interactions purportedly mediated by growth factors and cytokines. We show here that, for wound healing, transforming growth factor-beta-activated kinase 1 (TAK1) in keratinocytes activates von Hippel-Lindau tumor suppressor expression, which in turn represses the expression of platelet-derived growth factor-B (PDGF-B), integrin beta1, and integrin beta5 via inhibition of the Sp1-mediated signaling pathway in the keratinocytes. The reduced production of PDGF-B leads to a paracrine-decreased expression of hepatocyte growth factor in the underlying fibroblasts. This TAK1 regulation of the double paracrine PDGF/hepatocyte growth factor signaling can regulate keratinocyte cell proliferation and is required for proper wound healing. Strikingly, TAK1 deficiency enhances cell migration. TAK1-deficient keratinocytes displayed lamellipodia formation with distinct microspike protrusion, associated with an elevated expression of integrins beta1 and beta5 and sustained activation of cdc42, Rac1, and RhoA. Our findings provide evidence for a novel homeostatic control of keratinocyte proliferation and migration mediated via TAK1 regulation of von Hippel-Lindau tumor suppressor. Dysfunctional regulation of TAK1 may contribute to the pathology of non-healing chronic inflammatory wounds and psoriasis.