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BACKGROUND: Psoriasis is a chronic inflammatory skin disorder that affects 125 million people worldwide, with one-third having childhood onset. OBJECTIVES: The PURPOSE study evaluated long-term safety and effectiveness of etanercept in paediatric psoriasis. MATERIALS & METHODS: This observational study enrolled patients with paediatric psoriasis who were prescribed etanercept per routine care in eight EU countries. Patients were followed retrospectively (first dose prior to 30 days before enrolment) or prospectively (first dose within 30 days prior to or any time after enrolment) for five years. Safety endpoints included serious infections, opportunistic infections, malignancies, other serious adverse events (SAEs) and adverse events. Effectiveness endpoints (prospective patients) included treatment patterns, dose change/discontinuation, and physicians' global subjective assessment of change in disease severity from baseline to follow-up. RESULTS: In total, 72 patients were enrolled (32 prospectively, 40 retrospectively), with mean age of 14.5 years and mean disease duration of 7.1 years. No serious or opportunistic infections/malignancies were reported. Psoriasis (n=8) and subcutaneous tissue disorders (system organ class) (erythema nodosum, erythrodermic psoriasis; n=1 for each) were the most frequently reported SAEs, which occurred in six (8.3%) patients with current/recent treatment and four (7.4%) with previous treatment. Of 25 treatment-emergent SAEs, seven (28.0%) were possibly related to etanercept. Assessments of prospective patients revealed that 28 (87.5%) completed 24 weeks, five (15.6%) required at least one subsequent course, and 93.8% experienced decreased disease severity. It is possible that some rare adverse events were not noted in this relatively small sample. CONCLUSION: These real-world data are consistent with the known safety and efficacy profile of etanercept in paediatric patients with moderate to severe plaque psoriasis.

Introduction In the real-world APPRECIATE study (NCT02740218), most patients with psoriasis demonstrated notable improvements on disease severity measures and reported clinically meaningful treatment benefits with apremilast. Objective We aim to further describe patient-relevant needs and benefits and patient satisfaction with apremilast, including subgroup analyses based on patient characteristics. Methods APPRECIATE, a multinational, retrospective, cross-sectional study, enrolled patients with chronic plaque psoriasis who started apremilast according to the European label. Patient Benefit Index (PBI; range 0 (no patient-relevant benefit) to 4 (maximum patient-relevant benefit), global PBI score ≥ 1 indicating minimum patient-relevant benefit and ≥ 3 indicating high benefit) and nine-item Treatment Satisfaction Questionnaire for Medication (TSQM-9; range 0–100) were assessed 6 (± 1) months after apremilast initiation and summarized descriptively. Relationships between global PBI and TSQM-9 assessments were analyzed by Pearson correlations. Results Of 480 enrolled patients, 347 (72.3%) had remained on apremilast at 6 (± 1) months; 90.9% (300/330) achieved global PBI score ≥ 1. Mean (standard deviation) global PBI score was 2.8 (1.2). Higher achievement of global PBI score ≥ 3 was observed in patients with no prior treatments (61.1% (22/36)) or prior phototherapy (64.6% (42/65)) versus prior conventional systemic (54.4% (100/184)) or biologic (38.6% (17/44)) treatment. Strong correlations were observed between the global PBI score and the TSQM-9 global satisfaction and effectiveness subscale scores. Conclusion Patients continuing apremilast for 6 (± 1) months in APPRECIATE reported patient-relevant treatment benefits. Findings suggest that receiving apremilast earlier versus later in treatment management is consistent with greater improvements in patient-relevant treatment outcomes. Supplementary Information The online version contains supplementary material available at 10.1007/s13555-021-00628-3.

Persistent and impaired inflammation impedes tissue healing and is a characteristic of chronic wounds. A better understanding of the mechanisms controlling wound inflammation is needed. In this study, we show that in human wound-edge keratinocytes, the expressions of microRNA (miR)-17, miR-18a, miR-19a, miR-19b, and miR-20a, which all belong to the miR-17∼92 cluster, are upregulated during wound repair. However, their levels are lower in chronic ulcers than in acute wounds at the proliferative phase. Conditional knockout of miR-17∼92 in keratinocytes as well as injection of miR-19a/b and miR-20a antisense inhibitors into wound edges enhanced inflammation and delayed wound closure in mice. In contrast, conditional overexpression of the miR-17∼92 cluster or miR-19b alone in mice keratinocytes accelerated wound closure in vivo. Mechanistically, miR-19a/b and miR-20a decreased TLR3-mediated NF-κB activation by targeting SHCBP1 and SEMA7A, respectively, reducing the production of inflammatory chemokines and cytokines by keratinocytes. Thus, miR-19a/b and miR-20a being crucial regulators of wound inflammation, the lack thereof may contribute to sustained inflammation and impaired healing in chronic wounds. In line with this, we show that a combinatory treatment with miR-19b and miR-20a improved wound healing in a mouse model of type 2 diabetes.

Background\ud APPRECIATE is a multinational, observational, retrospective, cross‐sectional study in patients treated for psoriasis with apremilast, an oral phosphodiesterase 4 inhibitor.\ud \ud Objectives\ud To describe the characteristics of patients with psoriasis treated with apremilast in the clinical setting, to evaluate real‐world outcomes of psoriasis treatment with apremilast and to better understand the perspectives of patients and physicians on treatment outcomes.\ud \ud Methods\ud In six European countries, patients with chronic plaque psoriasis treated in clinical practice who could be contacted 6 (±1) months after apremilast initiation were enrolled. Patient characteristics, Dermatology Life Quality Index (DLQI) and Psoriasis Area and Severity Index (PASI) were obtained from medical records when available. Outcomes were evaluated using patient/physician questionnaires.\ud \ud Results\ud In 480 patients at treatment initiation, mean [median; 95% confidence interval (CI)] PASI and DLQI scores were 12.5 (10.7; 11.6–13.4) and 13.4 (13.0; 11.4–14.2), respectively. At 6 (±1) months, 72.3% of patients (n = 347) continued apremilast treatment [discontinuations: lack of efficacy (13.5%), safety (11.7%), other (2.5%)]. In patients continuing treatment, 48.6% achieved a ≥75% reduction in PASI score; mean (95% CI) DLQI score was 5.7 (4.5–6.9), and mean (SD) Patient Benefit Index score was 2.8 (1.2). Physicians perceived clinical improvement in 75.6% of patients. Physicians’ perspective on overall success of apremilast in meeting expectations correlated with patients’ perception of treatment benefit (r = 0.691). Most commonly reported adverse events (>5% of patients) were diarrhoea, nausea and headache.\ud \ud Conclusions\ud Patients in APPRECIATE reported high disease burden despite more moderate skin involvement than those who enrolled in clinical trials of apremilast. Findings from APPRECIATE demonstrate the real‐world value of apremilast for psoriasis treatment, as 7 of 10 patients continued therapy and showed notable improvement in disease severity and quality of life 6 (±1) months after apremilast initiation.

Background Psoriatic arthritis (PsA) develops in ~30% of patients with psoriasis. The diagnosis of PsA is challenging, and there are no reliable molecular markers in clinical use. MicroRNAs are short non-coding regulatory RNAs, which can be actively packaged into extracellular vesicles (EVs) and secreted to the circulation. Objectives To explore whether plasma-derived EV microRNAs may serve as biomarkers for PsA in patients with psoriasis. Methods Plasma samples were obtained from patients with cutaneous-only psoriasis (PsC) and patients with psoriasis and PsA. Plasma EVs were isolated using miRCURY™ Exosome Isolation Kit. RNA sequencing was used to identify differentially expressed EV miRNAs in the discovery phase (PsC, n = 15; PsA, n = 14). In the validation phase (PsC, n = 29; PsA, n = 28), 41 selected miRNAs were analysed in plasma EVs by qPCR. The association of the identified miRNAs with PsA was assessed by logistic regression analysis. Results RNA sequencing identified 19 plasma EV miRNAs with significantly different levels between PsA and PsC in the discovery cohort. Significantly lower levels of plasma EV let-7b-5p and miR-30e-5p in PsA vs. PsC were confirmed in the validation cohort, and their decreased levels were found to be associated with the presence of PsA. ROC analysis revealed an AUC of 0.68 (95% CI 0.53-0.83) for let-7b-5p and 0.69 (95% CI 0.55-0.84) for miR-30e-5p. Conclusions Circulating EV microRNA levels are altered in patients with PsA as compared with PsC. Findings of this exploratory study suggest that circulating EV microRNAs may serve as biomarkers for arthritis in psoriasis patients.

Background Patients with psoriatic arthritis (PsA) have increased risk of adverse events, including serious infections (SI), compared with psoriasis patients. Methods Patients eligible for, or receiving conventional systemic and biologic agents for psoriasis were followed prospectively using PSOLAR. Cohorts included: ustekinumab, tumor necrosis factor (TNF) inhibitors; infliximab; etanercept; adalimumab; non-biologic/methotrexate (MTX) (reference group); and non-biologic/non-MTX. Multivariate analyses using Cox hazard regression were used to identify factors associated with time to first SI. Rates of SI in PSOLAR psoriasis patients with self-reported PsA and possible risks with biologic therapy were evaluated. Results PSOLAR enrolled 4315 psoriasis patients with self-reported PsA. The overall population (N = 2401) included patients (n): 628 ustekinumab; 1413 TNF inhibitors; 258 infliximab; 481 etanercept; 674 adalimumab; 54 other biologics, 98 non-biologic/MTX; 208 non-biologic/non-MTX. Overall, 138 SI were reported with incidence rates per 100 patient-years as follows: a) ustekinumab: 1.00; b) TNF inhibitors: 2.22; c) infliximab: 2.12; d) etanercept: 2.58; e) adalimumab: 1.99; f) non-biologic/MTX: 3.01; g) and non-biologic/non-MTX: 2.31. Age, time-dependent disease activity Physician’s Global Assessment (PGA) of 4, 5, history of infection, and diabetes were associated with increased risk for SI (p Conclusions PSOLAR psoriasis patients with self-reported PsA in the TNF inhibitors, infliximab, adalimumab, etanercept, and MTX cohorts had numerically higher SI rates than the ustekinumab cohort, although not statistically significant. Age, PGA 4, 5, history of infection, and diabetes were associated with an increased risk for SI, irrespective of biologic exposure. Trial registration NCT00508547; Registered July 30, 2007.

Abundant polyclonal T cells infiltrate chronic inflammatory diseases and characterization of these cells is needed to distinguish disease-driving from bystander immune cells. Here, we investigated 52,000 human cutaneous transcriptomes of non-communicable inflammatory skin diseases (ncISD) using spatial transcriptomics. Despite the expected T cell infiltration, we observed only 1-10 pathogenic T cell cytokine per skin section. Cytokine expression was limited to lesional skin and presented in a disease-specific pattern. In fact, we identified responder signatures in direct proximity of cytokines, and showed that single cytokine transcripts initiate amplification cascades of thousands of specific responder transcripts forming localized epidermal clusters. Thus, within the abundant and polyclonal T cell infiltrates of ncISD, only a few T cells drive disease by initiating an inflammatory amplification cascade in their local microenvironment.

IMPORTANCE: Psoriasis is a heterogeneous disease. Improved understanding of prognosis and long-term outcomes in new-onset psoriasis may improve care. OBJECTIVE: To describe the clinical course of psoriasis and identify possible indicators of long-term outcomes. DESIGN, SETTING, AND PARTICIPANTS: The Stockholm Psoriasis Cohort was a noninterventional inception cohort study enrolling patients between 2001 and 2005. The present study was conducted from January 15, 2019, to February 5, 2021. At enrollment and 10 years, patients were examined by dermatologists and rheumatologists. Data from examinations were complemented by questionnaires, medical records, and registers. A total of 721 patients with recent-onset psoriasis (

Objective: Psoriatic arthritis mutilans (PAM) is the most severe phenotype of psoriatic arthritis due to excessive bone erosion causing joint destruction and decreased functional capacity. The aim of this study was to investigate the prevalence of comorbidities among patients with PAM and the association between comorbidities and joint involvement.Methods: A total of 66 patients aged ≥18 years from the Nordic countries with past or present psoriasis along with at least one mutilated joint were included in the present study.Results: The median number of comorbid conditions per patient was 1 [interquartile range (IQR) 0–2] and 16.7% reported three or more comorbidities. The most frequent comorbidity was hypertension (36.4%). The median number of mutilated joints per patient was 3 (IQR 1–8.3; range 1–38).Conclusion: Two thirds of the patients with PAM reported comorbid conditions and the most frequent was hypertension which affected more than a third of the patients. However, this study was unable to detect any association between comorbidities and the severity of PAM.

Psoriasis and inflammatory bowel disease (IBD) are immune-mediated diseases occurring in barrier organs whose main task is to protect the organism from attack. These disorders are highly prevalent especially in northern Europe where psoriasis has a prevalence of around 3-4% and IBD around 0.3%. The prevalence of IBD in North America has been estimated at around 0.4%. The total incidence rates in northern Europe have been estimated at around 6 for Crohns disease and 11 for ulcerative colitis per 100 000 person-years, compared with an incidence rate of around 280 per 100 000 person-years for psoriasis. Both diseases are less common in countries with a lower index of development. The rise in IBD appears to occur as populations adopt a westernized lifestyle, whereas psoriasis seems more stable and prevalence differences may derive more from variation in genetic susceptibility. The gut microbiota is clearly an important driver of IBD pathogenesis; in psoriasis, changes in gut and skin microbiota have been reported, but it is less clear whether and how these changes contribute to the pathogenesis. Large studies show that most identified genes are involved in the immune system. However, psoriasis and IBD are highly heterogeneous diseases and there is a need for more precise and deeper phenotyping to identify specific subgroups and their genetic, epigenetic and molecular signatures. Epigenetic modifications of DNA such as histone modifications, noncoding RNA effects on transcription and translation and DNA methylation are increasingly recognized as the mechanism underpinning much of the gene-environment interaction in the pathogenesis of both IBD and psoriasis. Our understanding of underlying pathogenetic mechanisms has deepened fundamentally over the past decades developing hand in hand with novel therapies targeting pathways and proinflammatory cytokines incriminated in disease. There is not only substantial overlap between psoriasis and IBD, but also there are differences with implication for therapy. In psoriasis, drugs targeting interleukin-23 and interleukin-17 have shown superior efficacy compared with anti-TNFs, whilst in IBD, drugs targeting interleukin-17 may be less beneficial. The therapeutic toolbox for psoriasis is impressive and is enlarging also for IBD. Still, there are unmet needs reflecting the heterogeneity of both diseases and there is a need for closer molecular diagnostics to allow for the development of precise therapeutics. Funding Agencies|Stockholm CountyStockholm County Council; Swedish Medical Society; MagTarm Fund; Bengt Ihre Fund; Ruth and Richard Julins Foundation; Nanna Svartz Foundation; Stockholm County (ALF); Bengt Ihre Foundation; Swedish Medical Research CouncilSwedish Medical Research Council (SMRC)European Commission; Stockholm County Council (ALF)Stockholm County Council; Swedish Psoriasis Foundation (Psoriasisfonden); Hudfonden; National Psoriasis Foundation (USA); Psoriasis Foundation

Background Hundreds of variants associated with atopic dermatitis (AD) and psoriasis, 2 common inflammatory skin disorders, have previously been discovered through genome-wide association studies (GWASs). The majority of these variants are in noncoding regions, and their target genes remain largely unclear. Objective We sought to understand the effects of these noncoding variants on the development of AD and psoriasis by linking them to the genes that they regulate. Methods We constructed genomic 3-dimensional maps of human keratinocytes during differentiation by using targeted chromosome conformation capture (Capture Hi-C) targeting more than 20,000 promoters and 214 GWAS variants and combined these data with transcriptome and epigenomic data sets. We validated our results with reporter assays, clustered regularly interspaced short palindromic repeats activation, and examination of patient gene expression from previous studies. Results We identified 118 target genes of 82 AD and psoriasis GWAS variants. Differential expression of 58 of the 118 target genes (49%) occurred in either AD or psoriatic lesions, many of which were not previously linked to any skin disease. We highlighted the genes AFG1L, CLINT1, ADO, LINC00302, and RP1-140J1.1 and provided further evidence for their potential roles in AD and psoriasis. Conclusions Our work focused on skin barrier pathology through investigation of the interaction profile of GWAS variants during keratinocyte differentiation. We have provided a catalogue of candidate genes that could modulate the risk of AD and psoriasis. Given that only 35% of the target genes are the gene nearest to the known GWAS variants, we expect that our work will contribute to the discovery of novel pathways involved in AD and psoriasis.

Wound healing is a high energy demanding process that needs a good coordination of the mitochondria with glycolysis in the characteristic highly hypoxic environment. In diabetes, hyperglycemia impairs the adaptive responses to hypoxia with profound negative effects on different cellular compartments of wound healing. miR-210 is a hypoxia-induced microRNA that regulates cellular metabolism and processes important for wound healing. Here, we show that hyperglycemia blunted the hypoxia-dependent induction of miR-210 both in vitro and in human and mouse diabetic wounds. The impaired regulation of miR-210 in diabetic wounds is pathogenic, since local miR-210 administration accelerated wound healing specifically in diabetic but not in non-diabetic mice. miR-210 reconstitution restores the metabolic balance in diabetic wounds by reducing oxygen consumption rate and ROS production and by activating glycolysis with positive consequences on cellular migration. In conclusion, miR-210 accelerates wound healing specifically in diabetes through improvement of the cellular metabolism., Narayanan et al. show that local administration of miR-210 accelerates wound healing specifically in diabetic mice. They find that miR-210 restores the metabolic balance in diabetic wounds by activating glycolysis and cellular migration. This study presents miR-210 as a potential therapeutic option to treat diabetic wound healing.

OBJECTIVES: The genetic contribution to psoriatic disease is substantial with a dominating influence of the HLA region. The profile of HLA class I genotypes likely contributes to shaping clinical phenotypes. Herein we aimed to explore such genotypes in cohorts of closely characterised subsets of psoriatic disease with special focus on psoriatic arthritis mutilans (PAM), a severe and rare form of psoriatic arthritis (PsA).METHODS: Cohorts of patients with the diagnosis of psoriasis vulgaris with or without arthritis (n=1217), psoriasis without arthritis (n=534), psoriatic arthritis without mutilating disease (n=337) and psoriatic arthritis mutilans (n=63) were collected and genotyped for HLA class I and II genes, with standardised methodologies. Cases were compared with a healthy control population (n=2468). Case-only and case-control association tests were performed to address the hypothesis of genetic contribution to clinical phenotypes.RESULTS: The presence of HLA-B*27 was strikingly increased in PAM (45%) compared with PsA without mutilating disease (13%) and with healthy controls (13%). However, within the PAM population, HLA-B*27 did not correlate with clinical markers such as number of mutilating joints, radiographic scoring, disease duration and age of disease onset.CONCLUSIONS: HLA-B*27 emerges as an important genotype marker for PAM.

Background Psoriatic arthritis mutilans (PAM) is the most severe phenotype of psoriatic arthritis (PsA). Purpose To describe the radiological features in PAM and explore whether existing scoring systems for radiological damage in psoriatic arthritis are applicable for PAM. Material and Methods Radiographs were scored according to the modified Sharp-van der Heijde (mSvdH) and the Psoriatic Arthritis Ratingen Score (PARS) systems for PsA. Results At inclusion, 55 PAM patients (49% women, mean age 58 ± 12 years) had conventional radiographs of both hands and feet. A total of 869 PAM joints were detected and 193 joints with ankylosis. The mean total mSvdH score was 213.7 ± 137.8 (41% of maximum) with a higher score for hands than for feet: 136.6 ± 90.1 vs. 79.1 ± 60.9. However, the total score was relatively higher in the feet than in the hands when compared to the highest possible scoring (47% vs. 38% of max). The mean total PARS score was 126.3 ± 79.6 (35% of max). Scoring for joint destruction was higher than for proliferation (22% vs. 11% of max). Strong correlation was found between mSvdH and PARS (r2 = 0.913). A significant correlation was found between scoring and duration of arthritis and the Health Assessment Questionnaire. History of smoking, BMI, and gender did not influence the scoring values. Conclusions The two scoring systems studied may not be ideal to indicate progression of PAM in advanced disease since they reach ceiling effects rather early. Therefore, reporting early signs suggestive of PAM, e.g. signs of pencil-in-cup deformities or osteolysis, is crucial. This would reveal the presence of PAM and might lead to improved treatment in order to minimize joint damage.

Tofacitinib is a Janus kinase (JAK) inhibitor, which has shown efficacy in treating psoriasis. The mode of action of tofacitinib is not completely understood but it has been thought to be mediated by the inhibition of CD4+ T-cell activation. Here, we investigated whether the molecular targets of tofacitinib are expressed in keratinocytes, and whether tofacitinib can modulate the activity of the JAK/Signal Transducer and Activators of Transcription (STAT)-pathway in keratinocytes. Transcriptomic profiling of human keratinocytes treated with IL-22 in combination with tofacitinib revealed that tofacitinib could prevent the majority of IL-22-mediated gene expression changes. Pathway analysis of tofacitinib-regulated genes in keratinocytes revealed enrichment of genes involved in the JAK/STAT signalling pathway. Quantitative real-time-PCR confirmed the upregulation of S100A7 and downregulation of EGR1 expression by IL-22, which was prevented by tofacitinib pre-treatment. These results indicate a direct effect of tofacinitib on keratinocytes, which can have relevance for systemic as well as for topical treatment of psoriasis with tofacitinib.

Significance The nine-member transglutaminase protein family includes five known autoantigens. Because of the frequent roles of transglutaminases in autoimmunity, we decided to explore whether the remaining members might also constitute autoantigens, but in as-yet-unexplained disorders. We turned to TGM1, and since this member is primarily expressed in squamous epithelia, we focused on skin disorders. By screening a broad range of acquired skin disorders, we identified TGM1 to be a major autoantigen in the severe blistering disease paraneoplastic pemphigus. This study illustrates a gene-centric approach to biomarker discovery—starting from a putative autoantigen to search for its corresponding disease—that may prove generally applicable for studies of autoimmunity., Autoantigen discovery is a critical challenge for the understanding and diagnosis of autoimmune diseases. While autoantibody markers in current clinical use have been identified through studies focused on individual disorders, we postulated that a reverse approach starting with a putative autoantigen to explore multiple disorders might hold promise. We here targeted the epidermal protein transglutaminase 1 (TGM1) as a member of a protein family prone to autoimmune attack. By screening sera from patients with various acquired skin disorders, we identified seropositive subjects with the blistering mucocutaneous disease paraneoplastic pemphigus. Validation in further subjects confirmed TGM1 autoantibodies as a 55% sensitive and 100% specific marker for paraneoplastic pemphigus. This gene-centric approach leverages the wealth of data available for human genes and may prove generally applicable for biomarker discovery in autoimmune diseases.

To the Editor: Patients with psoriasis are at increased risk of developing non melanoma skin cancer (NMSC), including squamous cell carcinoma (SCC) and basal cell carcinoma (BCC).1,2 The risk is especially elevated among those who previously received systemic treatment or phototherapy.2 Systemic treatments, including biologic therapies and methotrexate (MTX), are effective in managing immune-mediated diseases; however, they may increase susceptibility to NMSC due to immunosuppression or other factors.3

BACKGROUND The advent of biosimilars may render etanercept (ETN) and adalimumab (ADA) viable alternatives to methotrexate (MTX) as first-line systemics in psoriasis. However, real-world relative effectiveness data comparing ADA and ETN to MTX are limited. OBJECTIVE To estimate the relative effectiveness of ADA and ETN compared to MTX. METHODS We analysed data from DermaReg, a regional register in Stockholm, Sweden, to estimate drug survival and mean Psoriasis Area and Severity Index (PASI) and Dermatology Life Quality Index (DLQI) during maintenance treatment. RESULTS A total of 524 patients initiated 727 treatment episodes with ADA, ETN or MTX. After adjusting for confounders, patients treated with ADA had better drug survival (HR: 0.67; P = 0.003), lower mean PASI (-2.0; P

Chronic wounds represent a major and growing health and economic burden worldwide. A better understanding of molecular mechanisms of normal as well as impaired wound healing is needed to develop effective treatment. Herein we studied the potential role of long noncoding RNA LOC100130476 in skin wound repair. LOC100130476 is an RNA polymerase IIeencoded polyadenylated transcript present in both cytoplasm and nucleus. We found that its expression was lower in wound-edge keratinocytes of human chronic wounds compared to normal wounds of healthy donors and intact skin. In cultured keratinocytes, LOC100130476 expression was induced by TGF-beta signaling. By reducing LOC100130476 expression with antisense oligos or activating its transcription with CRISPR/Cas9 Synergistic Activation Mediator system, we showed that LOC100130476 restricted the production of inflammatory chemokines by keratinocytes, while enhancing cell migration. In line with this, knockdown of LOC100130476 impaired re-epithelization of human ex vivo wounds. Based on these results, we named LOC100130476 wound and keratinocyte migration-associated long noncoding RNA 2 (WAKMAR2). Moreover, we identified a molecular network that may mediate the biological function of WAKMAR2 in keratinocytes using microarray. In summary, our data suggest that WAKMAR2 is an important regulator of skin wound healing and its deficiency may contribute to the pathogenesis of chronic wounds.

Significance Although constituting the majority of the transcriptional output of the human genome, the functional importance of long noncoding RNAs (lncRNAs) has only recently been recognized. The role of lncRNAs in wound healing is virtually unknown. Our study focused on a skin-specific lncRNA, termed “wound and keratinocyte migration-associated lncRNA 1” (WAKMAR1), which is down-regulated in wound-edge keratinocytes of human chronic nonhealing wounds compared with normal wounds under reepithelialization. We identified WAKMAR1 as being critical for keratinocyte migration and its deficiency as impairing wound reepithelialization. Mechanistically, WAKMAR1 interacts with DNA methyltransferases and interferes with the promoter methylation of the E2F1 gene, which is a key transcription factor controlling a network of migratory genes. This line of evidence demonstrates that lncRNAs play an essential role in human skin wound healing., An increasing number of studies reveal the importance of long noncoding RNAs (lncRNAs) in gene expression control underlying many physiological and pathological processes. However, their role in skin wound healing remains poorly understood. Our study focused on a skin-specific lncRNA, LOC105372576, whose expression was increased during physiological wound healing. In human nonhealing wounds, however, its level was significantly lower compared with normal wounds under reepithelialization. We characterized LOC105372576 as a nuclear-localized, RNAPII-transcribed, and polyadenylated lncRNA. In keratinocytes, its expression was induced by TGF-β signaling. Knockdown of LOC105372576 and activation of its endogenous transcription, respectively, reduced and increased the motility of keratinocytes and reepithelialization of human ex vivo skin wounds. Therefore, LOC105372576 was termed “wound and keratinocyte migration-associated lncRNA 1” (WAKMAR1). Further study revealed that WAKMAR1 regulated a network of protein-coding genes important for cell migration, most of which were under the control of transcription factor E2F1. Mechanistically, WAKMAR1 enhanced E2F1 expression by interfering with E2F1 promoter methylation through the sequestration of DNA methyltransferases. Collectively, we have identified a lncRNA important for keratinocyte migration, whose deficiency may be involved in the pathogenesis of chronic wounds.

The ability to rapidly restore the integrity of a broken skin barrier is critical and is the ultimate goal of therapies for hard-to-heal-ulcers. Unfortunately effective treatments to enhance healing and reduce scarring are still lacking. A deeper understanding of the physiology of normal repair and of the pathology of delayed healing is a prerequisite for the development of more effective therapeutic interventions. Transition from the inflammatory to the proliferative phase is a key step during healing and accumulating evidence associates a compromised transition with wound healing disorders. Thus, targeting factors that impact this phase transition may offer a rationale for therapeutic development. This review summarizes mechanisms regulating the inflammation-proliferation transition at cellular and molecular levels. We propose that identification of such mechanisms will reveal promising targets for development of more effective therapies.

Psoriasis is an immune-mediated inflammatory disease, which is associated with a high risk of developing systemic comorbidities, such as obesity, cardiovascular disease, and diabetes mellitus. However, the mechanistic links between psoriatic skin inflammation and systemic comorbidities remain largely unknown. MicroRNAs (miRNAs) are recently discovered gene regulators that play important roles in psoriasis skin inflammation. In this study we aimed to explore whether the skin inflammation in psoriasis affects miRNA expression of the underlying subcutaneous adipose tissue and whether this may be a link between psoriasis and comorbidities. To this end, we compared the miRNA expression profile of subcutaneous adipose tissue underneath lesional and nonlesional psoriatic skin. We further validated the differential expression of several miRNAs and characterized their expression patterns in different cell types present in subcutaneous adipose tissue. We focused on miR-26b-5p, which was highly up-regulated in subcutaneous adipose tissue underneath lesional psoriasis skin. We showed that it targets and down-regulates neutral cholesterol ester hydrolase 1, an enzyme essential for cholesterol efflux, in monocytes/macrophages, adipocytes, vascular endothelial cells, and fibroblasts. We conclude that this miRNA may serve as a mechanistic link between psoriatic skin inflammation and its systemic comorbidities.

In addition to producing sebum, sebocytes link lipid metabolism with inflammation at a cellular level and hence, greatly resemble adipocytes. However, so far no analysis was performed to identify and characterize the adipocyte-associated inflammatory proteins, the members of the adipokine family in sebocytes. Therefore, we determined the expression profile of adipokines [adiponectin, interleukin (IL) 6, resistin, leptin, serpin E1, visfatin, apelin, chemerin, retinol-binding protein 4 (RBP4) and monocyte chemoattractant protein 1 (MCP1)] in sebaceous glands of healthy and various disease-affected (acne, rosacea, melanoma and psoriasis) skin samples. Sebaceous glands in all examined samples expressed adiponectin, IL6, resistin, leptin, serpin E1 and visfatin, but not apelin, chemerin, RBP4 and MCP1. Confirming the presence of the detected adipokines in the human SZ95 sebaceous gland cell line we further characterized their expression and secretion patterns under different stimuli mimicking bacterial invasion [by using Toll-like receptor (TLR)2 and 4 activators], or by 13-cis retinoic acid (13CRA; also known as isotretinoin), a key anti-acne agent. With the exception of resistin, the expression of all of the detected adipokines (adiponectin, IL6, leptin, serpin E1 and visfatin) could be further regulated at the level of gene expression, showing a close correlation with the secreted protein levels. Besides providing further evidence on similarities between adipocytes and sebocytes, our results strongly suggest that sebocytes are not simply targets of inflammation but may exhibit initiatory and modulatory roles in the inflammatory processes of the skin through the expression and secretion of adipokines.

Estimates of direct and indirect costs of psoriasis are limited. The aim of this study was to estimate: (i) costs in patients with psoriasis compared with controls; and (ii) impact on costs from initiating biologics. The study extracted data from Swedish administrative registers and compared 31,043 patients with 111,645 sex-, age- and residency-matched referents. Mean direct and indirect costs were estimated as US dollars (USD) 1,365 (62%) and USD 3,319 (50%) higher in patients compared with referents, respectively. The study included 352 patients treated with biologics who had at least 1-year follow-up before and after initiation of biologics. Among the 193 patients persistent with biologics for one year, 1-year costs of biologics were estimated at USD 23,293 (95% confidence interval (95% CI) 22,372-24,199). This cost was partially offset, with savings in direct cost estimated to range from USD -1135 (95% CI -2,050 to -328) to USD -4,422 (95% CI -6,552 to -2,771), depending on assumptions. The corresponding estimates for indirect costs savings were from USD -774 (95% CI -2,019-535) to USD -1,875 (95% CI -3,650 to -188). The study suggests that psoriasis is associated with substantial costs, which may be modifiable with treatment.

Venous ulcers are the most common type of human chronic nonhealing wounds and are stalled in a constant and excessive inflammatory state. The molecular mechanisms underlying the chronic wound inflammation remain elusive. Moreover, little is known about the role of regulatory RNAs, such as microRNAs, in the pathogenesis of venous ulcers. We found that both microRNA (miR)-34a and miR-34c were upregulated in the wound-edge epidermal keratinocytes of venous ulcers compared with normal wounds or the skin. In keratinocytes, miR-34a and miR-34c promoted inflammatory chemokine and cytokine production. In wounds of wild-type mice, miR-34a-mimic treatment enhanced inflammation and delayed healing. To further explore how miR-34 functions, LGR4 was identified as a direct target mediating the proinflammatory function of miR-34a and miR-34c. Interestingly, impaired wound closure with enhanced inflammation was also observed in Lgr4 knockout mice. Mechanistically, the miR-34-LGR4 axis regulated GSK-3β-induced p65 serine 468 phosphorylation, changing the activity of the NF-κB signaling pathway. Collectively, the miR-34-LGR4 axis was shown to regulate keratinocyte inflammatory response, the deregulation of which may play a pathological role in venous ulcers.

MicroRNAs are short non-coding RNAs that play key roles in regulating biological processes. In this study, we explored effects of chronological and photoageing on the miRNome of human skin. To this end, biopsies were collected from sun-exposed (outer arm, n = 45) and sun-protected (inner arm, n = 45) skin from fair-skinned (phototype II/III) healthy female volunteers of three age groups: young, 18–25 years, middle age, 40–50 years and aged, > 70 years. Strict inclusion criteria were used for photoageing scoring and for chronological ageing. Microarray analysis revealed that chronological ageing had minor effect on the human skin miRNome. In contrast, photoageing had a robust impact on miRNAs, and a set of miRNAs differentially expressed between sun-protected and sun-exposed skin of the young and aged groups was identified. Upregulation of miR-383, miR-145 and miR-34a and downregulation of miR-6879, miR-3648 and miR-663b were confirmed using qRT-PCR in sun-exposed skin compared with sun-protected skin. qRT-PCR analysis revealed that miR-383, miR-34a and miR-134 were differentially expressed in all three age groups both in chronological and photoageing, suggesting a synergetic effect of intrinsic and extrinsic ageing on their expression. In conclusion, our study identifies a unique miRNA signature which may contribute to skin ageing.

Melanoma is one of the deadliest human cancers with limited therapeutic options. MicroRNAs are a class of short noncoding RNAs regulating gene expression at the post-transcriptional level. To identify important miRNAs in melanoma, we compared the miRNome of primary and metastatic melanomas in The Cancer Genome Atlas dataset and found lower miR-203 abundance in metastatic melanoma. Lower level of miR-203 was associated with poor overall survival in metastatic disease. We found that the methylation levels of several CpGs in the MIR203 promoter negatively correlated with miR-203 expression and that treatment with the demethylating agent 5-aza-2-deoxycytidine induced miR-203 expression, which was associated with demethylation of the promoter CpGs, in melanoma cell lines. In vitro, there was a decreased expression of miR-203 in melanoma cell lines in comparison with primary melanocytes. Ectopic overexpression of miR-203 suppressed cell motility, colony formation, and sphere formation as well as the angiogenesis-inducing capacity of melanoma cells. In vivo, miR-203 inhibited xenograft tumor growth and reduced lymph node and lung metastasis. SLUG was shown as a target of miR-203, and knockdown of SLUG recapitulated the effects of miR-203, whereas its restoration was able to reverse the miR-203-mediated suppression of cell motility. These results establish a role for miR-203 as a tumor suppressor in melanoma which suppresses both early and late steps of metastasis. Hence, restoration of miR-203 has therapeutic potential in melanoma.

Treatment of psoriasis: before and now Psoriasis is a multisystem inflammatory disease primarily affecting the skin. Despite its prevalence and considerable effect on quality of life, psoriasis is still underdiagnosed and undertreated. Many patients seek initial evaluation and treatment at primary care level and therefore it is important to know that treatment of psoriasis has advanced tremendously in recent years. Decisions on psoriasis management should be based on assessment of disease severity and phenotype, the existence of physical and psychological comorbidities, the need for referral to dermatologist for specialist care, the patient's preferences and, when possible, identification and elimination of psoriasis trigger factors. Individual treatment goals should be agreed with the patient and treatment should aim to achieve these goals. An individualized, patient centered approach based on the potential of current treatments and a good interpersonal communication between patient and doctor, is essential for effective management of psoriasis.

Wound healing is a basic biological process restoring the integrity of the skin. The role of microRNAs during this process remains largely unexplored. By using an in vivo human skin wound healing model, we show here that the expression of miR-31 is gradually upregulated in wound edge keratinocytes in the inflammatory (1 day after injury) through the proliferative phase (7 days after injury) in comparison with intact skin. In human primary keratinocytes, overexpression of miR-31 promoted cell proliferation and migration, whereas inhibition of miR-31 had the opposite effects. Moreover, we identified epithelial membrane protein 1 (EMP-1) as a direct target of miR-31 in keratinocytes. The expression of EMP-1 in the skin was negatively correlated with the level of miR-31 during wound healing. Silencing of EMP-1 mimicked the effects of overexpression of miR-31 on keratinocyte proliferation and migration, indicating that EMP-1 is a critical target mediating the functions of miR-31 in keratinocytes. Finally, we demonstrated that transforming growth factor-β2, which is highly expressed in skin wounds, upregulated miR-31 expression in keratinocytes. Collectively, we identify miR-31 as a key regulator for promoting keratinocyte proliferation and migration during wound healing.

Epidemiological data in childhood psoriasis are accumulating. However, reliable information captured at onset is lacking. In a cross sectional study we recruited 109 children16 years within 12 months of psoriasis onset and explored the clinical characteristics. Pre-pubertal children, especially boys, more often had inverse involvement (OR = 2.8, 95% CI = 1.1, 7.1, p ≤ 0.05). HLA-C*06 was positively associated with facial lesions (OR = 3.8, 95% CI = 1.5, 9.7, p0.01) and guttate phenotype and was more common in pubertal children. A high PASI score was not associated with overweight or early age at onset, and gender did not influence disease onset. Psoriasis can be difficult to diagnose in children, especially in pre-pubertals. Thorough examination of facial and genital areas can help in establishing the diagnosis. Our published genetic data in combination with the clinical findings presented herein indicate that puberty may separate different populations of childhood psoriasis.