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Two new elastase inhibitors (SKALP, skin-derived antileucoproteases) were recently described in the lesional skin in psoriasis. The present study investigated the distribution of SKALP activity in the marginal zone of spreading psoriatic plaques. In a 4-mm zone immediately adjacent to the erythematosquamous plaques, SKALP activity was slightly increased compared to distant uninvolved skin. Within the lesion the anti-elastase activity was pronounced, but was significantly higher in the central zone of the plaque compared to the periphery. The appearance of SKALP in the psoriatic lesion appears to be a late event compared to endothelial involvement, intraepidermal accumulation of PMNs, epidermal proliferation and abnormal keratinization. This observation lends further support for the hypothesis that the induction of anti-elastase activity is associated with the off-switch of cutaneous inflammation. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to the article "Recurrent Neuropathy Associated With Ehlers–Danlos Syndrome," that was published in the previous issues of the "Journal of Neurology."

Background Recent genome-wide association studies have identified several genetic risk factors for psoriasis, but data on their association with age at onset are lacking. Objectives To compare the association between known risk alleles and psoriasis in well-defined cohorts with paediatric- and adult-onset psoriasis. Methods Based on previous studies we selected seven genes and loci associated with psoriasis. Patients with paediatric-onset (< 18 years) and adult-onset psoriasis (≥ 18 years) and controls were genotyped. Genotype frequencies were compared between controls ( n = 450) and all cases ( n = 217), and between controls and cases stratified for confirmed age at onset (paediatric onset n = 80, adult onset n = 85). Results Paediatric-onset psoriasis showed a significant association with single nucleotide polymorphisms in the ERAP1 ( P = 0·042) and IL23R loci ( P = 0·042), LCE3C_LCE3B-del ( P = 0·003) and HLA-C*06 ( P = 1·72 × 10−19) when compared with the control group. A significant association of these four genes was also demonstrated when all psoriasis cases were compared with controls. In adult-onset psoriasis a significant association was found for HLA-C*06 ( P = 5·11 × 10−6) and for LCE3C_LCE3B-del ( P = 0·042). No associations were found for the IFIH1, IL12B and TRAF3IP2 loci. Conclusions Notwithstanding the small cohort sizes, we demonstrated an association with established and recently discovered genetic risk factors in paediatric-onset psoriasis including genes involved in epidermal barrier function and adaptive immunity. Our data suggest that heritable factors may play a more important role in paediatric-onset psoriasis than in adult-onset psoriasis. [ABSTRACT FROM AUTHOR]

Abstract: Large-scale in vivo evaluation of biomaterials is time-consuming and limited by ethical considerations. The availability of a library of biomaterials would allow a fast and rational in vitro selection of those biomaterials to be evaluated in vivo. For this reason, we developed an array of 48 different, molecularly-defined films based on native fibrillar collagen. The films differed in the type and amount of extracellular matrix components (type I/IV collagens, fibrous/solubilised elastin, glycosaminoglycans, heparin, chondroitin sulfate or dermatan sulfate), method of preparation (homogenisation) and method and extent of crosslinking (carbodiimide (EDC/NHS) or glutaraldehyde). The array was evaluated by studying morphology, proliferation and differentiation of primary human keratinocytes/fibroblasts. Major differences were observed. Only a small selection of films (especially those containing elastin fibres) specifically stimulated the proliferation of keratinocytes, but not fibroblasts. Such films may be the biomaterials of choice for in vivo evaluation for skin tissue engineering and regenerative medicine. [Copyright &y& Elsevier]

Background The effectiveness of biologics for psoriasis shows heterogeneity among patients. With pharmacogenetic markers, it might be possible to predict treatment response. Objectives We aimed to test the association between genetic markers and the response to biologics in psoriasis (etanercept, adalimumab, ustekinumab) in a prospective cohort. Methods We investigated the copy number variation in the LCE3B and LCE3C genes, and eight single-nucleotide polymorphisms ( SNPs) in HLA-C*06, CD84, IL12B, IL23R, TRAF3 IP2, ERAP1, IFIH1 and TNFAIP3. The decrease in Psoriasis Area and Severity Index ( PASI) was calculated as ∆ PASI (absolute PASI decrease compared with baseline) and PASI 75 (proportion of patients with ≥ 75% improvement vs. baseline). Associations between genetic variants and treatment outcome were assessed using multivariable linear regression analysis (∆ PASI corrected for baseline PASI, primary analysis) and Pearson's χ2-test or Fisher's exact test ( PASI 75, secondary analysis). Results We included 348 treatment episodes in 234 patients. Patients heterozygous ( GA) for the SNP in CD84 (rs6427528) had a better ∆ PASI response to etanercept after 3 months ( P = 0·025) than the homozygous reference group ( GG). In addition, patients heterozygous ( CT) for the IL12B variant showed a better response (∆ PASI) to ustekinumab ( P = 0·017) than the reference group ( CC). Patients homozygous ( GG) for the SNP in TNFAIP3 showed a worse response (∆ PASI) to ustekinumab ( P = 0·031) than the reference group ( TT). The associations with ustekinumab resulting from the primary analysis were not confirmed in the secondary ( PASI 75) analysis. Conclusions We demonstrated a strong association between etanercept use in psoriasis and variations in CD84, a gene that was previously found to be a predictor of response to etanercept in rheumatoid arthritis. [ABSTRACT FROM AUTHOR]

The tenascin-X ( TNX) deficient type Ehlers-Danlos syndrome ( EDS) is similar to the classical type of EDS. Because of the limited awareness among geneticists and the challenge of the molecular analysis of the TNXB gene, the TNX-deficient type EDS is probably to be under diagnosed. We therefore performed an observational, cross-sectional study. History and physical examination were performed. Results of serum TNX measurements were collected and mutation analysis was performed by a combination of next-generation sequencing ( NGS), Sanger sequencing and multiplex ligation-dependent probe amplification ( MLPA). Included were 17 patients of 11 families with autosomal recessive inheritance and childhood onset. All patients had hyperextensible skin without atrophic scarring. Hypermobility of the joints was observed in 16 of 17 patients. Deformities of the hands and feet were observed frequently. TNX serum level was tested and absent in 11 patients (seven families). Genetic testing was performed in all families; 12 different mutations were detected, most of which are suspected to lead to non-sense mRNA mediated decay. In short, patients with the TNX-deficient type EDS typically have generalized joint hypermobility, skin hyperextensibility and easy bruising. In contrast to the classical type, the inheritance pattern is autosomal recessive and atrophic scarring is absent. Molecular analysis of TNXB in a diagnostic setting is challenging. [ABSTRACT FROM AUTHOR]

A letter to the editor on a research study on Autoinflammatory Disorders (AID) characterized by an unprovoked innate immune response, resulting in recurrent or ongoing systemic inflammation and fever, is presented.

Background Deletion of the late cornified envelope ( LCE) proteins LCE3B and LCE3C is a strong and widely replicated psoriasis risk factor. It is amenable to biological analysis because it precludes the expression of two epidermis-specific proteins, rather than being a single-nucleotide polymorphism of uncertain significance. The biology of the 18-member LCE family of highly homologous proteins has remained largely unexplored so far. Objectives To analyse LCE3 expression at the protein level in human epithelia, as a starting point for functional analyses of these proteins in health and disease. Methods We generated the first pan- LCE3 monoclonal antibody and provide a detailed analysis of its specificity towards individual LCE members. LCE2 and LCE3 expression in human tissues and in reconstructed human skin models was studied using immunohistochemical analyses and quantitative polymerase chain reaction. Results Our study reveals that LCE2 and LCE3 proteins are differentially expressed in human epidermis, and colocalize only in the upper stratum granulosum layer. Using an in vitro reconstructed human skin model that mimics epidermal morphogenesis, we found that LCE3 proteins are expressed at an early time point during epidermal differentiation in the suprabasal layers, while LCE2 proteins are found only in the uppermost granular layer and stratum corneum. Conclusions Based on the localization of LCE2 and LCE3 in human epidermis we conclude that members of the LCE protein family are likely to have distinct functions in epidermal biology. This finding may contribute to understanding why LCE3B/C deletion increases psoriasis risk. [ABSTRACT FROM AUTHOR]

Background Schnitzler's syndrome (SchS) is an autoinflammatory disease characterized by a chronic urticarial rash, a monoclonal component and signs of systemic inflammation. Interleukin ( IL)-1β is pivotal in the pathophysiology. Objectives Here we investigated the cellular source of proinflammatory mediators in the skin of patients with SchS. Methods Skin biopsies of lesional and nonlesional skin from eight patients with SchS and healthy controls, and patients with cryopyrin-associated periodic syndrome ( CAPS), delayed-pressure urticaria ( DPU) and cold-contact urticaria ( CCU) were studied. We studied in vivo IL-1β, IL-17 and antimicrobial protein ( AMP) expression in resident skin cells and infiltrating cells. In addition we investigated the in vitro effect of IL-1β, IL-17 and polyinosinic-polycytidylic acid (poly: IC) stimulation on cultured epidermal keratinocytes. Results Remarkably, we found IL-1β-positive dermal mast cells in both lesional and nonlesional skin of patients with SchS, but not in healthy control skin and CCU, and fewer in CAPS. IL-17-positive neutrophils were observed only in lesional SchS and DPU skin. In lesional SchS epidermis, mRNA and protein expression levels of AMPs were strongly increased compared with nonlesional skin and that of healthy controls. When exposed to IL-1β, poly: IC or IL-17, patient and control primary human keratinocytes produced AMPs in similar amounts. Conclusions Dermal mast cells of patients with SchS produce IL-1β. This presumably leads to activation of keratinocytes and neutrophil influx, and further amplification of inflammation by IL-17 (from neutrophils and mast cells) and epidermal AMP production leading to chronic histamine-independent neutrophilic urticarial dermatosis. [ABSTRACT FROM AUTHOR]

Background The use of recently introduced biologics targeting specific immune mechanisms has identified crucial steps in the pathogenesis of psoriasis. Studying the dynamics of changes of these target mechanisms in sequential skin biopsies during treatment with biologics may reveal potential biomarkers. Correlation between clinical parameters and the expression of specific genes during treatments may identify markers indicative of treatment response. Objectives This observational open-label study aimed to provide an overview of important cell biological changes in lesional skin during treatment with adalimumab, and their relationship to clinical improvement. Methods Ten patients with moderate-to-severe plaque psoriasis were included and treated with adalimumab for 16 weeks. At baseline, and after 10 days and 16 weeks of treatment clinical scores were assessed and biopsies were taken to examine gene expression at the mRNA and protein level. Results The expression of marker genes for innate immunity, and epidermal differentiation and proliferation was rapidly restored to normal levels, whereas genes of the adaptive immune system showed a delayed decrease. The static and dynamic course of CD1a+ Langerhans cells and Ki67+ nuclei showed a significant strong correlation to the Psoriasis Area and Severity Index score. No correlation between interleukin-17 expression and clinical scores was found. Conclusions The innate immune system is affected during adalimumab treatment well before the changes in the adaptive immune system become apparent. We may speculate that the addition of a treatment with an early effect on adaptive immunity to adalimumab may result in superior effectiveness compared with monotherapies. [ABSTRACT FROM AUTHOR]

Diseases of the skin are amenable to RNAi-based therapies and targeting key components in the pathophysiology of psoriasis using RNAi may represent a successful new therapeutic strategy. We aimed to develop a straightforward and highly reproducible in vitro psoriasis model useful to study the effects of gene knockdown by RNAi and to identify new targets for topical RNAi therapeutics. We evaluated the use of keratinocytes derived from psoriatic plaques and normal human keratinocytes (NHKs). To induce a psoriatic phenotype in NHKs, combinations of pro-inflammatory cytokines (IL-1α, IL-17A, IL-6 and TNF-α) were tested. The model based on NHK met our needs of a reliable and predictive preclinical model, and this model was further selected for gene expression analyses, comprising a panel of 55 psoriasis-associated genes and five micro-RNAs (miRNAs). Gene silencing studies were conducted by using small interfering RNAs (siRNAs) and miRNA inhibitors directed against potential target genes such as CAMP and DEFB4 and miRNAs such as miR-203. We describe a robust and highly reproducible in vitro psoriasis model that recapitulates expression of a large panel of genes and miRNAs relevant to the pathogenesis of psoriasis. Furthermore, we show that our model is a powerful first step model system for testing and screening RNAi-based therapeutics. [ABSTRACT FROM AUTHOR]

Background Recent studies have emphasized the importance of heritable and acquired skin barrier abnormalities in common inflammatory diseases such as psoriasis and atopic dermatitis (AD). To date, no comprehensive studies on the effect of experimental barrier disruption on cornified envelope protein expression have been performed. Objectives To analyse the effect of experimental skin barrier disruption on the expression of cornified envelope structural proteins and keratinocyte differentiation-regulating proteins. Methods We examined mRNA (day 1, 3 and 7) and protein (day 1, 2, 4 and 9) expression levels of structural proteins and regulatory molecules after sodium dodecyl sulphate (SDS) application on normal skin, and tape stripping of uninvolved epidermis of patients with psoriasis and AD and healthy controls. Results Upon tape stripping, several structural molecules were significantly downregulated (at the mRNA level as well as the protein level), including LCE5A, LCE2B, FLG, FLG2 and LOR, whereas others were upregulated: IVL, SPRR1, SPRR2, HRNR and most notably LCE3A. The epidermal crosslinking enzymes TGM1, TGM3 and TGM5 were all upregulated, whereas proteases involved in the desquamation process (CTSV, KLK5 and KLK7) were downregulated or unaffected. Most results were similar in SDS-instigated irritant contact dermatitis. There was no significant difference in response between normal epidermis and nonlesional skin of patients with psoriasis and AD. Conclusions Skin barrier disruption induces a temporary barrier repair response composed of increased expression of several cornification-related proteins, and decreased expression of some structural and desquamation-related proteins. [ABSTRACT FROM AUTHOR]

Tenascin-X is a large extracellular matrix glycoprotein that is widely distributed within connective tissues and is associated with an autosomal recessive type of Ehlers-Danlos syndrome (EDS). Tenascin-X represents the first EDS susceptibility gene that does not code for a fibrillar collagen or collagen-processing enzyme. We describe a paediatric case of tenascin-X deficiency and review the literature. [ABSTRACT FROM AUTHOR]

Psychological stressors might contribute to the severity of chronic inflammatory diseases such as psoriasis by dysregulating hypothalamic-pituitary-adrenal (HPA) axis activity. To evaluate the role of cortisol, a key component of the HPA axis, in reaction to psychological stress in patients with psoriasis. Serum cortisol, clinical indicators of disease severity (Psoriasis Area and Severity Index) and self-report measures of daily stressors were measured monthly for 6 months in 62 patients with psoriasis. In addition to the previous findings in this sample showing that peak levels of daily stressors predicted an increase in disease severity a month later, the peak levels of daily stressors were also significantly associated with a lower cortisol level. Moreover, patients who persistently experienced higher levels of daily stressors had lower mean cortisol levels than patients who experienced lower levels of daily stressors. Results suggest that daily stressors influence disease outcome in patients with psoriasis by affecting cortisol levels at moments of high stress. Furthermore, patients with persistently high levels of stressors seem to have a specific psychophysiological profile of lowered cortisol levels and may be particularly vulnerable to the influence of stressors on their psoriasis. [ABSTRACT FROM AUTHOR]

Background Microarray studies on the epidermal transcriptome in psoriasis and atopic dermatitis (AD) have revealed genes with disease-specific expression in keratinocytes of lesional epidermis. These genes are possible candidates for disease-specific pathogenetic changes, but could also provide a tool for molecular diagnostics of inflammatory skin conditions in general. Objectives To analyse if gene expression signatures as found in purified epidermal cells from AD are also present in other eczematous conditions such as allergic and irritant contact dermatitis. Methods We used real-time quantitative polymerase chain reaction, immunohistochemistry and bioinformatics to investigate gene expression in different forms of eczema. Normal epidermis and psoriatic epidermis were analysed for comparison. Results Carbonic anhydrase II was highly induced in epidermis from all forms of eczema but not in psoriasis. Remarkably, the presumed neuron-specific Nel-like protein 2 showed a strong induction only in AD epidermis. Interleukin-1F9, elafin, β-defensin-2 and vanin-3 were strongly induced in psoriasis, but not in any type of eczema. High levels of the chemokines CCL17 and CXCL10 were predominantly found in epidermis of allergic contact dermatitis. The chemokine CXCL8 was highly expressed in psoriasis, AD and allergic contact dermatitis, but not in irritant contact dermatitis. Cluster analysis or multinomial logistic regression indicated that expression levels of a set of seven genes are a strong predictor of the type of inflammatory response. Conclusions These observations contribute to molecular diagnostic criteria for inflammatory skin conditions. [ABSTRACT FROM AUTHOR]

Background There is increasing evidence that stressors contribute to the severity of chronic inflammatory diseases such as psoriasis. However, much less is known about possible individual differences between patients in their stress reactivity, particularly the role of cognitive and behavioural factors, such as the role of worrying or scratching behaviour, in reaction to itch. Objectives To investigate the direct and moderating role of individual stress reactivity factors, particularly of cognitive and behavioural patterns of worrying and scratching, on the relationship between daily stressors and changes in disease severity [Psoriasis Area and Severity Index (PASI)] and itch in patients with psoriasis. Methods Patients were followed for 6 months through monthly clinical and self-reported measures of daily stressors, itch, disease severity and individual reactivity factors. Data from 62 patients were suitable for analysis. Results Cognitive and behavioural patterns of worrying and scratching were both independently related to an increase 4 weeks later in disease severity (PASI) and itch, at moments when patients experienced a high level of daily stressors. At these moments, stressors also interacted with vulnerability factors, showing that patients with more daily stress and high worrying and scratching had particularly worsened disease severity and itch. Conclusions Patients with high levels of worrying and scratching are most vulnerable to the impact of stressors on their psoriasis, particularly at highly stressful periods. [ABSTRACT FROM AUTHOR]

There is evidence to suggest that genetic factors play an important role in the development of basal cell carcinomas (BCCs), and that skin neoplasms might be a sign for a genetic predisposition to cancer. We investigated whether the incidence of visceral and skin malignancies among first-degree relatives of BCC-patients was increased. Postal questionnaires were sent to 249 BCC-patients, who were divided into two groups (young = BCC under the age of 51 years and older = BCC over the age of 50 years), and asked them about cancer in their first-degree relatives. The reported numbers of cancer among the relatives were compared with the expected numbers based on sex and age-specific population-based incidence rates. The accuracy of the reported diagnoses was verified. A total of 157 BCC-patients reported 277 malignancies in 1,272 relatives. The incidence of the following cancers was higher than expected in relatives from young BCC-patients: bone and soft tissue (O/E = 3.91; 95% CI: 1.43–8.66), skin (O/E = 2.13; 95% CI: 1.30–3.29) and digestive tract (O/E = 1.59; 95% CI: 1.10–2.23). In relatives of older BCC-patients, only the incidence of digestive tract cancer was higher than expected (O/E = 1.44; 95% CI: 1.08–1.89). Diagnoses that were verified turned out to be accurate in 87% of the cases. This study suggests that the risk of certain cancers, particularly that of the digestive tract, in first-degree relatives of BCC-patients is increased. These findings may indicate a genetic predisposition to both skin and visceral malignancies in this patient group. [ABSTRACT FROM AUTHOR]