Experience of Being Young With Psoriasis: Self-Management Support Needs.

Psoriasis is a long-term condition with a possibly cumulative life course impairment. Young people struggle to minimize its effects on appearance and functioning. To date, the self-management needs of adolescents suffering from psoriasis have been underinvestigated. Using focus groups and individual interviews, we present an interpretive description of young people's experiences of living with psoriasis, the challenges they face, and the support they need to relieve suffering and come to terms with their condition. This process is characterized by loneliness, the self-imposition of limitations, and the lack of personalized knowledge and communication skills to manage the impact of disease and society's reactions. Our study provides insight into needs of early interventions tailored to address condition, role, and emotional management, involving parent education, peer support, storytelling, and roles for professionals. We argue that further research should involve young people, their parents, and professionals in the development and evaluation of interventions.

Interleukin 20 protein locates to distinct mononuclear cells in psoriatic skin.

We previously demonstrated that mRNA for the pro-inflammatory cytokine interleukin 20 (IL-20) is expressed in suprapapillary keratinocytes of lesional psoriatic skin (LS). Here, we describe the distribution of IL-20 protein and the identity of the IL-20-positive cells in LS. We found that the main part of IL-20 immunoreactivity is present in mononuclear cells of the dermal papillae, and that the IL-20-positive cells located in the papillae were langerin+, CD1a+, CD4+ and CD303+. These cells might be immature dendritic cell. In situ hybridization for IL-20 mRNA on non-LS, ex vivo stimulated with IL-1ß revealed a colocalization between IL-20 mRNA and the keratinocyte marker CK14. No IL-20 mRNA was detected in the dermal mononuclear cells. Our results suggest that IL-20 is produced by keratinocytes, released into the epidermis and then possibly taken up by papillary mononuclear cells. Our study supports that IL-20 is involved in the pathogenesis of psoriasis.

Implementing best practice in psoriasis: a Nordic expert group consensus.

In the absence of Nordic-wide guidelines on the best practice management of psoriasis, this paper aims to provide Nordic recommendations for treatment goals, evaluation of quality of life impact and assessment/management of co-morbidities. This Delphi approach consisted of telephone interviews, local Nordic face-to-face meetings, and a Nordic-wide meeting, in which questions on treatment goals, quality of life impact and assessment/management of co-morbidities were posed to 17 dermatologists with psoriasis-treatment experience to gain consensus (≥ 90% agreement). The dermatologists agreed on the individualisation of treatment goals using Psoriasis Area and Severity Index and Dermatology Life Quality Index, which should be measured at the same frequency. Training of healthcare professionals on the use of these tools and psychological assessments were considered important, along with the referral of psoriasis patients with cardio-metabolic risk factors to their general practitioner. In order to achieve the best practice management of psoriasis, Nordic dermatologists should be trained and adhere to these recommendations in conjunction with available treatment guidelines.

Studies of Jak/STAT3 expression and signalling in psoriasis identifies STAT3-Ser727 phosphorylation as a modulator of transcriptional activity.

Jak/Tyk proteins have recently aroused as possible therapeutic targets for the treatment of psoriasis. In psoriasis, these proteins signal through STAT molecules including STAT3, and STAT3 expression and activation has been shown augmented in psoriatic lesions. Here, we characterized the expression of Jak/Tyk proteins in lesional compared with non-lesional psoriatic skin. Jak1, Jak2 mRNA and protein and Tyk2 mRNA appeared to be downregulated, whereas Jak3 mRNA expression was increased. Moreover, STAT3 expression and activation was examined in psoriasis. STAT3 is activated at two phosphorylation sites: Tyr705 and Ser727. Both phosphorylation sites were phosphorylated in lesional psoriatic skin. The activation of STAT3 by Jak/Tyk proteins was studied in cultured normal human keratinocytes. Tyr705 phosphorylation was induced by IL-6 and IL-20 in a Jak2-dependent manner, and moreover, phosphorylation of Tyr705 produced a strong increase in STAT3 transcriptional activity. TNFα, 12-O-Tetradecanoylphorbol 13-acetate (TPA) and UVB irradiation induced Ser727 phosphorylation of STAT3 in an ERK1/2- and p38 MAPK-dependent manner, which resulted in a modulatory effect on STAT3 transcriptional activity. Our results demonstrate how different signalling pathways can integrate and lead to regulation of STAT3 transcriptional activity.

IL-20, IL-21 and p40: potential biomarkers of treatment response for ustekinumab.

Although biological drugs in psoriasis treatment show clinical efficacy, there are still a proportion of patients in whom little treatment response is obtained. The aim of this study was to identify molecular biomarkers for treatment response and to investigate the molecular effects of ustekinumab treatment of psoriasis. The mRNA expression of various genes in skin biopsies was analysed by quantitative polymerase chain reaction (qPCR). At baseline, there was no significant clinical difference be-tween responders and non-responders. Ten patients were clinical responders, with a mean baseline Psoriasis Area and Severity Index (PASI) score of 15.4 and a mean percentage improvement of 89.6%. No significant reduction in PASI during treatment was seen among the 5 non-responders. In the responder group, ustekinumab therapy reduced the mRNA expression of the majority of the studied genes in lesional psoriatic skin. IL-20, IL-21 and p40 mRNA expression in lesional psoriatic skin at baseline were significantly upregulated by factors of 2.7, 2.4 and 2.3, respectively, among non-responders compared with responders. The mRNA levels of p40, IL-20 and IL-21 at baseline may serve as potential predictors of treatment response to ustekinumab treatment.

Treatment patterns, treatment satisfaction, severity of disease problems, and quality of life in patients with psoriasis in three Nordic countries.

Biological drugs are expensive, but can reduce symptoms and increase quality of life for patients with psoriasis. The aim of this study was to examine quality of life, disease severity and treatment satisfaction in Danish, Finnish and Swedish patients with psoriasis. Based on 12 months' data from patient surveys and chart reviews, 3 treatment groups were identified: topical, systemic and/or biological <12 months, and biological for 12 months. Regression analyses were performed to investigate influence on treatment satisfaction, disease problems and quality of life. Patients treated with biological drugs for 12 months showed the highest treatment satisfaction and the lowest Dermatology Life Quality Index score. A number of patients with topical treatment reported low quality of life, severe or very severe disease problems, and low treatment satisfaction. Some patients with psoriasis may be under-treated and might benefit from a more aggressive treatment strategy. It is important, however, that resource utilization is optimized and patients are not treated with more advanced agents than necessary.

Tumor necrosis factor α-mediated induction of interleukin 17C in human keratinocytes is controlled by nuclear factor κB.

IL-17C is a member of the IL-17 family of cytokines. The expression of IL-17C has been demonstrated to be strongly induced by TNFα in human keratinocytes, and recently the level of IL-17C was found to be increased in the inflammatory skin disease psoriasis. However, little is known about the molecular mechanisms involved in the regulation of IL-17C. Here, we show that pretreatment of cultured human keratinocytes with the inhibitor of κB kinase 2 inhibitor, SC-514, resulted in a significant reduction in both IL-17C mRNA and protein expression, indicating the significance of this pathway in the regulation of IL-17C. NF-κB binding sites were identified upstream from the IL-17C gene, and by electrophoretic mobility shift assay NF-κB was shown to bind to all three identified binding sites. Moreover, NF-κB binding to these sites was inducible by TNFα. Supershift analysis revealed binding of the NF-κB subunits p65 and p50 to all three NF-κB binding sites. To determine the contribution of NF-κB in IL-17C expression, we conducted luciferase gene reporter experiments and demonstrated that a 3204-bp promoter fragment of IL-17C containing three putative NF-κB binding sites was strongly activated by TNFα. Interestingly, mutations of the three NF-κB binding sites revealed that one specific NF-κB binding site was crucial for the TNFα-mediated IL-17C induction because mutation of this specific site completely abolished TNFα-induced IL-17C promoter activation. We conclude that the activation of NF-κB (p65/p50) is crucial for the TNFα-induced stimulation of IL-17C expression in human keratinocytes.

Evaluation of recurrence after photodynamic therapy with topical methylaminolaevulinate for 157 basal cell carcinomas in 90 patients.

The aim of this study was to evaluate the effect of photodynamic therapy with topical methylaminolevulinate for the treatment of basal cell carcinomas in a single dermatological department. Ninety patients (34.4% men and 65.6% women) with a total of 157 basal cell carcinomas (111 superficial, 40 nodular, 6 unknown) were treated. Primary endpoint was clinically observed recurrence verified by biopsy 3, 6 and 12 months after treatment, then once a year. Estimated patient recurrence rates were 7% at 3 months, 19% at 6 months, 27% at 12 months and 31% at 24 months. Patients aged over 60 years had significantly higher estimated recurrence rates compared with patients aged 60 years or under (at 12 months, 35% vs. 19%, p?=?0.01). Estimated recurrence rates for tumours was 4% at 3 months, 11% at 6 months, 16% at 12 months and 19% at 24 months. There were significantly higher estimated recurrence rates for nodular basal cell carcinomas compared with superficial basal cell carcinomas (at 12 months, 28% vs. 13%, p?=?0.008). In conclusion, photodynamic therapy is only appropriate for treatment of superficial basal cell carcinoma, and, age above 60 years and histology showing nodular basal cell carcinoma are independent risk factors for developing a recurrent basal cell carcinoma.

CCL27 expression is regulated by both p38 MAPK and IKKß signalling pathways.

The skin-specific chemokine CCL27 is believed to play a pivotal role in establishing the inflammatory infiltrate characteristic for common inflammatory skin diseases. Through binding to the chemokine receptor 10 (CCR10), CCL27 mediates inflammation by promoting lymphocyte migration into the skin. Little is known about the regulation of CCL27 gene expression. The purpose of our study was to investigate the regulation of the IL-1ß-induced CCL27 gene expression in normal human keratinocytes (NHEK). Preincubation of NHEK with the inhibitory κB (IκB) kinase (IKK) inhibitor, SC-514, or the p38 mitogen-activated protein kinase (MAPK) inhibitor, SB202190, revealed a profound reduction in both CCL27 mRNA and CCL27 protein expression indicating the significance of these pathways in the regulation of CCL27 expression. Furthermore, the impact of inhibitors of mitogen- and stress-activated kinase 1 (MSK1) or the mitogen-activated protein kinase-interacting kinases (Mnk1+2), downstream kinases of p38 MAPK, on IL-1ß-induced CCL27 expression in NHEK were investigated. We identified seven NF-κB binding elements upstream from the CCL27 gene start codon using electrophoretic mobility shift assay (EMSA). Supershift analyses demonstrated the involvement of the p50/p65 NF-κB heterodimer. We conclude that IL-1ß-induced CCL27 gene expression in NHEK is regulated through the p38 MAPK/MSK1/Mnk1+2 as well as the IKKß/NF-κB signalling pathways.

Mice lacking MSK1 and MSK2 show reduced skin tumor development in a two-stage chemical carcinogenesis model.

UNLABELLED: Mitogen- and stress-activated protein kinase (MSK)1/2 are two kinases involved in inflammation as well as in cell transformation. PURPOSE: To examine the role of MSK1/2 in skin tumor development. RESULTS: MSK1/2 knockout mice developed significantly fewer skin tumors compared with wild-type mice. The myeloperoxidase activity in TPA-treated skin from MSK1/2 knockout mice was significantly elevated compared with wild-type mice. Furthermore, the mRNA and protein levels of IL-1ß as well as the mRNA expression of TNF-α were significantly increased in MSK1/2 knockout mice. CONCLUSION: These data provide in vivo evidence that MSK1/2 signaling represents a novel tumor-promoting axis in skin carcinogenesis.

Kinetics and differential expression of the skin-related chemokines CCL27 and CCL17 in psoriasis, atopic dermatitis and allergic contact dermatitis.

CCL27 and CCL17 are chemokines believed to be involved in the process of establishing the inflammatory infiltrate, characteristic for the various inflammatory skin diseases. The skin-specific CCL27 binds the chemokine receptor-10 (CCR10), and CCL17 is a chemokine receptor-4 (CCR4) ligand. The purpose of our study was to characterize the expression of CCL27 and CCL17 in the inflammatory skin diseases: psoriasis, atopic dermatitis (AD) and acute allergic contact dermatitis (ACD) induced in nickel-sensitive individuals. Surprisingly, our studies revealed a markedly decreased CCL27 mRNA and protein expression in psoriatic lesions compared with non-lesional psoriatic skin. A minor CCL17 mRNA increase was measured in lesional psoriatic skin. No alterations were found in AD. In ACD, we found a pronounced (90-fold) raise in CCL17 mRNA and a 50-fold increase in CCL17 protein compared with normal skin. A kinetic ACD study of CCL17 expression showed the highest mean value 24 h after hapten application. Furthermore, we found the mRNA levels of CCR10 and CCR4 paralleling the results of their corresponding ligands. Overall, our principal findings were a distinct decrease in CCL27 in lesional psoriatic skin and a marked upregulation of CCL17 in ACD. These findings underscore the differential cutaneous T-cell recruitment in different inflammatory diseases.

The role of mitogen- and stress-activated protein kinase 1 and 2 in chronic skin inflammation in mice.

Mitogen- and stress-activated protein kinase 1 and 2 (MSK1/2) are two kinases phosphorylated by both ERK1/2 and p38 MAPK. Recently, MSK1 and 2 have been reported to act as negative regulators of acute inflammation. In this study, we investigated the role of MSK1/2 in chronic skin inflammation using an oxazolone-induced allergic contact dermatitis model in MSK1/2 knockout mice and wild-type mice. MSK1/2 knockout mice were demonstrated to have significantly increased inflammation compared with wild-type mice. This was measured by an increased ear thickness, elevated infiltration of neutrophils in the skin and increased inflammatory histological changes. Furthermore, we found significantly elevated levels of the proinflammatory cytokines Tumor necrosis factor-α (TNF-α), IL-1ß and IL-6 at both mRNA and protein levels in MSK1/2 knockout mice compared with wild-type mice after oxazolone treatment. In addition, the mRNA expression of the chemokine Thymus and activation regulated chemokine (TARC) was demonstrated to be significantly elevated in oxazolone-treated MSK1/2 knockout mice compared with wild-type mice. The increased expression of TARC was paralleled by increased infiltration of cells positive for the TARC receptor, CCR4, in the dermis of MSK1/2 knockout mice. Our results indicate that MSK1/2 are involved in the activation of feedback mechanisms that dampen oxazolone-induced skin inflammation.

Role of p38 mitogen-activated protein kinase isoforms in murine skin inflammation induced by 12-O-tetradecanoylphorbol 13-acetate.

p38 mitogen-activated protein kinase plays a pivotal role in skin inflammation. The purpose of this study was to investigate the role of the various p38 isoforms. p38ß/δ-knockout-C57BL/6 mice were generated, studied in a 12-O-tetradecanoylphorbol 13-acetate (TPA)-induced skin inflammation model and compared with wild-type mice. The inflammatory response was determined by ear thickness, myeloperoxidase activity and histology. mRNA and protein expression of interleukin (IL)-1ß and IL-6 was determined by quantitative real-time reverse transcription PCR and enzyme-linked immunoassay. In both groups application of TPA resulted in a significant increase in inflammation, and pretreatment with the p38α/ß inhibitor, SB202190 resulted in a significant inhibition. A significantly slower onset but prolonged duration of the response was seen in p38ß/δ knockout mice. This was paralleled by a significant, but transient, lower IL-1ß and IL-6 protein expression in p38ß/δ knockout mice. Although the p38α isoform is important, our data also demonstrate an important role of the p38ß and/or δ isoforms in the regulation of TPA-induced skin inflammation.

Skin cancer risk among solid organ recipients: a nationwide cohort study in Denmark.

This study assessed the risk of skin cancer following transplantation of 4 types of solid organs, and the risk of skin cancer in patients with chronic diseases that lead to organ transplantations. A population-based cohort of 5279 Danish patients who underwent heart, lung, renal and liver transplantation, and 77,782 patients with chronic heart, lung, renal and liver diseases during 1977-2006 were included in the study. Linkage to the Danish Cancer Registry allowed complete follow-up for basal cell carcinoma, squamous cell carcinoma and malignant melanoma. Standardized incidence ratios (SIR) and 95% confidence intervals (CI) were calculated. The SIR for squamous cell carcinoma was highest among heart (SIR = 113; 95% CI: 74-166), then renal (SIR = 81; 95% CI: 68-96), lung (SIR = 65; 95% CI: 28-128) and liver (SIR = 60; 95% CI: 27-113) recipients. SIR for squamous cell carcinoma was 4.8 (95% CI: 2.2-9.0) among renal failure patients, but not greatly elevated among patients with the other chronic diseases studied. Organ transplantation is a risk factor for squamous cell carcinoma, with immunosuppressive treatments being the most likely explanation for the association.

Juvenile psoriasis and its clinical management: a European expert group consensus.

BACKGROUND: Psoriasis, an inflammatory disorder of the skin, can significantly impact on a patient's quality of life, affecting their daily activities and families. The onset of psoriasis in childhood is quite common; however, the treatment of moderate-to-severe disease in this population is challenging, with a paucity of data reported and few licensed agents available. METHODS: A Delphi survey was conducted among a panel of European expert dermatologists and physicians with a particular interest in pediatric inflammatory disorders. The survey covered the aspects of psoriasis types, psoriatic arthritis, diagnosis and treatment options in childhood. RESULTS: A series of consensus opinions were reached, detailing the current practice in Europe for the diagnosis and treatment of psoriasis in childhood. These opinions are presented in the context of evidence from the literature and the current licensure status and indications of therapies for psoriasis in childhood. CONCLUSIONS: These data provide detailed information on the current practices in Europe for treating psoriasis in childhood.

Caring for young people with moderate to severe psoriasis: an interpretive description of parental perspectives.

Introduction: Psoriasis often sets on during childhood or adolescence, when parents have great importance for the young people's self-management, well-being, and quality of life. The aim of this study was to understand parents' perspectives on young people's daily life with psoriasis in order to improve adolescents' self-management.Method: Adopting interpretive, description methodology (ID), focus group discussion, and interviews were conducted with eight parents of adolescents with psoriasis. The analysis was inductive with an iterative comparative approach. Main themes conveying participants' perceptions were identified for constructing a coherent narrative of parents' perspectives on their young people's transition with psoriasis through adolescence.Results: Parents initially perceived psoriasis mainly a physical and treatment-related burden and not until late realized its socio-emotional impact. They eventually found themselves balancing between declining treatment due to fear of side effects and acknowledging the impact on their young people's quality of life and their desire for effective treatment.Conclusions: Caring for young people with psoriasis is a stressful process involving experimental learning to understand and manage the complexity of psoriasis and its impact on adolescents' emotional and social life. Future research should consider integration of shared decision-making and self-management support interventions in routine daily care as focus points.

MK2 regulates the early stages of skin tumor promotion.

The association between inflammation and tumorigenesis is well recognized. Mitogen-activated protein kinase-activated protein kinase-2 (MK2) is known to play a pivotal role in inflammatory processes. Here, we studied the effect of MK2-deficiency and tumor necrosis factor (TNF)-alpha-deficiency on skin tumor development in mice using the two-stage chemical carcinogenesis model. We found that MK2(-/-) mice developed significantly fewer skin tumors compared with both TNF-alpha(-/-) and wild-type mice when induced by initiation with 7,12-dimethylbenz[a]anthracene (DMBA) and by promotion with 12-O-tetradecanoylphorbol-13-acetate (TPA). The TPA-induced inflammatory response was reduced in both, TNF-alpha(-/-) mice and MK2(-/-) mice, but most pronounced in TNF-alpha(-/-) mice, indicating that a reduced inflammatory response was not the only explanation for the inhibited tumorigenesis seen in MK2(-/-) mice. Interestingly, increased numbers of apoptotic cells were detected in the epidermis of MK2(-/-) mice compared with TNF-alpha(-/-) and wild-type mice, suggesting an additional role of MK2 in the regulation of apoptosis. This was further supported by: (i) increased levels of the tumor suppressor protein p53 in MK2(-/-) mice after DMBA/TPA treatment compared with controls, (ii) reduced phosphorylation (activation) of the negative p53 regulator, murine double minute 2 in MK2(-)(/-) mouse keratinocytes in vitro and (iii) a significant decrease in the DMBA/TPA induced apoptosis in cultured MK2(-/-) keratinocytes transfected with p53 small interfering RNA. Taken together, these findings demonstrate a dual role of MK2 in the early stages of tumor promotion through regulation of both the inflammatory response and apoptosis of DNA-damaged cells. These results also identify MK2 as a putative target for future skin carcinoma therapy.

Pro-inflammatory cytokine release in keratinocytes is mediated through the MAPK signal-integrating kinases.

The mitogen-activated protein kinases (MAPKs) are known to play a key role in the regulation of cytokine expression in several cell types. MAPK signal-integrating kinase 1 (Mnk1) is a kinase activated through both the stress- and cytokine-activated p38 MAPK pathway and the classical extracellular signal-regulated kinase 1/2 (ERK1/2) pathway. In this study, we demonstrate that in cultured normal human keratinocytes Mnk1 and its downstream target eukaryotic initiation factor 4E (eIF4E) are phosphorylated in a time-dependent manner in response to stimulation with anisomycin or interleukin (IL)-1beta. Both the stimuli are well-recognized activators of the p38 MAPK pathway. Furthermore, we show that the Mnk inhibitor CGP57380 is capable of inhibiting the phosphorylation of eIF4E in keratinocytes, and that the abolishment of eIF4E phosphorylation dramatically decreases the anisomycin-induced protein release of the pro-inflammatory cytokines tumor necrosis factor-alpha (TNF-alpha), IL-1beta and IL-6 as well as the IL-1beta-induced protein release of TNF-alpha. Therefore, we propose that Mnk1 might contribute to the expression of pro-inflammatory cytokines found in inflammatory skin diseases.

An innovation in topical therapy: insights from international dermatologists.

Topical therapies are appropriate for most patients with psoriasis. These therapies frequently are used as first-line agents for mild and moderate disease and as an adjuvant to phototherapy or systemic treatment. In Europe, vitamin D3 analogues (e.g., calcipotriene) are preferred as first-line therapies and often are used in combination with potent topical corticosteroids. Because calcipotriene and corticosteroids have different mechanisms of action, superior efficacy and reduced side effects can be achieved by their combined use; however, chemical incompatibility prevents combined application. This incompatibility has been overcome by the recent development of a stable formulation of calcipotriene and betamethasone dipropionate. In 7 clinical trials, more than 3000 subjects received once-daily or twice-daily treatment with the 2-compound ointment for 4- to 52-week periods. The overall results indicate that the 2-compound ointment elicits rapid and substantial reductions in Psoriasis Area and Severity Index (PASI) scores. The treatment Calso is well-tolerated.