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Research has revealed new insights into the pathogenesis of psoriasis, leading to new therapeutic options. So far the order of changes in the pathogenesis of psoriasis is unclear. The responses to cutaneous leukotriene B4 (LTB4) application have been studied in the past as an in vivo model for inflammation. The aim of the present study is to find out the order of changes of key steps in inflammation, which all have been shown to be involved in mature psoriatic lesions.To study the dynamics of the consecutive stages of inflammation in challenged skin as a reflection of a psoriasis-like inflammatory response.We examined the dynamics of epidermal growth control and the key representatives of the innate and acquired immune system during the first 72 h after challenging the skin by LTB4 application.Interleukin 17-positive (IL-17+) cells dominate the acute phase of inflammation, whereas T-Bet+ cells seem to increase gradually during the entire observation period. This indicates a more important role for IL-17 in the unstable phase of inflammation and a more prominent role for T-Bet+ cells within the chronic phase.The present model is highly reproducible and is useful in studying the dynamics of a psoriasis-like inflammation with respect to key components of immunity. It could provide a useful tool to study the immediate biological effects of new therapies like anti-IL-17 drugs on IL-17 production and effects on cutaneous inflammation and epidermal proliferation in vivo.

In the pathogenesis of psoriasis, proinflammatory T cells are strongly involved in the inflammatory process, where regulatory T-cell (Treg) function is impaired.As effective Treg function is associated with a numerical balance between Treg and effector T cells, we wondered whether Treg/T-helper cell ratios may be associated with certain stages of the inflammatory process. We opted for the margin zone model as a dynamic approach.From nine patients with chronic plaque psoriasis, 3-mm punch biopsies were obtained from the centre and margin of the lesion, perilesional skin and distant uninvolved skin. Skin biopsies of 10 healthy volunteers were included as a control. Samples were analysed using immunohistochemistry and immunofluorescence.In the transition from symptomless to lesional skin, a significant increase of CD3+, CD4+ and Foxp3+ cells was found. In seven of nine patients the ratio of Treg (Foxp3+) vs. CD4+ T cells was higher in the distant uninvolved skin than in the perilesional and lesional skin. Interestingly, the Foxp3/CD4 ratio in the distant uninvolved skin was even higher than in the skin of healthy controls. Notably, we found that most of the interleukin (IL)-17 expression was not related to CD4+ cells, but to mast cells.The relatively high Foxp3/CD4 ratio in symptomless skin of patients with psoriasis suggests an active immune controlling mechanism distant from the psoriatic plaque. In the margin and centre of the plaque the ratio appears skewed towards effector cells associated with inflammation. IL-17, an important driver of the psoriatic process, is mostly related to mast cells, and only sporadically to T cells.

Basal cell carcinoma (BCC) is the most frequently occurring cancer in humans. Worldwide incidences rise about 10% each year, increasing the burden on dermatologists, general practitioners and pathologists as well as increasing costs for the health care system. Increasingly non-surgical treatment options are used in the treatment of BCC, without histological confirmation of BCC subtype, potentially resulting in under-treatment.We evaluated the diagnostic accuracy of a punch biopsy for the BCC histological subytpe in a primary BCC and the prevalence of biopsy-based under-diagnosis of aggressive subtypes. Accuracy of a punch biopsy was defined as concordance of the diagnosis of subtype of BCC at punch biopsy and excision.A retrospective chart-review was performed of primary BCC, which were proven by punch biopsy and subsequently treated by excision. The first 100 consecutive BCCs per year during the years 2004-2009 were included, yielding a total of 500 evaluated BCCs.The overall accuracy of punch biopsy for BCC subtype at excision was 69%, in single-type BCC 83% (n = 343) and in mixed-type BCC 37% (n = 157). Accuracy varied substantially according to BCC subtype, being highest in the superficial subtype (84%) and subsequently in infiltrative (69%), nodular (63%) and micronodular subtype (38%). In 11% of all cases, an unsuspected more aggressive subtype was present.Punch biopsy has a high accuracy in single-type BCCs and a considerably lower accuracy in mixed-type BCCs for establishing BCC subtype compared to excision. The presence of an unsuspected aggressive subtype could explain therapy failure of non-surgical treatments like imiquimod or photodynamic therapy.

In vivo reflectance confocal microscopy (RCM) is a novel, noninvasive imaging technique which enables imaging of skin at a cellular resolution comparable to conventional microscopy.We performed a pilot study to evaluate RCM as a noninvasive tool for monitoring ultraviolet (UV) B phototherapy in psoriasis.In six patients with psoriasis, lesional and nonlesional skin was selected for RCM imaging using a standardized protocol. Well-known histological features of psoriasis were visualized: parakeratosis, acanthosis, agranulosis, papillomatosis, presence of epidermal inflammatory cells, increased number of papillary capillaries and increased capillary blood flow. RCM imaging was performed before the first irradiation with UVB phototherapy, after nine irradiations, at clearance and 12 weeks after clearance. In four patients, 4-mm punch biopsies were obtained and stained with haematoxylin-eosin. Additionally, immunohistochemical staining was performed with monoclonal antibodies specific for CD31, CD3, filaggrin, K16, Ki67 and CD1a for correlation to RCM images.There was a high correlation between clinical, RCM and histological features. Normalization of RCM and histological features corresponded highly to clinical improvement of psoriasis.This study is the first to establish the use of RCM as an effective tool for noninvasive monitoring of UVB phototherapy in patients with psoriasis. Potentially, RCM could be used in many other skin diseases for monitoring therapeutic response on a cellular level in a clinical or research setting.

Protoporphyrin IX is present in psoriatic skin without the preceding application of aminolevulinic acid. Therefore, endogenous photosensitizers in psoriasis are a potential target for photodynamic treatment with high-dose visible light.In the present pilot study, treatment with high-dose blue and red light in psoriasis were analysed with respect to clinical improvement and potential side-effects.In 20 patients, two stable psoriatic plaques were treated with either blue or red light, three times weekly for four consecutive weeks. To remove scaling that could potentially interfere with penetration of the light into the skin, daily application of 10% salicylic acid in petrolatum was started at the screening visit and continued until the end of the study.Clinical improvement was seen after treatment with blue as well as after treatment with red light. With respect to scaling and induration, no major differences between both light sources were seen. Improvement of erythema, however, continued in blue light irradiated plaques throughout the whole study period, whereas after red light no significant improvement was seen after six illuminations.The clinical improvement of psoriasis, with respect to erythema, in particular after blue light and to a lesser extent after red light indicates that visible light treatment could represent a treatment option for psoriasis.

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.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.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.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, beta-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.These observations contribute to molecular diagnostic criteria for inflammatory skin conditions.

Psoriasis has been shown to highly accumulate protoporphyrin IX (PpIX), but a variable distribution within plaques after fluorescence diagnosis is seen. It is unknown what causes this heterogeneity of fluorescence in psoriatic skin, despite adequate keratolytic treatment. Variations in fluorescence might explain the variable and the mostly partial clinical response of psoriasis seen after photodynamic therapy (PDT).This study examines morphological and immunohistochemical differences in inhomogeneous PpIX-induced fluorescence in stable plaque psoriasis.Fourteen patients with stable plaque psoriasis were included in this study. In each patient one psoriatic plaque was incubated with 20% 5-aminolaevulinic acid (ALA) ointment for 3 h after keratolytic treatment. Fluorescence diagnosis with ALA-induced porphyrins (FDAP) was performed and subsequently high- and low-fluorescent psoriatic skin samples were biopsied. Biopsies were investigated with respect to histological hyperkeratosis (thickness of stratum corneum), proliferation (Ki-67 antigen), keratinization (K10, filaggrin) and inflammation (CD3). Digital images acquired with FDAP were analysed using image analysis software.Inhomogeneous fluorescence was seen in 12 of the 14 plaques. A significantly thicker stratum corneum was found in low-fluorescent psoriatic skin compared with highly fluorescent skin. Fluorescence intensity and thickness of the stratum corneum proved to be negatively correlated. The variable-fluorescent parts of the lesional psoriatic skin showed no differences in epidermal proliferation, keratinization or inflammation.Heterogeneous ALA-induced fluorescence in psoriasis plaques related to inhomogeneous distribution of PpIX in the epidermis may result from differences in penetration of ALA and/or light within a plaque caused by differences in stratum corneum thickness. The variable clinical response seen after PDT in psoriasis could be explained by this. These findings are consistent with the general assumption that optimal desquamation prior to FDAP or PDT is required for the most favourable results.

Clinical presentation, therapeutic options, micro-environment and HLA-typing have been reported to be different in flexural psoriasis as compared to plaque psoriasis. We were interested in any difference concerning the pathogenesis of both conditions. By analysing T-cell subsets, NK-T cells and proliferation and differentiation markers, insight into the pathogenesis of both subtypes was obtained. Quantitative studies of T-cell subsets, cells expressing NK-receptors and markers of proliferation and differentiation in flexural and plaque psoriasis were investigated. Biopsies from 6 patients with both flexural and plaque lesions were obtained and processed for immunohistochemistry. Several T-cell subsets were stained: CD4+, CD8+, CD2+, CD25+, CD45RO+ and CD45RA+ T-cells. In addition cells expressing NK receptors were stained: CD94+ cells and CD161+ cells. T-cell subsets and cells expressing NK-receptors were analysed by immunohistochemical scoring. The proliferation marker Ki-67 and differentiation marker keratin-10 were revealed immunohistochemically by MIB-1 and RKSE60 respectively. Both markers were analysed using quantitative image analyses. The number of Ki-67 positive nuclei and the percentage of keratin-10 positive epidermal cells in flexural and plaque psoriasis were comparable. There is no difference between flexural and plaque psoriasis concerning other T-cell subsets. However a highly significant reduction is seen in flexural psoriasis with respect to CD161+ cells in the dermis. The similarity of chronic plaque psoriasis compared to flexural psoriasis with respect to T-cell subsets, epidermal proliferation and keratinization suggests that both conditions are pathogenetically identical. We propose the decreased quantity of lesional CD161+ cells in the dermis of flexural psoriatic lesions may result from chronic microbial challenge in flexural psoriasis.

Inflammatory linear verrucous epidermal nevus (ILVEN) is a rare skin disorder with a clinical and histological resemblance to psoriasis. In the past clinical and histological criteria have been defined. However, there remains a discussion as to whether ILVEN is a disease entity distinct from linear psoriasis. Our objective was to compare by quantitative immunohistochemistry the subsets of T-lymphocytes and markers for epidermal growth and keratinisation in biopsies taken from skin lesions of 4 patients with psoriasis and 3 patients with ILVEN: 1. patients with psoriasis (case 1-4) 2. patient with ILVEN cum psoriasis (case 5) 3. patients with ILVEN sine psoriasis (case 6 and 7). Our aim was to delineate ILVEN from psoriasis. Four patients with active psoriasis and three patients with signs and symptoms of ILVEN are described in this case report. Two patients of the ILVEN group had only linear verrucous lesions (ILVEN sine psoriasis), and one patient had linear lesions combined with widespread psoriasis outside the linear verrucous lesion (ILVEN cum psoriasis). The following markers were investigated in skin biopsies taken from the aforementioned patients by quantitative immunohistochemistry: CD2, CD4, CD8, CD25, CD161, CD94, CD45RO, CD45RA, HLA-DR, Keratin-10, Ki-67. In patients with ILVEN (cum and sine psoriasis) the number of Ki-67 positive nuclei, tended to be lower, the number of keratin-10 positive cells and HLA-DR expression higher as compared to psoriasis. In ILVEN sine psoriasis all T-cell subsets and cells expressing NK receptors were reduced as compared to psoriasis, except for CD45RA+ cells, whereas in the patient with ILVEN cum psoriasis the number of these T cell subsets had an intermediary position. In particular the density of CD8+, CD45RO+ and CD2+, CD94 and CD161 showed a marked difference between ILVEN sine psoriasis and psoriasis. In addition to the increased keratin 10 expression in ILVEN sine psoriasis, T cells relevant in the pathogenesis of psoriasis are markedly reduced in ILVEN sine psoriasis as compared to psoriasis. T-cell subsets in ILVEN cum psoriasis had an intermediary position.