Plaque psoriasis in children and adolescents – the role of etanercept

Federica Ricceri, Lara Tripo, Leonardo Pescitelli, Francesca PrignanoDivision of Clinical, Preventive and Oncology Dermatology, Department of Critical Care Medicine and Surgery, University of Florence, Florence, ItalyBackground: Childhood-onset psoriasis affects approximately one-third of the psoriatic population. Among many potential treatments of childhood psoriasis, biological agents are emerging as a valuable option in the management of this disease. In Europe, etanercept has recently been approved for children aged 6 years and over. Data from a well-designed clinical trial indicate that in children, etanercept effectively reduces psoriasis symptoms, with beneficial effects evident as early as 4 weeks after the onset of therapy. The treatment is generally well tolerated; mild injection site reactions are the most common adverse events reported in the literature. Published data of etanercept use in children show promising results, but further clinical studies are necessary to confirm its long-term efficacy and safety.Keywords: pediatric psoriasis, anti-TNF-α, etanercep

Itch in psoriasis: epidemiology, clinical aspects and treatment options

F Prignano, F Ricceri, L Pescitelli, T LottiDepartment of Dermatological Sciences, University of Florence,Florence, ItalyBackground: Pruritus is an important symptom in psoriasis vulgaris, may be severe and seriously affect the quality of life of patients, but published data on its frequency and characteristics are limited.Objective: The study objective was to characterize the prevalence of itch in psoriatic patients and the effect of treatment modalities by using a comprehensive itch questionnaire of our own design.Methods: A structured itch questionnaire was given to 90 patients with moderate to severe chronic-plaque psoriasis selected consecutively from the patients visiting the Department of Dermatology of the University of Florence. The questionnaire concerned the areas involved in psoriasis and pruritus, the pruritus characteristics, the worsening and relieving factors and treatment modalities. Itch intensity was reflected by a 10 point visual analog scale (VAS) and the degree of symptoms discriminated between mild (1–3), moderate (4–7) and severe (8–10).Results: Almost 85% of psoriatic patients suffered from itching; the frequency of pruritus was daily and mean intensity by VAS scale was moderate. Presence and intensity of pruritus and body mass index (BMI) were correlated. 40% of patients with pruritus were overweight (BMI > 25 < 30) and 10% obese (BMI > 30). Almost all patients appeared unsatisfied with the available treatment modalities for pruritus in psoriasis. Emollients, topical steroids and calcipotriol cream could relieve pruritus but their effect was temporary. Among the antipsoriatic therapies, phototherapy with narrow band ultraviolet B (nb-UVB) was the most effective treatment in reducing pruritus. Biological therapies, mainly etanercept and efalizumab, proved useful in its control.Conclusions: The questionnaire was a useful tool to characterize itch, and the results might help us to better understand pruritus in psoriasis. The results confirmed the need for a global study of psoriasis with regard to both the cutaneous manifestations and the itch symptom.Keywords: itch, psoriasis, pruritus, epidemiology, phototherapy, etanercept, efalizuma

The psoriatic shift induced by interleukin 17 is promptly reverted by a specific anti-IL-17A agent in a three-dimensional organotypic model of normal human skin culture

Interleukin 17A (IL-17A), mainly produced by the T helper subclass Th17, plays a key role in the psoriatic plaque formation and progression. The clinical effectiveness of anti-IL-17A agents is documented, but the early and specific mechanisms of their protection are not identified yet. The challenge of the present study is to investigate the possible reversal exerted by a specific anti-IL-17A agent on the psoriatic events induced by IL-17A in a three-dimensional organotypic model of normal human skin. Bioptic skin fragments obtained after aesthetic surgery of healthy women (n=5) were incubated with i) IL-17A biological inhibitor (anti-IL-17A), ii) IL-17A, iii) a combination of IL-17A and its specific IL-17A biological inhibitor (COMBO). A Control group was in parallel cultured and incubation lasted for 24 and 48 h epidermal-side-up at the air-liquid interface. All subjects were represented in all experimental groups at all considered time-points. Keratinocyte proliferation and the presence of epidermal Langerhans cells were quantitatively estimated. In parallel with transmission electron microscopy analysis, immunofluorescence studies for the epidermal distribution of keratin (K)10, K14, K16, K17, filaggrin/occludin, Toll-like Receptor 4, and Nuclear Factor kB were performed. IL-17A inhibited cell proliferation and induced K17 expression, while samples incubated with the anti-IL-17A agent were comparable to controls. In the COMBO group the IL-17A-induced effects were almost completely reverted. Our study, for the first time, elucidates the most specific psoriatic cellular events that can be partially affected or completely reverted by a specific anti-IL-17A agent during the early phases of the plaque onset and progression. On the whole, this work contributes to expand the knowledge of the psoriatic tableau

Morphological analysis of JAK1 intracellular pathway activation after pro-inflammatory psoriatic cytokines exposure: inside-out and outside-in the epidermis

For their normal growth, cells depend on a continuous flow of signals from the environment. The Janus kinases (JAK) 1 transducers signalling pathway is a pleiotropic cascade used to transduce a multitude of signals among cells. A variety of ligands including cytokines, hormones, growth factors, and their receptors stimulate the JAK1 pathway. Cytokines, a large and very heterogeneous family of small and generally soluble glycoproteins, both control multiple biological processes as haematopoiesis, inflammation, and immunity playing a central role in cell-cell communication. Their action is mediated by the binding to specific receptors on the cell surface, thus transducing biological information to target cells [1]. Pro-inflammatory cytokines play a pivotal role in several inflammatory illnesses including psoriasis. Among them, interleukin (IL)-17, IL-22, IL-23 and tumor necrosis factor (TNF)-alpha play a central role. In the formation and progression of the psoriatic lesion a typical marker is keratin (K) 17 which is correlated with psoriasis severity. The aims of this study were to evaluate the early, direct, and specific effects of pro-inflammatory psoriatic cytokines i) on the activation of the intracellular pathway JAK1 and ii) on the correlation with the induction of K17 expression in a three-dimensional model (3D) of human skin (n=7) by immunofluorescence. Biopsies were cultured overnight epidermal side-up in a Transwell system and exposed to 50 ng/ml IL-17, or 100 ng/ml IL-22, or 50 ng/ml IL-23 or 100 ng/ml TNF-alpha. Samples were harvested 24 (T24), 48 (T48), and 72 (T72) hours after cytokine incubation. In samples not exposed to cytokines, a JAK1 slight labelling was observed throughout the epidermis, decreasing at T72 in the lower layers. At T24, IL-17 and IL-22, but not IL-23 and TNF-alpha, induced an expression of JAK1 in the spinous layer. At T72, JAK1 immunostaining decreased in all samples, similarly to controls. K17 immunopositivity was induced and progressively increased with time in the suprabasal layers of epidermis in all experimental groups, with the exception of the TNF-alpha group. These results suggest that cytokines exert parallel effects on JAK1 pathway activation and K17 induction. In conclusion, 3D this model, reproducing some features of psoriatic microenvironment, represents a useful experimental approach to dissect the specific role of each cytokine in the different steps of psoriatic lesion formation

Erythrodermic psoriasis treated with ustekinumab: An Italian multicenter retrospective analysis

Erythrodermic psoriasis (EP) is one of the most severe cutaneous conditions which may lead to serious morbidity and even mortality. This condition is often difficult to manage and, due to its rarity (estimated prevalence 1–2.25% of psoriatic patients) there is a lack of high-quality medical literature examining treatment options [1]

Modulation of epidermal proliferation and terminal differentiation in a promising ex vivo human skin model mimicking a psoriatic microenvironment

Epidermal keratinocyte hyperproliferation is one of the key features involved in the formation/progression of psoriatic lesions and is driven by cytokines, among which TNF-\u3b1, IL-17, IL-22 and IL-23, secreted by both activated resident immune cells and keratinocytes (1). The network orchestrated by these cytokines is essential for the communication between resident cells and infiltrating cells and is due to redundancy, synergism and, sometimes, the reciprocal antagonism of cytokines. The aims of our study were to investigate whether the exposure of normal human skin to four main psoriatic cytokines, i.e. TNF-\u3b1, IL-17, IL-22, and IL-23 (cytokine mix) induced i) a modulation of epidermal proliferation and ii) a modification of keratinocyte terminal differentiation (TD). Human skin samples (n = 5) obtained from healthy 20-40 years-old women after plastic surgery, were exposed to the cytokine mix in a Transwell system at air-liquid interface as previously described (2). For each patient a control (ctr) group was not exposed to cytokine mix. Samples were harvested 5 (T5), 24 (T24), 48 (T48) and 72 (T72) hours after cytokine stimulation, processed for paraffin embedding and immunofluorescence analysis for the quantitative analysis of epidermal proliferation and the expression of the TD biomarkers, keratin (K) 10 and 17. A decrease of cell proliferation was evident starting from T5 in samples exposed to cytokine mix and was progressively more marked at later time points (T5 ctr 47.44 \ub1 6.90 vs mix 23.07 \ub1 8.84; T24 ctr 41.12 \ub1 12.78 vs mix 12.16 \ub1 1.53; T48 ctr 25.88 \ub1 10.21 vs mix 2.19 \ub1 2.44; T72 ctr 10.49 \ub1 2.52 vs mix 0.65 \ub1 1.02) (p<0.05). K17 expression was evident in samples exposed to the cytokine mix. Altogether the present results suggest that cell proliferation inhibition and K17 expression could be regarded as the basis for a later response to injury leading to psoriatic lesion formation/progression. In conclusion, this model allows to investigate the intimate interplay among different psoriatic cytokines and new insights may be of potential value for future clinical treatments

Interleukin 17 affects early and late biomarkers of terminal differentiation in a three-dimensional model of normal human skin

Interleukin (IL)-17 expression has been correlated with the pathogenesis of multiple autoimmune diseases, as rheumatoid arthritis, multiple sclerosis, and, more recently, psoriasis (1). During plaque formation, the interplay between immunocytes and keratinocytes is deregulated, resulting in the altered expression of keratin (K) 17, occludin, and filaggrin in psoriatic lesional epidermis (2, 3). The involvement of IL-17 in psoriasis pathogenesis has been identified (4), but the specific and intrinsic effects exerted by this cytokine have not been thoroughly investigated. The aim of the present work was to study by indirect immunofluorescence the expressions of K17, K10, filaggrin, and occludin in a three-dimensional model of normal human skin standardized in our laboratory (5). Human skin samples (n = 5) obtained from healthy 20-40 years-old women after plastic surgery, were exposed to IL-17 in a Transwell system at air-liquid interface as previously described (5). Samples were harvested 24 (T24), 48 (T48), and 72 (T72) hours after IL-17 stimulation and processed for paraffin embedding and immunofluorescence analysis for expressions of K17, K10, filaggrin, and occludin. After IL-17 exposition, K17 immunostaining progressively increased with time in the upper stratum spinosum, while K10 expression resulted homogeneously distributed in the suprabasal layers. In IL-17 treated samples occludin staining became irregular starting from 24 hours. On the other hand, filaggrin distribution was affected in T48 samples, where the immunolabelling was discontinuously punctuate. In conclusion, our results strongly support the use of this experimental setting for investigating the time-dependent early effects induced by IL-17 in normal human skin

Role of Network Topology in the Synchronization of Power Systems

We study synchronization dynamics in networks of coupled oscillators with bimodal distribution of natural frequencies. This setup can be interpreted as a simple model of frequency synchronization dynamics among generators and loads working in a power network. We derive the minimum coupling strength required to ensure global frequency synchronization. This threshold value can be efficiently found by solving a binary optimization problem, even for large networks. In order to validate our procedure, we compare its results with numerical simulations on a realistic network describing the European interconnected high-voltage electricity system, finding a very good agreement. Our synchronization threshold can be used to test the stability of frequency synchronization to link removals. As the threshold value changes only in very few cases when aplied to the European realistic network, we conclude that network is resilient in this regard. Since the threshold calculation depends on the local connectivity, it can also be used to identify critical network partitions acting as synchronization bottlenecks. In our stability experiments we observe that when a link removal triggers a change in the critical partition, its limits tend to converge to national borders. This phenomenon, which can have important consequences to synchronization dynamics in case of cascading failure, signals the influence of the uncomplete topological integration of national power grids at the European scale.Comment: The final publication is available at http://www.epj.org (see http://www.springerlink.com/content/l22k574x25u6q61m/

Effect of TNF-alpha and IL-17 on TLR expression and Langerhans cells phenotype in a three-dimensional model of normal human skin: a morphological study

Toll-like receptors (TLRs) are essential for innate immunity and contribute to create the skin barrier. Their abnormal stimulation is involved in the development of several dermatological diseases, among which psoriasis. Tumor Necrosis Factor (TNF)-alpha and interleukin (IL)-17 play a pivotal role in the pathogenesis of psoriatic plaques and their proinflammatory activity can affect Langerhans cell (LC) phenotype. In a well characterized three-dimensional model of organotypic cultures of normal human skin [1-3] we evaluated the effect of TNF-alpha and IL-17 on the expression of TLR2 and 9 by immunofluorescence, on the ultrastructural morphology of keratinocytes and LCs by transmission electron microscopy (TEM). Human skin explants (n=7) were cultured at the air-liquid interface overnight in a Transwell system and exposed to 50 ng/ml IL-17 or 100 ng/ml TNF-alpha or a combination of both cytokines. Samples were harvested 24 (T24) and 48h (T48) after cytokines incubation. After incubation with IL-17 and IL-17+TNF-alpha, TLR2 immunostaining was not detectable in the basal layer, differently from controls and TNF-alpha-treated samples. Conversely, TLR9 expression was progressively induced in granular keratinocytes in all cytokine-exposed groups. By TEM, enlargements of intercellular spaces were evident especially and, after IL-17 treatment, LCs showed an activated phenotype. At T24 LCs number increased indicating that TNF-alpha and IL-17+TNF-alpha exert a chemoattractant activity, while at T48 only IL-17+TNF-alpha maintained this effect on trapping LCs in epidermis. TNF-alpha and IL-17 differently affect LCs behaviour and TLR expression, with a specific contribution to the inflammatory loop underlying the lesion formation. The simultaneous inhibition of the effect of different cytokines - all with a defined role in the pathogenesis of psoriasis - could further improve psoriasis treatment