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Background An increasing number of antimycotics have become available for the treatment of dermatophytoses; however, there are reports suggesting recalcitrance to therapy or resistance of a dermatophyte against conventional treatment. Lipopeptides represent novel therapeutic drugs with a new mode of action. Objectives The aim of this study was to investigate the in vitro effects of the lipopeptide Pal-Lys-Lys-NH2 (PAL) alone and in combination with standard antifungal agents, such as fluconazole (FLU), itraconazole (ITRA) and terbinafine (TER) against 24 clinical isolates of dermatophytes belonging to four species. Methods A broth microdilution method following the Clinical and Laboratory Standards Institute recommendations (M38-A) was used for testing drugs alone and in combination. Results PAL minimum inhibitory concentrations (MICs) ranged from ≤ 0·25 to > 16 μg mL−1 and they were similar to those of FLU and higher than those of either ITRA or TER. Synergy, defined as a fractional inhibitory concentration (FIC) index of ≤ 0·50, was observed in 67%, 52% and 15% of PAL/ITRA, PAL/TER and PAL/FLU interactions, respectively. None of these combinations yielded antagonistic interactions (FIC index > 4). When synergy was not achieved, there was still a decrease in the MIC of one or both drugs used in the combination. Conclusions Our study demonstrates that PAL has potential activity against dermatophytes. In addition, the in vitro activity of PAL can be enhanced upon combination with standard drugs. This lipopeptide applied in the form of lacquer, spray or ointment, could represent an interesting new therapy, particularly when combined with conventional treatment in recalcitrant or resistant dermatophyte infections. [ABSTRACT FROM AUTHOR]

The usefulness of TNF alpha inhibitors for the treatment of psoriasis is well known, while data concerning biologics in vitiligo are discordant. We reported a case of a successful use of etanercept and NB-UVB phototherapy in a 13-year-old girl suffering from psoriasis and vitiligo, and discussed therapeutic results taking into consideration the more recent data of literature on the use of TNF alpha inhibitors in psoriasis and vitiligo. [ABSTRACT FROM AUTHOR]

Psoriasis is a complex disease often needing a multidisciplinary approach. In particular, the collaboration between dermatologist and rheumatologist is crucial for the management of patients suffering from both psoriasis (PSO) and psoriatic arthritis (PsA). Here we report a series of recommendations from a group of experts, as a result of a Consensus Conference, defining the circumstances in which it is preferable or even mandatory, depending on the available settings, to rely on the opinion of the two specialists, jointly or in a deferred manner. Indications are given on how to organize a 3 rd level joint Dermatology- Rheumatology care unit, in connection with 1 st and 2 nd level clinicians of both specialties, GPs, and other specialists involved in the management of psoriasis. A potential patient journey is suggested, that can be used as a basis for future design and validation of national and/or local diagnostic therapeutic and assistance pathways., (©Copyright: the Author(s).)

Oral malignant melanoma (OMM) is an aggressive tumour, and shows deep tissue invasion at initial presentation. The prognosis is worse than that for cutaneous melanoma (CM), and the overall 5-year survival rate is 10-25%. A study of the molecular mechanisms involved in the development of OMM is necessary to identify new prognostic markers. In this study, we evaluated the possible role of nicotinamide N-methyltransferase (NNMT) in OMM. We carried out immunohistochemical analyses to evaluate the expression of NNMT in 15 OMM and 15 CM, measuring the percentage of positive cells and the value of NNMT expression intensity. Furthermore, we explored the relationship between NNMT levels and the prognostic parameters of patients with OMM. NNMT was significantly more expressed in CM compared with OMM, whereas higher staining intensity for NNMT was observed in OMM cases (P<0.05). In addition, a significant relationship was found between NNMT staining intensity and the presence of ulceration (P<0.05). Furthermore, univariate analysis showed a negative effect of NNMT expression on the disease-free survival rate (P<0.05). This study is the first to report the expression of NNMT in OMM and to compare OMM enzyme levels with those detected in CM. Data obtained seem to suggest the presence of potential molecular differences between these two tumours.

Nicotinamide N-methyltransferase (NNMT) is an enzyme that catalyzes the N-methylation of nicotinamide and pyridine compounds, participating in xenobiotic and drug metabolism. Data on literature have evidenced a possible role of NNMT in many solid cancers, but no data are currently available in cutaneous melanoma. Recent important advances have been achieved in the treatment of advanced melanoma with targeted therapy and immunotherapy. However, the identification of biomarkers that can be used for the detection of early stage disease as well as for monitoring the therapeutic response during treatment is of utmost importance. The aim of this study was to study the possible role of NNMT in melanoma. In the present study, we carried out immunohistochemical analyses to evaluate the expression of the enzyme NNMT in 34 melanomas and 34 nevi. Moreover, we explored the relationship between NNMT levels and the prognostic parameters of patients with melanoma. The results obtained showed significantly (P<0.0001) higher NNMT expression in melanoma compared with that detected in nevi. In addition, a significant (P<0.05) inverse relationship was found between enzyme levels and Breslow thickness, Clark level, the presence/number of mitoses, and ulceration. Taken together, these data seem to suggest that NNMT could represent a molecular biomarker for melanoma, thus highlighting its potential for both diagnosis and prognosis of this neoplasm.

Background: Switching is a "hot" topic and the main reasons for switching prior biologic agent are for a primary failure, a secondary failure or drug intolerance, patient's dissatisfaction, physician decision. The aim of the study was to assess the optimization of the switching from a biologic agent to another., Methods: Five Dermatological Units have participated to PsOMarche working group have studied thirty-eight patients affected moderate to severe chronic plaque psoriasis at time 0 (patient recruitment at time of switching from biological therapy to another), 8 weeks (T8), 16 weeks (T16)., Results: Twenty-eight males and 10 females were included in the study. At T0, 18 of 22 patients treated with etanercept had been switched to adalimumab and 4 to ustekinumab. Among 10 patients treated with adalimumab, 5 had been switched to ustekinumab, 2 to golimumab and 3 to certolizumab pegol. One patient treated with Infliximab and 5 patients treated with ustekinumab had been switched to adalimumab. Switching had been performed for primary inefficacy in 9 patients (23.6%) and a secondary failure was evidenced in 29 patients (73.4%). PASI75 was achieved in 53% and in 89.4% of patients after 8 weeks and 16 weeks of switching to the second biologic agent respectively; similarly, PsoDISK score significantly decreased at T8 and T16., Conclusions: The experience of PsOMarche group have shown that the switching to a biologic agent to another is a valuable treatment choice in patients with moderate to severe psoriasis experiencing a treatment failure with one biologic therapy, leading to a good improvement in skin disease and in patient's quality of life.

Objectives: To validate in a multicentric cohort of patients a self-administered PsA screening tool, called Simple Psoriatic Arthritis Screening (SiPAS) questionnaire, to screen psoriasis patients for signs and symptoms of PsA., Methods: The SiPAS questionnaire was validated in a multicentric Italian cohort of psoriasis patients referred to two rheumatological centres., Results: A total of 202 psoriasis patients were screened with SiPAS in the validation study. Sixty-two psoriasis patients (30.7%) were diagnosed with PsA. The five screening questions (1. Have you ever had a finger or a toe and/or another joint swollen and painful without any apparent reason?; 2. Occasionally, has an entire finger or toe become swollen, making it look like a 'sausage'?; 3. Do you wake up at night because of low back pain?; 4. Have you had pain in your heels?; 5. Has a doctor ever diagnosed you with psoriatic arthritis?) with a dichotomous response, demonstrated high sensitivity and specificity for predicting PsA. Likelihood ratios for individual parameters varied between 2.06 and 4.75. Using the Bayesian Analysis, the presence of three of five items answered as "yes" showed respectively a sensibility and a specificity of 79% and 87%, with a positive likelihood ratio of 6.14., Conclusions: The SiPAS questionnaire is able to quickly screen psoriasis patients for PsA. A SiPAS score ≥3 is an indication for referral to a rheumatologist. The SiPAS needs further validation.

Psoriasis is a disease characterized by an imbalance between Th 1 and Th 17 and Th 2 inflammatory axes, in which cutaneous mesenchymal stem cells (MSCs) are early involved, as they show a greater relative expression of several genes encoding for Th 1 and Th 17 cytokines. Therapeutic implications of TNF-α inhibitors on differentiated skin cells have been largely described in psoriasis; however, their effects on MSCs derived from patients with psoriasis have been only partially described. The aim of this work was to evaluate the effect of TNF-α inhibitors on cytokine milieu expressed by MSCs isolated from the skin of patients with psoriasis. Resident MSCs from skin of patients with psoriasis and healthy subjects have been isolated, characterized and profiled by PCR and ELISA for the expression of 22 cytokines involved in Th 1 , Th 2 and Th 17 pathways, both before and after 12 weeks therapy with TNF-α inhibitors. The administration of TNF-α inhibitors for 12-weeks acts on MSCs as follows: it reduces the expression of several Th 1 -Th 17 cytokines whose levels are elevated at baseline (IL-6, IL-8, IL-12, IL-23A, IFN-γ, TNF-α, CCL2, CCL20, CXCL2, CXCL5, IL-17A, IL-17C, IL-17F, IL-21, G-CSF). Similarly, it enhances the expression of several Th 2 cytokines which are underexpressed at baseline (IL-2, IL-4, IL-5), reducing the expression of those overexpressed at baseline (TGF-β and IL-13). TNF-α inhibitors could contribute to reduce the pathological imbalance between the Th 1 -Th 17 vs Th 2 axis in MSCs of patients with psoriasis., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Darier-White Disease (DW), otherwise known as keratosis follicularis, is a rare genodermatosis with autosomal dominant inheritance, characterized by loss of adhesion between epidermal cells and abnormal keratinization. The distinctives lesions of DW Disease include rough papules in seborrheic areas, palmoplantar pits, mucosal involvement, and nail changes. DW Disease can be occasionally associated with bacterial complications, but rarely with viral ones. Kaposi's varicelliform eruption (KVE) is a secondary herpes simplex virus infection that affects patients in the setting of primary dermatologic conditions. KVE, frequently misdiagnosed as impetigo, can be severe, progressing to disseminated infections and potentially life threatening. It occurs with a variety of skin disorders, although association with DW Disease has rarely been reported in the literature. This report describes a case of KVE in a patient suffering from DW Disease, focusing on its clinical course. A review of the literature on KVE including disease associations, pathogenesis, and treatment has been also reported.

Objective: To evaluate salivary interleukin (IL)-1β levels in patients with psoriasis, before and after treatment with tumour necrosis factor (TNF)-α inhibitors., Methods: In this pilot study, salivary secretions were collected from patients with psoriasis and untreated healthy control subjects at baseline, and from patients after 12 weeks' treatment with TNF-α inhibitors. IL-1β levels were determined in saliva samples via enzyme-linked immunosorbent assays, undertaken before and after TNF-α inhibitor treatment. Psoriasis-specific analysis of disease severity and activity were also undertaken., Results: At baseline, patients (n = 25) had significantly higher salivary IL1β levels than controls (n = 20). In patients with psoriasis, TNF-α inhibitor treatment resulted in significantly reduced IL1β levels compared with baseline, but IL1β levels remained significantly higher than in control subjects even after treatment. There was a positive correlation between IL-1β levels, psoriasis activity and disease index score after TNF-α inhibitor treatment., Conclusion: Saliva is a valid noninvasive tool for monitoring inflammation in psoriasis. TNF-α inhibitor treatments appear to interfere with the oral inflammatory process in patients with psoriasis., (© The Author(s) 2016.)

Objective: To evaluate prospectively the effect of etanercept (a tumour necrosis factor [TNF]-α inhibitor) on vascular endothelial growth factor (VEGF) production by mesenchymal stem cells (MSC) from patients with psoriasis., Methods: MSCs from lesional and perilesional skin were isolated, cultured and characterized. VEGF production was evaluated at baseline and after 12 weeks' etanercept treatment., Results: Etanercept treatment resulted in significant reductions in VEGF production compared with baseline in both lesional MSCs (256.42 ± 3.07 pg/ml per 10 6 cells at baseline vs 27.66 ± 2.03 pg/ml per 10 6 cells after treatment) and perilesional MSCs (235.03 ± 2.52 pg/ml per 10 6 cells vs 41.65 ± 4.72 pg/ml per 10 6 cells)., Conclusions: Etanercept reduces the production of VEGF in MSCs, which may modulate angiogenesis and contributes towards preventing the start of the "psoriatic march"., (© The Author(s) 2016.)

Background: STRATOS is the acronym of the "STRuctured Approach to the Treatment of psOriatic patientS". The optimization of the psoriasis's therapeutic management is one of the most important goals for dermatologists. According to Mrowietz's consensus report, the transitioning from conventional therapy to biological therapy is mainly due to the lack/loss of efficacy and/or for safety reasons. The aim of the manuscript was to describe the principal results obtained by the Dermatologic Clinic of Polytechnic University of Marche Region and the Units of Dermatology of the Marche Region applying, in our regional reality, Mrowietz's protocol for the daily management of patients with moderate-to-severe plaque., Methods: Forty-seven patients with moderate to severe chronic plaque psoriasis have been monitored during the six-months study period., Results: Psoriatic patients with diabetes showed further concomitant comorbidities compared to non-diabetics, as hypertension and hypercholesterolemia. Moreover, based on WHO classification, overweight was diagnosed in female patients, whereas obesity was prevalent in male patients. This aspect confirms the strict link between the multifaceted aspects of psoriatic patient which is primarily related to the persistent low-grade inflammation. In our psoriatic group, 10% of monitored patients were affected by Crohn disease or ulcerative colitis., Conclusions: The Mrowietz's transitioning protocol is a useful, reliable and feasible tool to manage the therapeutic iter of psoriatic patients in an Italian clinical setting also at regional level.

Psoriasis is a chronic inflammatory immune-mediated skin disease, frequently associated with systemic comorbidities. According to recent data, patients with psoriasis show a greater prevalence of metabolic syndrome, which confers a higher cardiovascular risk. The link between these pathological conditions appears to be a chronic low-grade inflammatory status. The aim of this review is to focus on the multiple epidemiological and physio-pathogenetic aspects linking non-alcoholic fatty liver disease, psoriasis, and cardiovascular disease.

We present a patient with HPV 70/85-positive widespread cutaneous warts characterized by clinical and histological features atypical for classic generalized verrucosis or epidermodysplasia verruciformis. The cutaneous HPV infection is characterized by verrucous papules or plaques variable in size, number, and distribution depending on the genotype of HPV involved and the immune status of the patient. Human papillomaviruses comprise five genera (alpha, beta, gamma, mu, and nu papillomavirus) with different life-cycle characteristics, epithelial tropisms, and disease associations. Epidermodysplasia verruciformis (EV) is a rare, lifelong, autosomal recessive skin disease characterized by persistent cutaneous human papillomavirus infection not necessarily associated with immune system defects. The disease results from an unusual genetic susceptibility to infections with various types of HPVs (especially β-HPV), some of which cause malignant transformation. Conversely, generalized verrucosis has been more typically associated with generalized warts, which are associated with immunocompromised conditions.

Background/objective: This study aims at the evaluation of the efficacy and safety of a combination therapy based on pidobenzone 4% and fractional CO2 laser or cryotherapy in the treatment of solar lentigines and the prevention of eventual posttreatment hyperchromia., Methods: Efficacy was clinically evaluated by grading the pigmentation level with the Skin Tone Color Scale (STCS), and by grading patients' impression through a Visual Analog Scale (VAS)., Results: Our study shows that the associated treatment was safe and that it improves the therapeutic results on solar lentigines and prevents postiatrogenic hyperpigmentation compared with physical therapy alone., Conclusion: The combination of cryotherapy and pidobenzone 4% has been found to be the most useful treatment., (© 2016 S. Karger AG, Basel.)

Biologic treatments have modified the therapeutic armamentarium in the treatment of many dermatological and non- dermatological diseases and data on literature have widely focused on the efficacy and safety of TNF-alpha inhibitors in psoriasis. Although the etiopathogenesis has not completely elucidated, inflammation appears the lait motif unifying the immune-pathogenesis of diverse skin disease, as atopic dermatitis, alopecia areata and hidradenitis suppurativa. Actually, data on the off-label use of biologics in cutaneous immune-mediated inflammatory diseases are scarce and restricted to anecdotal cases and case series. The present review aims to evidence the major off- label use of TNF-alpha inhibitors in dermatology.

This review focuses on the emerging concepts concerning the efficacy profile of biological drugs in psoriasis ranging from moderate to severe, and attempts to provide the most recent individual positioning of biologics in treating psoriasis. Biologic agents targeting towards specific immune mediators have emerged as treatment options for patients with moderate to-severe plaque psoriasis unresponsive or intolerant to traditional systemic agents. Data on the safety of biologics are available for up to 5 years in psoriasis and are on the whole reassuring. National registries are still evolving and will provide data on safety, to help the long-term monitoring of patients with psoriasis ongoing biological treatment. Although several biologics have demonstrated good efficacy and tolerability in short-term trials, treatment guidelines recommend them as third line therapies due to relative lack of long-term safety data, especially for those who have been commercialized recently. Here, we have reviewed the long-term safety data obtained from National Registries, randomized controlled trials, open-label extension studies and meta-analyses on etanercept, infliximab, adalimumab, and ustekinumab in the treatment of adults with moderate to severe plaque psoriasis.

Lecithin:cholesterol acyltransferase (LCAT) deficiency is associated with hypoalphalipoproteinemia, generally a predisposing factor for premature coronary heart disease. The evidence of accelerated atherosclerosis in LCAT-deficient subjects is however controversial. In this study, the effect of LCAT deficiency on vascular tone and endothelial function was investigated in LCAT knockout mice, which reproduce the human lipoprotein phenotype. Aortas from wild-type (Lcat(wt)) and LCAT knockout (Lcat(KO)) mice exposed to noradrenaline showed reduced contractility in Lcat(KO) mice (P<0.005), whereas acetylcholine exposure showed a lower NO-dependent relaxation in Lcat(KO) mice (P<0.05). Quantitative PCR and Western blotting analyses suggested an adequate eNOS expression in Lcat(KO) mouse aortas. Real-time PCR analysis indicated increased expression of β2-adrenergic receptors vs wild-type mice. Aorta stimulation with noradrenaline in the presence of propranolol, to abolish the β-mediated relaxation, showed the same contractile response in the two mouse lines. Furthermore, propranolol pretreatment of mouse aortas exposed to L-NAME prevented the difference in responses between Lcat(wt) and Lcat(KO) mice. The results indicate that LCAT deficiency leads to increased β2-adrenergic relaxation and to a consequently decreased NO-mediated vasodilation that can be reversed to guarantee a correct vascular tone. The present study suggests that LCAT deficiency is not associated with an impaired vascular reactivity., (Copyright © 2015. Published by Elsevier Inc.)

Toxic epidermal necrolysis (TEN), also known as Lyell syndrome, is a potential life-threatening muco-cutaneous disease with important systemic implications. It affects the skin and mucous membranes, with involvement of more than 30% of body surface and it is mostly caused by drugs. Although the pathogenesis is not fully elucidated, it is probably linked to the inability to detoxicate reactive metabolites of drugs, to genetic susceptibility and to immune factors leading to cellular apoptosis. Currently, there are no randomized control trials and stardardized therapeutical approaches for the management of Lyell syndrome; therefore controversial clinical responses to the most common used drug in TEN make it difficult for the clinical-therapeutic approach. The authors reported their experience on three patients affected by Lyell syndrome treated with infliximab.

Background: Adipocytokines are bioactive molecules that are deeply involved in the occurrence of atherosclerosis, obesity, and autoimmune inflammatory diseases., Objectives: This study was conducted to evaluate the effects of tumor necrosis factor-α (TNF-α) inhibitors on serum levels of adipocytokines in patients with chronic plaque psoriasis., Methods: Serum levels of adiponectin, resistin, visfatin, leptin, TNF-α, and interleukin-6 (IL-6) were evaluated in sera obtained from 47 patients with psoriasis, both at baseline and after they had received TNF-α inhibitors for 24 weeks. Equivalent data were obtained for 39 control subjects matched by age, sex, body mass index, waist : hip ratio, geographical origin, Mediterranean dietary habits, and smoking habits., Results: At baseline, mean serum levels of TNF-α, IL-6, leptin, resistin, and visfatin were higher in the psoriasis group than in healthy controls; these differences were statistically significant (P < 0.05). Conversely, mean serum levels of adiponectin were significantly lower in patients with psoriasis than in controls (P < 0.0001). Serum levels of adipocytokines did not linearly correlate with anthropometric indices in psoriasis patients (P > 0.05), except in the case of leptin, for which serum levels were related to waist : hip ratio in both men and women (P < 0.05). After 24 weeks of treatment, although serum levels of proinflammatory adipocytokines were decreased, only that of leptin showed a statistically significant reduction (P = 0.0003). Serum levels of adiponectin, an anti-inflammatory adipocytokine, were only mildly increased and persisted at a significantly lower level than in healthy controls (P > 0.005)., Conclusions: Patients with psoriasis show an imbalance between pro- and anti-inflammatory adipocytokines, which is reduced but not normalized after administration of TNF-α inhibitors for 24 weeks. This partial rebalancing seems to be mainly related to a reduction in proinflammatory adipocytokines, rather than an increase in anti-inflammatory adipocytokines., (© 2015 The International Society of Dermatology.)