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Anna Campanati*, Veronica Consales*, Monia Orciani, Katia Giuliodori, Giulia Ganzetti, Ivan Bobyr, Giulia Sorgentoni, Roberto di Primio, Annamaria Offidani Dermatological Clinic, Department of Clinical and Molecular Sciences, Polytechnic Marche University, Ancona, Italy *These authors contributed equally to this work Abstract: Mesenchymal stem cells (MSCs) are multipotent nonhematopoietic stromal cells studied for their properties and importance in management of several skin diseases. This review collects and analyzes the emerging published data, which describe the function of MSCs in the pathogenesis of psoriasis. Keywords: mesenchymal stem cells, pathogenesis of psoriasis, review

Summary: The clinical characteristics associated with hidradenitis suppurativa (HS) severity are poorly understood. In this study, 124 patients with HS from 6 Italian dermatology centres participated in this study. Disease severity was assessed using the Hidradenitis Suppurativa Physician's Global Assessment score (HS‐PGA) and Hurley score. The impact of clinical characteristics on disease severity was assessed by logistic regression. Clinical characteristics were similar between men (n = 53) and women (n = 71). Disease severity was also similar; 75% of the patients had Hurley stage II or III disease, and > 60% had moderate, severe or very severe HS as judged by HS‐PGA. Lesions were more frequent in the gluteal region in men (32.3% in men vs. 8.7% in women, P < 0.001) and more frequent on the breast in women (16.3% in women vs. 4.6% in men, P = 0.02). Obesity was associated with increased disease severity as measured by HS‐PGA (OR: 3.28, 95% CI 1.55–6.95, P < 0.01) and Hurley classification (OR: 3.22, 95% CI 1.34–7.31, P < 0.01). Although severity of HS is similar between the sexes, the localization of lesions is different. [ABSTRACT FROM AUTHOR]

The article offers information on the comparison of clinical and ultrasound scores in patients with hidradenitis suppurativa (HS). Topics discussed include information on the use of the ultrasound techniques for diagnosis and assessment of HS disease severity; discussions on the using sonographic scoring system for HS; and the information on the clinical assessment for the complementary tests.

Background Atopic dermatitis ( AD) is a chronic and inflammatory disease characterized by a marked imbalance of T helper (Th)2 vs. Th1/Th17 cells in the early phase of AD, whereas a mixed Th1/Th2 pattern of inflammation is usually found at the chronic stage. These features have not been extensively evaluated in undifferentiated skin cells of patients affected by AD. Objectives To evaluate the relative expression of 22 genes encoding Th1, Th2 and Th17 cytokines and the secretion of the corresponding proteins in cutaneous mesenchymal stem cells ( MSCs) isolated from skin of patients with AD ( AD- MSCs) and their role in AD onset. Methods AD- MSCs were isolated, characterized and profiled by polymerase chain reaction array and enzyme-linked immunosorbent assay for the relative expression and secretion of cytokines involved in the Th1, Th2 and Th17 pathways. MSCs isolated from the skin of healthy people were used as controls (C- MSCs). Results AD- MSCs showed an upregulation of many Th1/Th17 cytokines [interleukin ( IL)-6, IL-8, IL-12, IL-13, IL-17A, IL-17F, transforming growth factor-β, interferon-γ], while Th2 chemokines ( IL-2, IL-4, IL-5, IL-23A) were downregulated in AD- MSCs. Finally, some genes/proteins ( CCL1, IL-17C, tumour necrosis factor-α) did not show variations between C- MSCs and AD- MSCs. Conclusions The profile of MSCs obtained from patients with chronic AD retraces the Th1/Th17 cell environment observed in differentiated cells of chronic AD. This evidence could open a new scenario in the pathogenesis of AD, according to which the inflammatory process may involve MSCs early on. [ABSTRACT FROM AUTHOR]

Objective:TNF alpha inhibitors are usually associated with anthropometric changes over the time, however whether and how the visceral adipose tissue (VAT) is involved in this phenomenon, still remains unclear. Aim of the study is to evaluate if the increases in trunk fat percentage (TF%) and VAT are directly involved in anthropometric changes occurring during treatment, and whether and how a calorie restricted diet could prevent these changes. Material and methods:Twenty patients receiving TNF-alpha inhibitors for psoriasis was evaluated at baseline (T0) and after 24 weeks of therapy (T24), and then compared with 25 patients receiving a combined treatment based on TNF alpha inhibitors and low-carbohydrates calorie-restricted diet. Results:TNF-alpha inhibitors do not influence the VAT expression. The combined treatment is associated with a significant decrease in body weight (kg) (p < .0001), BMI (p = .0001), WC (cm) (p < .0001), TF% (p < .0001), VAT (p < .0001), serum levels of triglycerides (mg/dL) (p = .0018) and total cholesterol (mg/dL) (p = .0005). Conclusions:The administration of TNF-alpha inhibitors can induce anthropometric changes after 24 weeks, but it does not cause an increase in VAT. The association between low-carbohydrates calorie-restricted diet and anti-TNF-alpha therapy seems to be able to improve the anthropometric profile of psoriasis patients. [ABSTRACT FROM AUTHOR]

Angiogenesis plays a key role in the pathogenesis of psoriasis. New blood vessel formation occurs early during plaque lesion development in psoriatic skin, and sometimes precedes disease recurrence. TNF-α, a well established mediator of inflammation in psoriasis, up-regulates the transcription of several pro-angiogenic chemokines that are over-expressed in psoriatic skin and serum, promoting microvascular modifications in psoriatic plaque. Adalimumab is a fully human monoclonal antibody that blocks the interaction between TNF-α and its cell surface receptor, thus inhibiting the TNF-α dependent inflammatory cascade. The aims of this study were to investigate several angiogenic parameters involved in the pathogenesis of psoriasis, and to evaluate the ability of adalimumab to modulate them. Fifteen patients affected by psoriasis received Adalimumab 40 mg EOW for twelve weeks and were evaluated at baseline (T0) and after treatment (T12) for the following parameters: i) new blood vessels formation in lesional skin assessed by intra-vital video-capillaroscopy analysis (IVCP) and histology; ii) VEGF and Factor VIII expression in lesional skin detected by immunohistochemistry; iii) serological levels of several angiogenic chemokines detected by luminex assay. At baseline, newly formed capillaries in psoriatic plaque correlated with skin expression of VEGF and factor VIII and with serum levels of angiopoietin-2, IL-8, PDGF-BB, VEGF, but not with serum levels of follistatin, TNF-α, G-CSF, HGF, FGF, PECAM, IFN-γ, and TGF-α. All patients responded to adalimumab, reached PASI 50, and 70% achieved PASI 75 after twelve weeks of treatment. Although adalimumab administration for twelve weeks caused a dramatic decrease of new blood vessel formation, confirmed by IVCP(p<0.05), histology and immunohistochemical (p<0.05) analysis, we did not observe a parallel significant reduction of angiogenic chemokines in the serum. However, a positive correlation between the density of newly formed blood vessels in lesional skin and the serum levels of angiopoietin-2, IL-8, PDGF-BB, and VEGF, was still persisting after treatment. [ABSTRACT FROM AUTHOR]

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]

Background Tumour necrosis factor-α upregulates the expression of a cutaneous T cell-attracting chemokine (CTACK/CCL27), that promotes migration of cutaneous lymphocyte-associated antigen-positive lymphocytes into the skin. The role of CTACK/CCL27 in pathogenesis of psoriasis has recently been documented but no data are available at the present time on its modification in psoriatic cutaneous tissue after administration of etanercept. Objectives To evaluate modifications of CTACK/CCL27 expression in skin of patients with psoriasis after administration of etanercept and their relation with disease activity. Methods Twenty-two patients with moderate to severe psoriasis underwent clinical, histological and immunohistochemical evaluations of disease activity at baseline and at 12 and 24 weeks after starting treatment with etanercept. Results All selected patients experienced an improvement of Psoriasis Area and Severity Index (PASI) score ( P < 0·001) and Dermatology Life Quality Index score ( P < 0·001) during the treatment. Skin histological abnormalities showed statistically significant modifications during treatment ( P < 0·001). Immunohistochemical expression of CTACK/CCL27 decreased significantly ( P < 0·001) and its relation with final PASI score was statistically significant ( P < 0·05); the pattern of distribution of CTACK/CCL27 immunoreactivity significantly moved from diffuse and predominantly suprabasal to basal ( P < 0·001) and the restoration of basal distribution of CTACK/CCL27 was also significantly related to clinical improvement of cutaneous disease ( P < 0·001). Conclusions Etanercept induces a clinical and histological improvement of psoriatic disease, promoting a reduction in CTACK/CCL27 cutaneous immunostaining and favouring the restoration of physiological CTACK/CCL27 epidermal expression. Moreover, CTACK/CCL27 reduction in cutaneous expression during administration of etanercept could be considered a favourable prognostic marker. [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.)

Introduction: Psoriasis is a chronic immunomediated and inflammatory disease involving mainly skin and joints, often associated with several metabolic and non-metabolic comorbidities. TNF-alpha inhibitors have shown long-term efficacy and safety/tolerability in psoriasis, and preliminary data support the use of certolizumab pegol (CZP) as well. Areas covered: The authors review the pharmacological properties of CZP, as well as its safety data and efficacy profile. They also review the quality of life outcomes related to CZP in psoriasis. The authors also provide their expert opinion on the subject. Expert opinion: CZP is a promising treatment for psoriasis owing to its rapid reduction of disease activity, long-term therapeutic efficacy - both in bio-naive and non-bio-naive patients, long term safety and low rate of site injection reactions. CZP seems to be a promising therapeutic option for psoriasis patients, although further evidence supporting the continuing clinical program for development of CZP in psoriasis is needed.

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.)