Effectiveness of guselkumab in patients with facial and/or genital psoriasis: Interim analysis results at Week 12 from the GULLIVER study.

BACKGROUND: Facial (FP) and genital psoriasis (GP) significantly affect patients' quality of life. Despite the advances in treatments, limited data on efficacy and safety are available on these difficult-to-treat areas. Guselkumab is an interleukin (IL)-23 inhibitor which has been proven effective in treating patients with moderate-to-severe plaque psoriasis. OBJECTIVES: The aim of this interim analysis was to report the efficacy and safety of guselkumab in the treatment of patients with FP and/or GP. MATERIALS AND METHODS: GULLIVER is a 52-week Italian observational study to evaluate the effectiveness and safety of guselkumab in a real-life setting in patients with FP and/or GP. Adult patients with facial and/or genital moderate-to-severe psoriasis (sPGA score ≥ 3) were included. The primary endpoint of this analysis was the percentage of patients achieving a facial or genital sPGA score of 0 (clear) or 1 (almost clear), at Week 12. The change in the score of the facial or genital sPGA components in patients with a score ≥3 for each sPGA component was assessed. PASI score in patients with a baseline PASI above or below 10 was evaluated. RESULTS: Overall, 351 patients were included in the study; 83.3% of FP and 76.5% of GP patients achieved the primary endpoint. Similar response rates were observed for the facial or genital sPGA components in patients with a baseline facial or genital sPGA score ≥3 in each component. Among patients with a baseline PASI score >10, mean PASI score improved from 19.0 (SD 8.3) to 2.2 (SD 4.8). Forty-four AEs were observed in 32 patients; two mild and transient AEs (fatigue and nausea) were considered treatment related. No SAEs were observed. CONCLUSIONS: Guselkumab, showing to be effective and safe in treating FP and GP, may be a valid therapeutic option for patients with psoriasis localized in these difficult-to-treat areas.

Autoantibody profile and clinical patterns in 619 Italian patients with cutaneous lupus erythematosus.

BACKGROUND: Anti-nuclear antibodies (ANA), anti-extractable nuclear antigens (ENA) and anti-dsDNA antibodies are often associated with cutaneous lupus erythematosus (CLE), with variable frequency depending on skin subtype. However, specific data based on large case-series on the pathogenetic, diagnostic and prognostic meaning of such autoantibodies are still lacking. OBJECTIVE: To characterize the correlations between CLE subtypes as well as LE-non-specific skin lesions and their autoantibody pattern. METHODS: Epidemiological, clinical and immunopathological data of 619 Italian patients with CLE and LE-non-specific skin lesions were analysed. Differences in age, sex, clinical features and autoantibody profile were evaluated in each LE subgroup. RESULTS: Anti-nuclear antibodies (P < 0.0001), anti-dsDNA (P < 0.0001), ENA (P = 0.001), anti-Sm (P = 0.001), anti-RNP (P = 0.004) and anti-histone (P = 0.005) antibodies were associated with SLE. A strong association between ANA (P < 0.0001) and anti-dsDNA (P < 0.0001) and female gender was also found: positive ANA and positive anti-dsDNA had a higher prevalence among females. Chronic CLE resulted to be negatively associated with ENA (OR = 0.51, P < 0.0001), anti-Ro/SSA (OR = 0.49, P < 0.0001) and anti-dsDNA (OR = 0.37, P < 0.0001). Intermittent CLE resulted to be negatively associated with ENA (OR = 0.50, P = 0.007) and ANA (OR = 0.61, P = 0.025). Subacute CLE resulted to be associated with ENA (OR = 5.19, P < 0.0001), anti-Ro/SSA (OR = 3.83, P < 0.0001), anti-Smith (OR = 2.95, P = 0.004) and anti-RNP (OR = 3.18, P = 0.007). Acute CLE resulted to be strongly associated with anti-dsDNA (OR = 6.0, P < 0.0001) and ANA (OR = 18.1, P < 0.0001). LE-non-specific skin lesions resulted to be significantly associated with systemic involvement. Livedo reticularis was significantly associated with ENA (P = 0.007) and anti-Ro/SSA (P = 0.036). Palpable purpura and periungual telangiectasia were significantly associated with ANA. CONCLUSION: According to our findings, some well-known associations between CLE subtypes and autoantibody profile were confirmed; moreover, specific association between autoantibodies and LE-non-specific skin lesions was highlighted. A strict association between anti-ENA and anti-Ro/SSA antibodies and livedo reticularis, ANA and palpable purpura, and ANA and periungual telangiectasia was evidenced.

New insights into potential risk factors and associations in genital lichen sclerosus: Data from a multicentre Italian study on 729 consecutive cases.

BACKGROUND: Limited data are available on risk factors associated with lichen sclerosus and no data are available on gender differences in genital lichen sclerosus (GLS). OBJECTIVE: This multicentre study aimed at identifying potential risk factors for GLS, through data collection from a large, mixed-sex sample of patients comparing gender-related differences in relation to data from the general population. METHODS: This was a cross-sectional study on 729 subjects (53.8% females, 46.2% males) affected with GLS, consecutively observed within a network of 15 Italian dermatology units. The following information was collected: demographic data, anthropometric measures, comorbidities, family history of LS, clinical features and symptoms related to GLS. RESULTS: Overweight and obesity, blood hypertension, hypothyroidism and an educational attainment equal or above upper secondary school level were more frequent among the study patients than among the general Italian population. Moreover, a family history of GLS was reported more frequently than expected among GLS patients. These factors were similar in males and females. The disease tended to occur later in females than in males. CONCLUSIONS: Our findings suggest that metabolic factors, and possibly a sedentary lifestyle, may play a role in GLS pathogenesis in genetically predisposed patients, and that risk profile is similar in males and females despite some difference in the onset of symptoms.

Phenotypical characterization of circulating cell subsets in pyoderma gangrenosum patients: the experience of the Italian immuno-pathology group.

BACKGROUND: No data are available as to the phenotype of circulating lymphocyte subsets in pyoderma gangrenosum (PG). AIM: To analyse the expression of different chemokine receptors associated to T-helper (Th)1 (CCR5), Th2 (CCR4) and Th17 (CCR6), as well as the regulatory T-cell subset (Treg) and dendritic cell polarization in the blood of newly diagnosed untreated PG patients. MATERIALS AND METHODS: Multi-parameter flow cytometry was performed on blood samples from 10 PG patients collected at first diagnosis among centres belonging to the Italian Immuno-pathology Group. Blood samples from 10 age- and sex-matched healthy controls (HC) were used as controls. RESULTS: PG patients are characterized by an over-expression in the blood of the CD4+CCR5+ and CD4+CCR6+ and a down-regulation of CD4+CCR4+ counts with respect to healthy subjects. Moreover, they show increased levels of myeloid derived dendritic cells type1 and reduced levels of the Treg CD4+CD25highFOXP3+ subset. CONCLUSIONS: The pattern of chemokine expression argues in favour of a Th1 (CCR5+) and Th17 (CCR6+) polarization with a down-regulation of Th2 (CCR4+).

Differences in clinicopathological features and distribution of risk factors in Italian melanoma patients.

BACKGROUND: No studies are available in the literature on the distribution of different melanoma features and risk factors in the Italian geographical areas. OBJECTIVE: To identify the differences in clinical-pathological features of melanoma, the distribution of risk factors and sun exposure in various Italian macro-areas. METHODS: Multicentric-observational study involving 1,472 melanoma cases (713 north, 345 centre, 414 south) from 26 referral centres belonging to the Italian Multidisciplinary Group for Melanoma. RESULTS: Melanoma patients in northern regions are younger, with thinner melanoma, multiple primaries, lower-intermediate phototype and higher counts of naevi with respect to southern patients; detection of a primary was mostly connected with a physician examination, while relatives were more involved in the south. Northern patients reported a more frequent use of sunbeds and occurrence of sunburns before melanoma despite sunscreen use and a lower sun exposure during the central hours of the day. CONCLUSIONS: The understanding of differences in risk factors distribution could represent the basis for tailored prevention programmes.

A project by the SIDeMaST Immunopathology Group on cutaneous vasculitis.

Vasculitides are a challenge to the clinician, in terms of both diagnosis and therapy. Multiple classification systems have been implemented and the numerous classification schemes reflect the complexity of establishing a simple classification that could be functional for daily care. Although vasculitis classification has become increasingly elaborated, some areas remain ill defined. Some forms of vasculitis are still difficult to assign to a specific disease entity. Generally accepted operational criteria are available for many vasculitides, but for some entities there are no effective criteria. Moreover, diagnostic criteria for vasculitis with sufficient strength and/or confidence that can be universally accepted are not yet available. The need for diagnostic criteria validated and agreed upon is particularly relevant in the context of cutaneous vasculitis. The project of the SIDeMaST Italian Group of Immunopathology on cutaneous vasculitis is a national prospective observational study designed to develop and validate diagnostic criteria and to improve and validate classification criteria for cutaneous small vessel vasculitis also known as leukocytoclastic vasculitis (CLV). Primary objective of the study will also be that of developing the CUtaneous VAsculitis Severity Index (CUVASI). Secondary objectives of the project will be: 1) definition of the etiological agents that are most frequently associated with CLV; 2) search for possible correlations between causative agent and peculiar clinical and/or histopathological aspects; 3) evaluation of immunofluorescence pattern observed in this specific group of primitive cutaneous vasculitis in order to characterize the diagnostic sensitivity and specificity of this technique; 4) identification of a set of clinical investigations and laboratory tests to be performed for a correct CLV assessment. Actually 15 Italian dermatological clinics are contributing to the project and anticipated recruiting >100 patients with CLV. A pilot retrospective study to assess the feasibility of the project is going to be launched and if its results are positive then the prospective study will be started and it promises to be a unique opportunity to evaluate a large database on CLV in Italian population.

Vasculitis associated with connective tissue diseases.

Vasculitis in connective tissue disease (CTD) is quite rare, it is reported in approximately 10% of patients with CTD; systemic lupus erythematosus (SLE) shows the highest association rate. Vessels of any size may be involved, but mainly small vessels vasculitis is reported. At present the classification of these vasculitis is unsatisfactory. According to the 2012 revised International Chapel Hill Consensus Conference, vasculitides secondary to CTD are a well identified entity and are classified under the category of "vasculitis associated with systemic disease". However only lupus vasculitis and rheumatoid vasculitis are explicitly listed, while the remaining are generically included under the heading "others". Petechiae, purpura, gangrene and ulcers are the most frequent cutaneous manifestations that should investigated in order to rule out potentially dangerous systemic involvement, especially if cryoglobulinemic or necrotizing vasculitis are suspected. This review will focus on the cutaneous involvement in CTD associated vasculitis.

Stratigraphic context and paleoenvironmental significance of minor taxa (Pisces, Reptilia, Aves, Rodentia) from the late Early Pleistocene paleoanthropological site of Buia (Eritrea).

The Buia Homo site, also known as Wadi Aalad, is an East African paleoanthropological site near the village of Buia that, due to its very rich yield from the late Early Pleistocene, has been intensively investigated since 1994. In this paper, which reports on the finds of the 2010-2011 excavations, we include new fossil evidence on previously identified taxa (i.e., reptiles), as well as the very first description of the small mammal, fish and bird remains discovered. In particular, this study documents the discovery of the first African fossil of the genus Burhinus (Aves, Charadriiformes) and of the first rodent from the site. This latter is identified as a thryonomyid rodent (cane rat), a relatively common taxon in African paleoanthropological faunal assemblages. On the whole, the new occurrences documented within the Buia vertebrate assemblage confirm the occurrence of taxa characterized by strong water dependence. The paleoenvironmental characteristics of the fauna are confirmed as fully compatible with the evidence obtained through sedimentology and facies analysis, documenting the sedimentary evolution of fluvio-deltaic and lacustrine systems.

Skin and nail mycoses in patients with diabetic foot.

Diabetes mellitus affects all socioeconomic and age groups and its incidence is rapidly increasing worldwide. The diabetic foot complication represents one of the most complex and serious complications in these patients. Fungal infections can also contribute to the severity of the diabetic foot. The aim of the present study was to evaluate the prevalence of foot skin and toenail mycosis in a group of 75 patients with diabetic foot complication and in a matched control group. Diabetic patients showed onychomycosis in 53.3% and foot skin mycosis in 46.7% of the cases, with a prevalence of both fungal infections significantly higher than that observed in the control group. At least one type of these fungal infections was present in 69.3% of diabetic subjects with a highly significant difference compared to control group (P<0.001). Trichophyton rubrum and Trichophyton interdigitale were the most common species responsible of both nail and skin infections. Candida spp, Fusarium spp, Aspergillus spp and other moulds. were found in about 1/3 onychomycosis. Previous toe amputation was significantly associated with both skin and nail mycosis. The present study confirms that both tinea pedis and onychomycosis have a high prevalence in subjects suffering from diabetic foot complication, and that the problem of fungal infections of the foot in diabetic subjects is still highly underestimated. Consequently, there is an important clinical rationale for careful mycological examination of diabetic foot and an adequate treatment tailored for each individual patient according to the fungal species involved.

Dermatophytosis in animals: epidemiological, clinical and zoonotic aspects.

AIM: Dermatophytosis are the most frequent fungal infections of pets and livestock and play an important role in animal and human health due to their zoonotic potential. Another important aspect of these infections is linked to the economic consequences in farm animal and fur production systems. An overview of dermatophytosis in animals is described in this paper. Epidemiological, clinical and zoonotic aspects are addressed, considering individual species, both pets and farmed animals. METHODS: In particular, most recent investigations in the field of animal mycology, carried out in Central Italy, are reported, with particular reference to rabbit, ruminants, horse, dog, cat and some wild species. RESULTS: The information in this article show how dermatophytes infect a wide range of animals which may be in contact with human beings either directly or indirectly. Consequently they are frequently a source of infection for human beings who, vice versa, may sometimes become contagious for animals. CONCLUSION: Fungal pathogens derive their power to spread from contamination of the animal's habitat - whether the animal is a conventional pet or not, a farm animal or living in the wild. Thus if treatment of the animal or human patient is to achieve optimal efficacy, it needs to be associated with adequate environmental measures.

Flow cytometric analyses of circulating regulatory T cells in patients with dermatitis herpetiformis and other immune mediated dermatoses.

Regulatory T cells (Tregs) play a crucial role by maintaining the peripheral tolerance and inhibiting autoimmunity. In recent years, numerous autoimmune and immune-mediated diseases have been shown to present significant number depletion and/or function impairment of this subset. In the present study, we present a brief overview of the results obtained by our group in association with the centers belonging to the Italian Immunopathology Group, as to the expression levels and biological significance of circulating regulatory CD4+CD25+brightFOXP3+ T cells in a variety of immune-mediated skin diseases (such as psoriasis, scleroderma, bullous pemphigoid and GvHD), together with preliminary results achieved in patients with inflammatory bowel disease-related dermatoses. This review shows that this series of different cutaneous diseases characterised by an immune-mediated pathogenesis, share a significant down-regulation of circulating FOXP3+ Treg cells, whilst the treatment and the achievement of clinical response are generally associated with an opposite phenomenon with up-regulation of Treg cells. Future studies are mandatory to identify the effective role of these modifications in the disease pathogenesis as well as its relationship with the clinical response.

Risk of multiple primary cancers following melanoma and non-melanoma skin cancer.

BACKGROUND: The relationship between cutaneous malignancies and successive primary cancers has been studied since several years, but it still remains controversial. OBJECTIVE: The aim of this study was to evaluate the excess risk of multiple primary cancer among the population of Umbria, Italy, that survived a skin cancer. METHODS: The data registered in the Umbrian Population Cancer Registry from 1994 to 2006 were collected, recorded, and analysed in accordance to the standard methods recommended for cancer registries. Among skin cancer patients, those with multiple cutaneous and non-cutaneous cancers were selected. Only sites with a frequency of more than five cases were considered. The expected number of cases was obtained from indirect standardization with regional incidence rates in several sites that incurred in the overall period. The significance of the observed/expected ratios and the corresponding 95% CI were based on the Poisson distribution. RESULTS: In men, a significant standardized incidence ratio (SIR) was found for melanoma (2.21), non-melanoma skin cancers (1.86), Hodgkin's (4.95) and non-Hodgkin lymphoma (1.82), and tongue/mouth cancer (2.47). In women, melanoma, non-melanoma skin and breast cancer showed a significant high SIRs (4.13, 1.55 and 1.28 respectively). All other cancers showed a non-significant SIR. Considering all sites combined and all sites except skin cancers, the analysis showed a significant excess in men, whereas a significant risk was observed in women only when also skin cancers were considered. CONCLUSIONS: Data from the whole of Umbrian population revealed that skin cancer patients experience marked excess risk of further primary cancers. The main risk in both genders is skin melanoma and other skin cancers. The excess of lymphomas and tongue/mouth cancers is also significant in men, and breast cancer in women. These observations prompt us to include a screening for these cancers in the follow-up of our patients surviving a skin malignancy.

Herpes genitalis without frontiers: from clinical aspects to viral identification.

Genital herpes simplex virus infection is a recurrent, lifelong disease with no cure. The strongest predictor for infection is a person's number of lifetime sex partners. HSV-2 is the commonest responsible, although infections caused by HSV-1 are rapidly increasing, particularly in adolescents, women and men who have sex with men. The natural history includes first-episode of mucocutaneous infection, establishment of latency in the dorsal root ganglion, and subsequent reactivation. Most infections are transmitted via asymptomatic viral shedding. Atypical manifestations are common. Genital HSV-2 recurs six times more frequently than type 1. Laboratory confirmation of the clinical diagnosis is recommended in all patients in order to guide a correct counselling and management. Real-time PCR and viral culture represent the gold standard for diagnosis. Serologic testing can be useful in persons with a questionable history. Counselling patients about the risk of transmission is crucial and helps prevent the spread of disease and neonatal complications.

Localized Wegener's granulomatosis.

BACKGROUND: Wegener's granulomatosis (WG) is a rare granulomatous necrotizing vasculitis of small and medium vessels which has predilection for upper airways, lungs and kidney. However, any other organ, including the skin and oral cavity, can be involved. Although mucocutaneous lesions are relatively common, they have only rarely been reported as localized manifestation of the disease. OBJECTIVES: Our aim was to evaluate the type and sites of skin and mucosal lesions, clinical course and response to treatment, histologic features and laboratory findings in localized WG. METHODS: The medical records of three patients (two women and one man) with localized WG followed up at our hospitals for a mean time of 10 years were studied. RESULTS: All patients presented with facial plaques infiltrating the nasal and palatal mucosae and cartilages and, in one case, perforating the palatal bone. Anti-neutrophil cytoplasmic antibodies, which are the marker for multisystem WG, were negative. The disease, refractory to various immunosuppressants, responded well, albeit incompletely, to prednisone plus cyclophosphamide. LIMITATIONS: The limited number of patients is counterbalanced by the rarity of the disease. CONCLUSIONS: Our cases may represent a rare distinctive subset of WG limited to the facial region and upper airway mucosa but showing a locally aggressive behaviour leading to cartilage and bony destruction.

A nonlinear biphasic fiber-reinforced porohyperviscoelastic model of articular cartilage incorporating fiber reorientation and dispersion.

A nonlinear biphasic fiber-reinforced porohyperviscoelastic (BFPHVE) model of articular cartilage incorporating fiber reorientation effects during applied load was used to predict the response of ovine articular cartilage at relatively high strains (20%). The constitutive material parameters were determined using a coupled finite element-optimization algorithm that utilized stress relaxation indentation tests at relatively high strains. The proposed model incorporates the strain-hardening, tension-compression, permeability, and finite deformation nonlinearities that inherently exist in cartilage, and accounts for effects associated with fiber dispersion and reorientation and intrinsic viscoelasticity at relatively high strains. A new optimization cost function was used to overcome problems associated with large peak-to-peak differences between the predicted finite element and experimental loads that were due to the large strain levels utilized in the experiments. The optimized material parameters were found to be insensitive to the initial guesses. Using experimental data from the literature, the model was also able to predict both the lateral displacement and reaction force in unconfined compression, and the reaction force in an indentation test with a single set of material parameters. Finally, it was demonstrated that neglecting the effects of fiber reorientation and dispersion resulted in poorer agreement with experiments than when they were considered. There was an indication that the proposed BFPHVE model, which includes the intrinsic viscoelasticity of the nonfibrillar matrix (proteoglycan), might be used to model the behavior of cartilage up to relatively high strains (20%). The maximum percentage error between the indentation force predicted by the FE model using the optimized material parameters and that measured experimentally was 3%.

Ballistic impact of single particles into gelatin: experiments and modeling with application to transdermal pharmaceutical delivery.

The impact and penetration of high speed particles with the human skin is of interest for targeted drug delivery by transdermal powder injection. However, it is often difficult to perform penetration experiments on dermal tissue using micron scale particles. To address this, a finite element model of the impact and penetration of a 2 µm gold particle into the human dermis was developed and calibrated using experiments found in the literature. Using dimensional analysis, the model was linked to a larger scale steel ball-gelatin system in order to extract key material parameters for both systems and perform impact studies. In this manner, an elastic modulus of 2.25 MPa was found for skin, in good agreement with reported values from the literature. Further gelatin experiments were performed with steel, polymethyl methacrylate, titanium, and tungsten carbide balls in order to determine the effects of particle size and density on penetration depth. Both the finite element model and the steel-gelatin experiments were able to predict the penetration behavior that was found by other investigators in the study of the impact of typical particles used for vaccine delivery into the human dermis. It can therefore be concluded that scaled up systems utilizing ballistic gelatins can be used to investigate the performance of transdermal powder injection technology.

Use of poly-beta-hydroxy-butyrate as a slow-release electron donor for the microbial reductive dechlorination of TCE.

In situ anaerobic reductive dechlorination, using slow-release electron donors, is emerging as an effective and sustainable (low-cost and low-maintenance) technology to remediate aquifers contaminated by chloroethenes. In the present study, we investigated the use of poly-beta-hydroxy-butyrate (PHB), a fully biodegradable polymer, as a slow-release source of hydrogen and acetate for the reductive dechlorination of trichloroethene (TCE). Results of this study indicated that TCE dechlorination in PHB-amended microcosms was 2.3-times higher than in non-amended controls. This higher activity was explained by a higher H(2) level in PHB-amended microcosms. As usual, acetate was the major sink (approximately 90%) of reducing equivalents available from PHB degradation, whereas no acetotrophic dechlorination was observed.