Differences in Osteoimmunological Biomarkers Predictive of Psoriatic Arthritis among a Large Italian Cohort of Psoriatic Patients.

(1) Background: In literature it is reported that 20-30% of psoriatic patients evolve to psoriatic arthritis over time. Currently, no specific biochemical markers can either predict progression to psoriatic arthritis or response to therapies. This study aimed to identify osteoimmunological markers applicable to clinical practice, giving a quantitative tool for evaluating pathological status and, eventually, to provide prognostic support in diagnosis. (2) Methods: Soluble (serum) bone and cartilage markers were quantified in 50 patients with only psoriasis, 50 psoriatic patients with psoriatic arthritis, and 20 healthy controls by means of multiplex and enzyme-linked immunoassays. (3) Results: Differences in the concentrations of matrix metalloproteases (MMPs), tissue inhibitors of metalloproteinases (TIMPs), receptor activator of nuclear factor kappa-B- ligand (RANK-L), procollagen type I N propeptide (PINP), C-terminal telopeptide of type I collagen (CTx-I), dickkopf-related protein 1 (DKK1), and sclerostin (SOST) distinguished healthy controls from psoriasis and psoriatic arthritis patients. We found that MMP2, MMP12, MMP13, TIMP2, and TIMP4 distinguished psoriasis from psoriatic arthritis patients undergoing a systemic treatment, with a good diagnostic accuracy (Area under the ROC Curve (AUC) > 0.7). Then, chitinase-3-like protein 1 (CHI3L1) and MMP10 distinguished psoriasis from psoriatic arthritis not undergoing systemic therapy and, in the presence of onychopathy, MMP8 levels were higher in psoriasis than in psoriatic arthritis. However, in these latter cases, the diagnostic accuracy of the identified biomarkers was low (0.5 < AUC < 0.7). (4) Conclusions. By highlighting never exploited differences, the wide osteoimmunological biomarkers panel provides a novel clue to the development of diagnostic paths in psoriasis and psoriasis-associated arthropathic disease.

Increased frequency of activated CD8+ T cell effectors in patients with psoriatic arthritis.

The aim of this study is to identify subsets of T cells differentially represented in the circulation of patients with psoriatic arthritis and to evaluate the possibility that they can recirculate between peripheral blood and the inflamed joints. We analyzed the phenotype and cytokine expression in circulating CD8+ and CD4+ T cells in 69 subjects: 28 with cutaneous psoriasis, 15 patients with psoriatic arthritis, and 26 healthy subjects. In the circulation, the percentage of each subset was compared among the groups and correlation was calculated with the serum concentration of C-reactive protein. To investigate the migration of T cells towards the inflamed joints, we performed a transwell migration assay towards patient serum and synovial fluid. In selected patients we analyzed in parallel T cells from peripheral blood and from synovial fluid. In the circulation, we found increased percentage of CD8+ CCR6+ T cell effectors expressing CD69 and of IL-17-producing T cells in patients with psoriatic arthritis. CD8+ effector/effector memory T cells showed increased migration towards synovial fluid. Finally, in synovial fluid we found accumulation of CXCR3+ CD8+ T cells and CD69+ cells. CD4+ T cells in the two compartments shared many similarities with CD8+ T cells. The results indicate a role for memory T cell effectors in systemic and joint manifestations of psoriatic arthritis.

Acquired lymphangiomas mimicking multiple hallux warts.

Lymphangioma is an uncommon benign vascular tumour that involves lymphatic vessels. It can be acquired or, most frequently, congenital. The acquired form presents with dilated lymphatic channels due to an obstruction. These lesions have no risk of malignant transformation, but they have a high rate of recurrence whether removed. We present a case of a 52-year-old woman with acquired lymphangiomas mimicking warts. She came to our observation for some keratotic lesions on her feet. Clinically, we found three warts on the sole of her left foot, but we also noticed the presence of swelling and papillomatous wart-like papules on both halluces. The hallux papules were studied by performing an excisional biopsy and were found to be lymphangiomas.

Blood to skin recirculation of CD4+ memory T cells associates with cutaneous and systemic manifestations of psoriatic disease.

Blood to skin recirculation could play a role in the pathogenesis of psoriasis. To investigate this possibility we dissected the phenotype of circulating T cells in psoriasis patients, calculated the correlation the clinical parameters of the disease and performed a parallel bioinformatics analysis of gene expression data in psoriatic skin. We found that circulating CCR6+ CD4+ TEM and TEFF cells significantly correlated with systemic inflammation. Conversely, the percentage of CXCR3+ CD4+ TEM cells negatively correlated with the severity of the cutaneous disease. Importantly CLA+ CD4+ TCM cells expressing CCR6+ or CCR4+CXCR3+ negatively correlated with psoriasis severity suggesting recruitment to the skin compartment. This assumption was reinforced by gene expression data showing marked increase of CCR7 and CLA-encoding gene SELPLG expression in psoriatic skin and strong association of their expression. The data enlightens a role for CD4+ T cells trafficking between blood and skin in cutaneous and systemic manifestations of psoriasis.

Prevalence and risk factors of actinic keratosis in patients attending Italian dermatology clinics.

Actinic keratosis (AK) is a common keratinocyte intra-epidermal neoplasia. To assess AK prevalence and potential risk factors in patients attending Italian general dermatology clinics. This retrospective study was conducted on clinical data from consecutive white outpatients aged ≥30 years, attending 24 general dermatology clinics between December 2014 and February 2015. AK prevalence (entire population) and multivariate risk factor analysis (patients with current/previous AK and complete data) are presented. AK prevalence in 7,284 patients was 27.4% (95% CI: 26.4-28.4%); 34.3% in men and 20.0% in women (p<0.001). Independent AK risk factors in 4,604 patients were: age (OR: 4.8 [95% CI: 3.5-6.5] for 46-60 years, increasing with older age to OR: 41.5 [95% CI: 29.5-58.2] for >70 years), history of other non-melanoma skin cancers (OR: 2.7 [2.2-3.3]), residence in southern Italy/Sardinia (OR: 2.6 [2.1-3.0]), working outdoors >6 hours/day (OR: 1.9 [1.4-2.4]), male gender (OR: 1.7 [1.4-2.0]), facial solar lentigos (OR: 1.6 [1.4-1.9]), light hair colour (OR: 1.5 [1.2-1.8]), prolonged outdoor recreational activities (OR: 1.4 [1.2-1.7]), light eye colour (OR: 1.3 [1.1-1.6]), skin type I/II (OR: 1.3 [1.1-1.6]), and alcohol consumption (OR: 1.2 [1.0-3.3]). BMI ≥25.0 (OR: 0.6 [0.5-0.7]), regular sunscreen use (OR: 0.7 [0.6-0.8]), and a lower level of education (OR: 0.8 [0.7-1.0]) were independent protective factors. AK prevalence was high in Italian dermatology outpatients. We confirm several well-known AK risk factors and reveal possible novel risk and protective factors. Our results may inform on the design and implementation of AK screening and educational programmes.

Acquired lymphangiomas mimicking multiple hallux warts

Abstract: Lymphangioma is an uncommon benign vascular tumour that involves lymphatic vessels. It can be acquired or, most frequently, congenital. The acquired form presents with dilated lymphatic channels due to an obstruction. These lesions have no risk of malignant transformation, but they have a high rate of recurrence whether removed. We present a case of a 52-year-old woman with acquired lymphangiomas mimicking warts. She came to our observation for some keratotic lesions on her feet. Clinically, we found three warts on the sole of her left foot, but we also noticed the presence of swelling and papillomatous wart-like papules on both halluces. The hallux papules were studied by performing an excisional biopsy and were found to be lymphangiomas.

T Helper Cell Subsets in Clinical Manifestations of Psoriasis.

Psoriasis is a chronic inflammatory skin disease, which is associated with systemic inflammation and comorbidities, such as psoriatic arthritis and cardiovascular diseases. The autoimmune nature of psoriasis has been established only recently, conferring a central role to epidermal CD8 T cells recognizing self-epitopes in the initial phase of the disease. Different subsets of helper cells have also been reported as key players in the psoriasis pathogenesis. Here, we reviewed the knowledge on the role of each subset in the psoriatic cascade and in the different clinical manifestations of the disease. We will discuss the role of Th1 and Th17 cells in the initiation and in the amplification phase of cutaneous inflammation. Moreover, we will discuss the recently proposed role of tissue resident Th22 cells in disease memory in sites of recurrent psoriasis and the possible involvement of Th9 cells. Finally, we will discuss the hypothesis of a link between T helper cell subsets recirculating from the skin and the systemic manifestations of psoriasis.

A role for CCR5(+)CD4 T cells in cutaneous psoriasis and for CD103(+) CCR4(+) CD8 Teff cells in the associated systemic inflammation.

Recent results have identified critical components of the T cell response involved in the initiation and amplification phases of psoriasis. However the link between T cell responses arising in the skin and the systemic inflammation associated with severe psoriasis is largely unknown. We hypothesized that specific subsets of memory T cells recirculating from the skin could play a role. We therefore dissected the circulating memory T cell compartment in patients by analyzing the TCM, TEM and Teff phenotype, the pattern of CCR4 and CCR5 chemokine receptor expression and the expression of the tissue homing molecule CD103. For each subset we calculated the correlation with the Psoriasis Area and Severity Index (PASI) and with the extent of systemic inflammation measured as serum level of the prototypic short pentraxin, C reactive protein (CRP). Validation was performed by comparison with gene expression data in psoriatic plaques. We found that circulating CD103(+)CCR4(+)CCR5(+) and CCR4(+)CCR6(-) CD8(+) Teff cells, were highly correlated with CRP levels as well as with the validated index PASI, reflecting a link between skin involvement and systemic inflammation in patients with severe psoriasis. In addition we observed a contraction of circulating CCR5(+) T cells in psoriasis patients, with a highly significant inverse correlation between CCR5(+)CD4 T cells and the PASI score. Increased expression of CCR5 and CCL5 genes in psoriatic skin lesions was consistent with an accumulation of CCR5(+) cells in psoriatic plaques indicating a role for CCR5/CCL5 axis in disease pathogenesis.

Skin microbiota of first cousins affected by psoriasis and atopic dermatitis.

BACKGROUND: Psoriasis and atopic dermatitis (AD) are chronic inflammatory skin diseases, which negatively influence the quality of life. In the last years, several evidences highlighted the pivotal role of skin bacteria in worsening the symptomatology of AD and psoriasis. In the present study we evaluated the skin microbiota composition in accurately selected subjects affected by (AD) and psoriasis. METHODS: Three first cousins were chosen for the study according to strict selection of criteria. One subject was affected by moderate AD, one had psoriasis and the last one was included as healthy control. Two lesional skin samples and two non-lesional skin samples (for AD and psoriatic subjects) from an area of 2 cm(2) behind the left ear were withdrawn by mean of a curette. For the healthy control, two skin samples from an area of 2 cm(2) behind the left ear were withdrawn by mean of a curette. DNA was extracted and sequencing was completed on the Ion Torrent PGM platform. Culturing of Staphylococcus aureus from skin samples was also performed. RESULTS: The psoriatic subject showed a decrease in Firmicutes abundance and an increase in Proteobacteria abundance. Moreover, an increase in Streptococcaceae, Rhodobacteraceae, Campylobacteraceae and Moraxellaceae has been observed in psoriatic subject, if compared with AD individual and control. Finally, AD individual showed a larger abundance of S. aureus than psoriatic and healthy subjects. Moreover, the microbiota composition of non-lesional skin samples belonging to AD and psoriatic individuals was very similar to the bacterial composition of skin sample belonging to the healthy control. CONCLUSION: Significant differences between the skin microbiota of psoriatic individual and healthy and AD subjects were observed.

Methotrexate: practical use in dermatology.

Methotrexate (MTX) is an anti-inflammatory, anti-proliferative and immunosuppressant drug largely used worldwide with a well-known efficacy, and it is considered a safe and easy to use agent. MTX was first used in psoriasis, but it represents an effective and safe therapeutic option in a wide range of skin diseases. Despite its common employ, it is still the subject of numerous researches, with the purpose to develop new strategies to increase the manageability and evaluate the efficacy of the treatment, alone and in association with other therapies. Starting up from the official guidelines, we have reviewed the scientific literature, along with our clinical experience, in order to update the uses of MTX in dermatology.

Cyclosporine in psoriasis: comparison of a 25-year real-world Italian experience to current European guidelines.

Cyclosporine (CsA) is an effective and safe therapeutic option in various dermatoses in both adults and children. Over the last 25 years, Italian dermatologists have gained relevant experience about the use of CsA in the treatment of psoriasis and atopic dermatitis, and an Italian Consensus Conference has recently provided recommendations in adult patients. A comparison between these real-world indications and current European guidelines is hereby provided.

T cell responses in psoriasis and psoriatic arthritis.

According to the current view the histological features of psoriasis arise as a consequence of the interplay between T cells, dendritic cells and keratinocytes giving rise to a self-perpetuating loop that amplifies and sustains inflammation in lesional skin. In particular, myeloid dendritic cell secretion of IL-23 and IL-12 activates IL-17-producing T cells, Th22 and Th1 cells, leading to the production of inflammatory cytokines such as IL-17, IFN-γ, TNF and IL-22. These cytokines mediate effects on keratinocytes thus establishing the inflammatory loop. Unlike psoriasis the immunopathogenic features of psoriatic arthritis are poorly characterized and there is a gap in the knowledge of the pathogenic link between inflammatory T cell responses arising in the skin and the development of joint inflammation. Here we review the knowledge accumulated over the years from the early evidence of autoreactive CD8 T cells that was studied mainly in the years 1990s and 2000s to the recent findings of the role of Th17, Tc17 cells and γδ T cells in psoriatic disease pathogenesis. The review will also focus on common and distinguishing features of T cell responses in psoriatic plaques and in synovial fluid of patients with psoriatic arthritis. The integration of this information could help to distinguish the role played by T cells in the initiation phase of the disease from the role of T cells as downstream effectors sustaining inflammation in psoriatic plaques and potentially leading to disease manifestation in distant joints.

Differential management of mild-to-severe psoriasis with biologic drugs: An Italian Delphi consensus expert panel.

BACKGROUND: In the management of moderate-to-severe psoriasis, increasingly complex clinical scenarios necessitate practical tools for appropriate biologic therapy selection in individual patients. An Italian Delphi consensus panel provided guidance on biologic use in selected clinical scenarios. METHODS: Ten experts defined statements under consideration, which were distributed as an online survey to a dermatologist panel. Plenary discussions of contentious statements were held to achieve consensus. RESULTS: The survey was sent to 30 clinicians. After plenary discussions, consensus was reached on all 20 statements on the following topics: special populations; infections; comorbidities; immunogenicity; extra-cutaneous involvement; pregnancy; and adherence. Three statements required further discussion in order to gain consensus: use of subcutaneous biologics in mild liver impairment (final 94% agreement), use of any biologic in discoid lupus erythematosus (final 100% disagreement), and use of etanercept in patients with history of hypersensitivity reactions to drugs and/or food (final 75% disagreement). CONCLUSIONS: This Delphi expert consensus on the use of biologics in psoriasis provides practical recommendations for dermatologists to use when choosing an appropriate biologic in challenging but common clinical scenarios. More data are required to clarify clinical differences of biologic drugs used to treat psoriasis.

Treatment of atopic dermatitis eczema with a high concentration of Lactobacillus salivarius LS01 associated with an innovative gelling complex: a pilot study on adults.

GOALS: To evaluate the efficacy of a highly concentrated Lactobacillus salivarius preparation containing a gelling complex formed by Streptococcus thermophilus ST10 and tara gum in the treatment of atopic dermatitis (AD). BACKGROUND: Previous studies have demonstrated an improvement in AD symptoms after administration of the probiotic strain L. salivarius LS01. S. thermophilus ST10 and tara gum create a gelling complex that adheres to intestinal mucus and improves barrier function. STUDY: A prospective, controlled pilot trial was carried out to evaluate how the association of S. thermophilus ST10 and tara gum could improve the activity of L. salivarius LS01 administered at high doses to adults with AD. Twenty-five patients were included into the study: 13 were treated for 1 month with the active formulation, whereas 12 represented the placebo group. Scoring Atopic Dermatitis index was determined before and at the end of probiotic administration. Fecal samples were also collected to evaluate changes in bacterial counts of Staphylococcus aureus and clostridia. RESULTS: A significant improvement in SCORAD index was observed in the probiotic group after 1 month of treatment, whereas no significant changes occurred in placebo patients. A slight decrease in fecal S. aureus count was observed in probiotic-treated patients. CONCLUSIONS: Data obtained in this study suggest a potential role for L. salivarius LS01 in the treatment of AD. The addition of tara gum and S. thermophilus ST10 seems to improve the overall efficacy of the probiotic strain, in particular shortening the time required for the onset of the positive effects. Further studies to investigate the activity of this preparation are advisable.

The cost effectiveness of biologic therapy for the treatment of chronic plaque psoriasis in real practice settings in Italy.

BACKGROUND AND OBJECTIVES: Biologic therapies are considered to be cost effective by leading Health Technology Assessment (HTA) agencies and, therefore, eligible for reimbursement by public health services. However, biologic therapies entail sizable incremental costs and, besides, have a considerable financial impact that in Italy amounts to 13.7 % of the national health service's pharmaceutical expenditure. In the reimbursability decision process, an important role is played by both the drug efficacy data observed in pre-licensing RCTs and the economic modelling assumptions, as they give evidence on cost effectiveness. The administration of therapies in real practice settings is likely to produce a significant deviation from the results predicted by the models, theoretically outweighing the assumption on which the decision process is founded. This is a matter of concern for public health services and, consequently, an interesting topic to investigate. METHODS: To overcome the lack of knowledge concerning the actual cost effectiveness of biologic therapies for the treatment of plaque psoriasis in the clinical practice setting in Italy, an observational study was conducted in 12 specialist centres on patients switching to biologic therapy within a 6-month enrolment window. RESULTS: The study confirms in clinical practice the efficacy of the switch to biologic therapies, analysed using a number of clinical [Psoriasis Area and Severity Index (PASI), pain visual analogue scale (VAS) and itching VAS] and quality-of-life parameters. A general health-related quality of life (HR-QOL) improvement, with a 0.23 quality-adjusted life-year (QALY) mean gain per patient, has been reported in the 6-month observation period. The direct medical costs to treat plaque psoriasis with biologic therapies amount to 15,073.7 per year (prior to their enrolment, the same patients cost 2,166.2 on an annual basis). After the switch to biologic agents, the cost per QALY during the first year of treatment amounts to 28,656.3. CONCLUSION: At least in the short-term, the clinical practice of the specialised Italian centres taking part in the study confirms that switching patients to a biologic drug produces an incremental cost-effectiveness ratio comparable with the values predicted by the HTA bodies.

The Italian Euromelanoma Day: evaluation of results and implications for future prevention campaigns.

BACKGROUND: Melanoma incidence/mortality is increasing worldwide. "Euromelanoma Day" is a pan-European campaign for skin cancer prevention. Results of the 2010 Euromelanoma Day in Italy are reported herein. MATERIALS AND METHODS: A questionnaire was used to collect data on participants' characteristics and suspected skin cancers. RESULT: A total of 1085 participants was screened (64.1% females, median age 44 years). Suspicion rate, detection rate, and positive predictive values for melanoma were 1.3, 0.28 and 21.4%, respectively. Poorly educated, ≥35 years old, pale-skinned males were at higher risk for skin cancer than highly educated, <35 years old, darker-skinned females, although the latter groups reported sun-seeking behaviors. Full skin examination and dermoscopy were performed in 85.5 and 79.2% of participants. CONCLUSIONS: The 2010 Italian Euromelanoma Day produced good results in terms of melanoma detection/suspicion rates, likely due to the extensive use of full clinical and dermoscopic examinations. The campaign failed to attract many high-risk individuals. Targeted communication strategies are needed to this regard.