Elisa Molinelli

Pseudoxanthoma elasticum and skin: Clinical manifestations, histopathology, pathomechanism, perspectives of treatment.

Pseudoxantoma elasticum (PXE), also known as Groenblad-Strandberg syndrome, is a rare heritable disease with an estimated prevalence of 1:50,000 in the general population. PXE is considered a prototype of multisystem ectopic mineralization disorders and it is characterized by aberrant mineralization of soft connective tissue with degeneration of the elastic fibers, involving primarily the eyes, the cardiovascular system, and the skin. Cutaneous lesions consist of small, asymptomatic, yellowish papules or larger coalescent plaques, typically located on the neck and the flexural areas. PXE is caused by mutations in the ABCC6 (ATP-binding cassette subfamily C member 6) gene that encodes a transmembrane ATP binding efflux transporter, normally expressed in the liver and the kidney; however, the exact mechanism of ectopic mineralization remains largely unknown. The histological examination of cutaneous lesions, revealing accumulation of pleomorphic elastic structures in middermis, is essential for the definitive diagnosis of PXE, excluding PXE-like conditions. PXE is currently an intractable disease; although the cutaneous findings primarily present a cosmetic problem, they signify the risk for development of ocular and cardiovascular complications associated with considerable morbidity and mortality. The purpose of this review is to present a comprehensive overview of this rare form of hereditary connective tissue disorders, focus on the pathogenesis, the clinical manifestation, and the differential diagnosis of PXE. Emphasis is also placed on the management of cutaneous lesions and treatment perspectives of PXE.

Psoriasis, non-alcoholic fatty liver disease, and cardiovascular disease: Three different diseases on a unique background

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.

Biologic Therapy in Psoriasis: Safety Profile.

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.

Biologic Therapy in Immune Mediated Inflammatory Disease: Basic Science and Clinical Concepts

During the last decades, the advent of biological therapies has revolutionized the management of several immune-mediated inflammatory disorders, as inflammatory bowel diseases, autoimmune arthritis and psoriasis, which significantly impact both quality of life and health care economics. Biological therapies currently available can be divided into two main categories: the tumor necrosis factor-α antagonists (infliximab, adalimumab, etanercept, golimumab, certolizumab pegol) and interleukin 12/23 monoclonal antibodies (ustekinumab). Biologics, reducing TNFα bioavailability or inhibiting proximal regulators of inflammatory cascade, represent an established therapeutic strategy of inflammatory autoimmune diseases, with remarkable efficacy and a safety profile that is extensively examined and monitored. The biology and the immunological effects of TNFα, IL-12, IL-23 and related signalling pathways are accurately summarized. The dosing regimens, methods of administration, pharmacodynamics profiles, and side effects of the currently licensed TNFα antagonists and IL12/IL23 inhibitor are discussed in detail.

IL-17, IL-23, and p73 expression in cutaneous melanoma: a pilot study.

The incidence of cutaneous malignant melanoma is increasing worldwide, resulting in the demand for clinically useful prognostic biomarkers, especially for invasive and metastatic disease. We studied the immunohistochemical expression of interleukin-17 (IL-17), IL-23, and p73 in 35 malignant melanomas and compared them with benign melanocytic nevi and Spitz nevi, correlating them with clinical-pathological variables. A higher and statistically significant difference (P<0.05) in the intensity and percentage of stained cells of IL-17 and IL-23 was found in the melanoma group than in ordinary benign nevi that did not correlate with Breslow thickness nor Clark level. Moreover, p73 staining and percentage of stained cells was significantly higher (P<0.05) in all the melanomas studied, with a peculiar cytoplasmatic distribution. Our findings could suggest a possible IL-17, IL-23, and p73 involvement in cutaneous melanomas with a hypothetical impact on melanoma invasiveness.

Periodontal Disease: An Oral Manifestation of Psoriasis or an Occasional Finding?

Postmarketing Phase IV

Salivary interleukin-1β: Oral inflammatory biomarker in patients with psoriasis.

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.

Biologic Therapy in Inflammatory and Immunomediated Skin Diseases: Safety Profile.

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.

Nicotinamide : potential involvement in cutaneous malignant melanoma n : potential involvement in cutaneous malignant melanoma-methyltransferase: potential involvement in cutaneous malignant melanoma

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.

Biologic Therapy in Psoriasis (Part II): Efficacy and Safety of New Treatment Targeting IL23/IL-17 Pathways

BACKGROUND Psoriasis is a chronic immune-mediated inflammatory skin disorder that is estimated to affect 2-3% of the general population. The IL-23/IL-17 axis is currently considered to be crucial in the pathogenesis of psoriasis. METHODS Biologics licensed for psoriasis include the TNFα inhibitors (infliximab, adalimumab, etanercept), the interleukin (IL)-12/23 monoclonal antibody (ustekinumab), and IL-17 inhibitor (secukinumab, ixekizumab). RESULTS In this section, we analyse the role of IL-12, IL-23, and IL-17 in psoriasis and evaluated the efficacy and safety of biologic therapies targeting this cytokine. CONCLUSION Dosing regimens, administration modality, and pharmacodynamics profiles of currently available anti-IL-12/IL-23 and IL-17 inhibitors are also examined.