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Background: Although long-term management of psoriasis is paramount, this approach is challenging in clinical practice. In the recent PSO-LONG trial, a fixed-dose combination of betamethasone dipropionate (BD) and calcipotriol (Cal) foam applied twice a week on non-consecutive days for 52 weeks (proactive treatment) reduced the risk of relapse. However, the role of Cal/BD foam in the long-term management of psoriasis needs further clarifications. The ProActive Management (PAM) program, a nationwide Italian project, aims at reaching a consensus on the role of proactive management of psoriasis. Methods: A steering committee generated some statements through the nominal group technique (NGT). The statements were voted by an expert panel in an adapted Delphi voting process. Results: Eighteen statements were proposed, and the majority of them (14/18) reached a consensus during the Delphi voting. The need to provide long-term proactive topical treatment to reduce the risk of relapse for the treatment of challenging diseases sites or in patients where phototherapy or systemic therapies are contraindicated/ineffective was widely recognized. A consensus was reached about the possibility to associate the proactive treatment with systemic and biological therapies, without the need for dose intensification, thus favoring a prolonged remission. Moreover, the proactive treatment was recognized as more effective than weekend therapy in increasing time free from relapses. Approaches to improve adherence, on the other hand, need further investigation. Conclusions: The inclusion in guidelines of a proactive strategy among the effective treatment options will be a fundamental step in the evolution of a mild-moderate psoriasis therapeutic approach.

Caterina Lanna,* Gaia Maria Cesaroni,* Sara Mazzilli, Luca Bianchi, Elena Campione Dermatologic Unit, University of Rome Tor Vergata, Rome, Italy*These authors contributed equally to this workCorrespondence: Caterina LannaDermatologic Unit, Department of Systems Medicine, University of Rome Tor Vergata, Viale Oxford 81, Rome 00133, ItalyEmail caterinalanna.cl@gmail.comAbstract: Psoriasis is a common inflammatory skin condition frequently associated with cardiometabolic diseases such as diabetes. Indeed, the state of systemic inflammation typical of psoriasis leads to an increase in the level of IL-1, IL-6 and TNF-alpha which may cause a reduced sensitivity to insulin and, ultimately, can lead to type 2 diabetes mellitus. Particularly, the derangement of PDE4-cAMP signaling has a critical role in disordered glucose and lipid metabolism. Apremilast, as a selective inhibitor of PDE4-cAMP signalling, represents an innovative therapeutic strategy for psoriasis. Here, we report a case of a patient affected by psoriasis and diabetes, who – after using Apremilast – improved his glucose metabolism as well as his need of anti-diabetic drugs and his psoriasis. This suggests that, in addition to its role against psoriasis, Apremilast may even act as a metabolic modulator.Keywords: psoriasis, diabetes, PDE4-inhibitor

Elena Campione,1 Terenzio Cosio,1 Monia Di Prete,2 Caterina Lanna,1 Annunziata Dattola,1 Luca Bianchi1 1Dermatologic Unit, Department of Systems Medicine, University of Rome Tor Vergata, Rome, 00133, Italy; 2Anatomic Pathology, University of Rome Tor Vergata, Rome, 00133, ItalyCorrespondence: Elena CampioneDermatologic Unit, Department of Systems Medicine, University of Rome Tor Vergata, Via Montpellier,1, Rome, 00133, ItalyTel +39.06.20900252Email elena.campione@uniroma2.itAbstract: Psoriasis is a chronic, relapsing, immune-mediated systemic disease. Its pathogenesis is complex and not fully understood yet. Genetic and epigenetic factors interact with molecular pathways involving TNF-α, IL-23/IL-17 axis, and peculiar cytokines, as IL-36 or phosphodiesterase 4. This review discusses the mechanisms involved in the development of the disease, as well as the therapeutic options proposed following the investigation of the inflammatory psoriatic pathways. We performed a comprehensive search using the words “psoriasis” and the newest molecules currently under investigation and approval. From these data, a new scenario in psoriasis is occurring to personalize the therapies - especially systemic ones and those using small molecules – and avoid topical and injectable drugs. We reported the newest therapeutic opportunities, including the inhibitors of Janus kinase/tyrosine kinase 2, phosphodiesterase-4 and IL-36 receptor. Today, more than 20 molecules are under investigation for the treatment of cutaneous psoriasis. Most of them are constituted by small molecules or biologic therapies. This underlines how psoriasis needs systemic therapies, due to its complex pathogenesis and multisystemic involvement.Keywords: psoriasis, janus kinase inhibitors, tyrosine kinase 2 inhibitors, phosphodiesterase 4 inhibitors, IL-36 receptors inhibitors

Caterina Lanna,* Gaia Maria Cesaroni,* Sara Mazzilli, Luca Bianchi, Elena Campione Dermatologic Unit, University of Rome Tor Vergata, Rome, Italy*These authors contributed equally to this workCorrespondence: Caterina LannaDermatologic Unit, Department of Systems Medicine, University of Rome Tor Vergata, Viale Oxford 81, Rome 00133, ItalyEmail caterinalanna.cl@gmail.comAbstract: Psoriasis is a common inflammatory skin condition frequently associated with cardiometabolic diseases such as diabetes. Indeed, the state of systemic inflammation typical of psoriasis leads to an increase in the level of IL-1, IL-6 and TNF-alpha which may cause a reduced sensitivity to insulin and, ultimately, can lead to type 2 diabetes mellitus. Particularly, the derangement of PDE4-cAMP signaling has a critical role in disordered glucose and lipid metabolism. Apremilast, as a selective inhibitor of PDE4-cAMP signalling, represents an innovative therapeutic strategy for psoriasis. Here, we report a case of a patient affected by psoriasis and diabetes, who – after using Apremilast – improved his glucose metabolism as well as his need of anti-diabetic drugs and his psoriasis. This suggests that, in addition to its role against psoriasis, Apremilast may even act as a metabolic modulator.Keywords: psoriasis, diabetes, PDE4-inhibitor

Laura Vollono1, Arianna Piccolo1, Caterina Lanna1, Maria Esposito2, Mauro Bavetta1, Elena Campione1, Luca Bianchi1, Laura Diluvio1 1Dermatology Department, University of Rome, Tor Vergata, Italy; 2Dermatology Department, University of L’Aquila, L’Aquila, ItalyCorrespondence: Laura VollonoDermatology Department, University of Rome Tor Vergata, Viale Oxford 81, Rome 00133, ItalyTel +39 06 2090 0252Email laura.vollono@gmail.comIntroduction: Omalizumab is a recombinant humanized anti-IgE monoclonal antibody, approved for patients affected by chronic spontaneous urticaria resistant to antihistamines. Although the clinical benefit of omalizumab has been established in several clinical trials, there are very little data about long-term treatment with this drug and real-life reports regarding its use in patients affected by comorbidities other than urticaria are lacking.Objectives: To assess omalizumab efficacy and safety in a heterogeneous population of patients affected by chronic spontaneous urticaria and several comorbidities in a real-world setting.Materials and methods: Patients affected by chronic spontaneous urticaria with weekly urticaria activity score >16 resistant to antihistamines were treated with omalizumab 300 mg injection as add-on to H1-antihistamines administered every 4 weeks for 6 months. Clinical assessment of weekly urticaria activity score, dermatology life quality index and blood tests were performed at baseline, 12, 24 and 52 weeks of treatment. Response was assessed based on reduction weekly urticaria activity score.Results: Thirty-two patients (22F; 10M) with a mean age of 52.4 years (range 27–72) affected by chronic spontaneous urticaria were enrolled. Comorbidities affecting our study population were divided into 6 categories: cardio-metabolic (77%), oncologic (19%), infectious (16%), allergic (45%) immunologic (41%) and others (18%). Omalizumab determined a satisfactory reduction of symptoms of chronic spontaneous urticaria and an amelioration of quality of life within our population. No relevant alterations regarding patients’ underlying conditions were encountered. This is the first study regarding the use of omalizumab for chronic spontaneous urticaria in a population of adult patients affected by several comorbidities, eg, cardio-metabolic, oncologic, infectious, allergic, immunologic and psychiatric diseases. Real-life data represent a valuable source of information about a drug’s safety and efficacy profile, especially in patients affected by different comorbidities that are widely diffused in Western countries.Keywords: chronic spontaneous urticaria, omalizumab, oncologic, cardiovascular, allergic and immunologic conditions, comorbidities

We report the case of a seventy-four-year-old man with a slow-growing 2 cm mass on the back that arose near the surgical scar of previously excised melanoma, invasive to a Breslow depth of 3 mm. Preoperative clinical diagnosis was “in-transit” melanoma metastasis. After surgical excision, histopathologic examination revealed a dermal nodular proliferation of spindle cells arranged in storiform pattern, with mild pleomorphism, infiltrating around appendages and into the subcutaneous tissue. Immunohistochemical investigation documented diffuse positivity for CD34 and vimentin of spindle cells. Scattered dendritic cells, containing dark pigment in varying proportion and positive for S100, Melan-A and HMB-45, were also observed. A final diagnosis of Bednar tumour was formulated. Subsequently, the patient developed numerous metastases from the primary melanoma and died after 18 months. Bednar tumour is a rare pigmented variant of dermatofibrosarcoma protuberans of intermediate malignant potential. The presence of pigmented cells in Bednar tumour requires careful differential diagnosis with malignant or benign pigmented skin tumours. The clinical history of a Bednar tumour developing close to the scar of a previous melanoma gives the opportunity of a critical and intriguing discussion about the potential origin of pigmented cells in this rare variant of dermatofibrosarcoma protuberans.

Alessandra Ventura,1 Mauro Mazzeo,1 Roberta Gaziano,2 Marco Galluzzo,1 Luca Bianchi,1 Elena Campione1 1Department of Dermatology, University of Rome “Tor Vergata”, Rome, Italy; 2Department of Experimental Medicine and Surgery, Rome, Italy Abstract: Psoriasis is a chronic inflammatory disease affecting up to 3% of the general population. The prevalence of nail involvement in psoriasis patients varies between 15% and 79%. While the nails represent a small portion of the body surface area, psoriasis in these areas can have a disproportionate influence on a patient’s physical and psychosocial activities. Differential diagnosis between an onychomycosis and a psoriatic nail could be challenging; nevertheless, coexistence of onychomycosis and nail psoriasis also occurs and both are common disorders in the general population. Nail psoriasis can be difficult to treat. Treatment of nail psoriasis should consider the body surface area of skin disease, psoriatic arthritis, severity of nail disease, and the impairment in the quality of life. All patients should be tested for onychomycosis before starting a therapy. This recommendation is underlined by the fact that nail psoriasis is mostly treated by immunosuppressive drugs, like steroids, methotrexate, or biologics, which may aggravate mycotic nail infections. Conventional systemic therapy, such as use of steroids, cyclosporine, methotrexate, and retinoid in the long term, can cause organ toxicities. Currently, use of apremilast and tofacitinib favors an early healing of nail psoriasis because they act directly on the pathogenic targets, distressing the inflammatory signals associated with the initiation and maintenance of the disease activity, and as with several conventional synthetic disease modifying antirheumatic drugs, they are characterized by the convenience of oral administration. The number of treatment options has increased considerably in recent years; however, given the heterogeneity of the disease, the therapy should be personalized to individual cases. Keywords: nail, psoriasis, onychomycosis

Elena Campione,1 Evelin Jasmine Paternò,2 Eleonora Candi,3,4 Mattia Falconi,5 Gaetana Costanza,2 Laura Diluvio,1 Alessandro Terrinoni,4 Luca Bianchi,1 Augusto Orlandi2,6,7 1Department of Dermatology, 2Department of Biomedicine and Prevention, 3Department of Experimental Medicine and Surgery, University of Rome “TorVergata”, 4Biochemistry Laboratory IDI-IRCCS, Faculty of Medicine, University of Rome “Tor Vergata”, 5Department of Biology, University of Rome “TorVergata”, 6Institute of Anatomic Pathology, University of Rome “TorVergata”, 7TorVergata University-Policlinic of Rome, Rome, Italy Abstract: Piroxicam (PXM), a nonsteroidal anti-inflammatory drug, is an enolic benzothiazine and a potent member of the oxicam series. The drug suppresses the synthesis of proinflammatory enzymes, such as cyclooxygenases-1 and -2 (COX-1 and 2), downregulates the production of prostaglandins (PGs) and tromboxanes, and inhibits polyamines production by blocking ornithine decarboxylase induction involved in nonmelanoma skin carcinogenesis. In addition, PXM is able to induce tumor cell apoptosis and suppresses metalloproteinase 2 activities. Skin carcinogenesis is a multistep process in which the accumulation of genetic events leads to a gradually dysplastic cellular expression, deregulation of cell growth, and carcinomatous progression. COX-1 upregulation plays a significant role in PG and vascular epidermal growth factor production supporting tumor growth. Increased level of PGs in premalignant and/or malignant cutaneous tumors is also favored by upregulation of COX-2 and downregulation of the tumor suppressor gene 15-hydroxy-prostaglandin dehydrogenase. Chemoprevention can be a hopeful approach to inhibit carcinoma occurrence before an invasive tumor develops. The chemopreventive effect of nonsteroidal anti-inflammatory drugs on nonmelanoma skin cancers has been established. In this study, we highlighted the different modalities of action of PXM on the pathogenesis of nonmelanoma skin cancer, analyzing and evaluating binding modes and energies between COX-1 or COX-2 and PXM by protein–ligand molecular docking. Our clinical experience about the local use of PXM on actinic keratoses and field cancerization is also reported, confirming its efficacy as target therapy. Keywords: COXs inhibitor, actinic keratosis, tumor progression, binding mode

No abstract available

Epidemiologic data highlight sex differences in melanoma outcome. A putative role of sex hormones is still under investigation. Very few laboratory investigations have focused on the level of expression of estrogen receptors in melanoma. We evaluated the presence of estrogen receptors alpha (ERα) and beta (ERβ) in melanoma specimens from female patients with a previous history of breast carcinoma (BC). Moreover, another group of female patients undergoing ovarian stimulation (OS) were also compared to two control groups matched for age and melanoma staging. The study was performed at the IRCCS Policlinico di Sant'Orsola Hospital's Melanoma Unit from January 2017 to December 2019. The nuclear and cytoplasmatic immunohistochemical staining was evaluated and scored by the percentage of stained tumour cells: 0 (≤20%), 1 (21-50%) or 2 (≥50%). Twenty-eight specimens were analysed. ERβ nuclear presence was detected in all cases of women with a history of breast cancer. Cytoplasmatic ERβ was clearly expressed with a score of 2 in seven cases. In the respective control group, nuclear and cytoplasmatic ERβ expression was much lower. A cytoplasmatic ERα positivity was also detected in almost all cases. In the second group of women who experienced ovarian stimulation for Assisted Reproductive Technology (ART), a lower abundance of nuclear ERs was detected. Conversely, cytoplasmatic ERβ and α expression ranged widely. Melanoma of women treated with anti-estrogen therapy is generally more prone to express estrogen receptors compared with women of the same age and CM staging but also compared with women in fertile age with and without a history of OS.

Background: Actinic keratosis (AK) is considered an "in situ" non-melanoma skin cancer induced by ultraviolet chronic exposure. Sunscreen and topical anti-inflammatory agents like diclofenac could improve the evolution of this kind of lesions. A topical product containing piroxicam 0.8% and sun filters (50 SPF) (ACTX) has shown to be very effective in reducing AK lesions. So far, no data are available regarding the effects of this product on skin modifications evaluated by reflectance confocal microscopy (RCM) and dermoscopy at the lesions site and on the skin around the lesions (field cancerization). Study aim: To evaluate in a two-center, assessor-blinded, prospective trial the effect of ACTX on AK number, RCM and dermoscopy parameters evolution of a target lesion in subjects with multiple AK lesions. Subjects and methods: A total of 54 subjects (42 men and 12 women; mean age 65 years) with AK lesions grade I-III located on the scalp (n = 36) or face (n = 18) were enrolled after their written informed consent. ACTX was applied twice daily on the face and scalp for 6 consecutive months. AK lesion count was performed at baseline and after 3 and 6 months. Lesion count was assessed in a blind fashion evaluating digital color high definition images performed at each visit and coded in a blinded fashion. An RCM evaluation were performed at the same time-points. A dermoscopy evaluation was performed at baseline and after 6 months. RCM and dermoscopy were assessed on a pre-specified target lesion. The RCM severity score was used evaluating 11-item examining stratum corneum, stratum granulosum, stratum spinous and dermal layers (maximum score 11 points). The dermoscopy score evaluated erythema, scaling and follicular plugs (from 0 to 4 for each item) and pigmentation (from 0 to 5). Results: Forty-nine subjects (90%) concluded the trial. At baseline, the mean(SD) number of AK lesions was 9.6(5.2). AK lesions significantly decreased to 5.9 and to 5.6 after 3 and 6 months of ACTX treatment (P = 0.001; Intention to treat analysis), representing a -42% reduction. A reduction of AK lesion number >50% in comparison with baseline was observed in 51% of subjects at month 6. New AK lesions appeared in 5 subjects (9%). The RCM mean(SD) severity score at baseline was 6.4(2.0). ACTX treatment was associated with a progressive and significant (P = 0.002) reduction to 4.9 after 3 months and to 4.8(2.3) at month 6 (a -25% reduction). The Dermoscopy score at baseline was 5.5(2) and it was reduced significantly (P = 0.007) to 4.5(2) at the end of the study. The product was in general very well tolerated. Conclusion: A 6-month application of ACTX in subjects with AK lesions was associated with an improvement of AK lesion count and with a reduction in the RCM/dermoscopy severity scores of the target lesion. (Trial Registration Number: ISRCTN22070974).

In the last three decades cutaneous melanoma has been widely investigated as a steroid hormone-sensitive cancer. Following this hypothesis, many epidemiological studies have investigated the relationship between estrogens and melanoma. No evidence to date has supported this association due to the great complexity of genetic, external and environmental factors underlying the development of this cancer. Molecular mechanisms through which estrogen and their receptor exert a role in melanoma genesis are still under investigation with new studies increasingly focusing on the discovery of new molecular targets for therapeutic treatments.

BACKGROUND: The reasons for the appearance of acne in adulthood are largely unknown. OBJECTIVE: We explored the role of personal and environmental factors in adult female acne. METHODS: We conducted a multicenter case-control study in the outpatient departments of 12 Italian cities. Cases (n = 248) were consecutive women ≥25 years of age with newly diagnosed acne of any grade. Controls (n = 270) were females diagnosed with conditions other than acne. RESULTS: In multivariate analysis, a history of acne in parents (odds ratio [OR] = 3.02) or siblings (OR = 2.40), history of acne during adolescence (OR = 5.44), having no previous pregnancies (OR = 1.71), having hirsutism (OR = 3.50), being an office worker versus being unemployed or being a housewife (OR = 2.24), and having a high level of reported psychological stress (OR = 2.95) were all associated with acne. A low weekly intake of fruits or vegetables (OR = 2.33) and low consumption of fresh fish (OR = 2.76) were also associated with acne. LIMITATIONS: We did not establish an onset date for acne. Some of our associations may reflect consequences of established acne. CONCLUSION: Lifestyle factors may play an important role for acne development in adulthood, but their role should be further assessed in prospective studies.