Tocilizumab and its usage for skin diseases.

The monoclonal anti-IL6 receptor antibody called Tocilizumab is widely used by rheumatologists for joint diseases. Its application in dermatology has mainly concerned scleroderma and Systemic Sclerosis in the last years. The most varied skin diseases treated with tocilizumab, such as psoriasis, psoriatic arthritis, Behcet's Syndrome, Lupus, and the already mentioned scleroderma up to multi-organ syndromes with skin involvement will be discussed. At the same time, there have been several side reactions to the drug involving the skin forcing careful skin monitoring during treatment. Despite the evidence currently available in the appropriate literature, there is no formal recommendation for any of these diseases to use Tocilizumab for therapeutic purposes. The aim of this review was to collect all the main evidence on the use and involvement of the drug in dermatological practice in order to stimulate further research or hypothesize on possible therapeutic options.

CD27 mRNA expression in mycosis fungoides.

BACKGROUND: The etiopathogenesis of MF remains obscure. CD27 is a member of the tumor necrosis factor receptor superfamily (TNFRS) that regulates lymphocyte function. Expression of CD27 protein and mRNA has been reported in B-cell lymphomas and adult T-cell leukemia/lymphoma. In this study, we examined the expression of CD27 in the skin of MF patients by real time PCR. The amount of CD27 was measured in MF patients and healthy controls. METHODS: A total of 98 skin biopsies were analyzed: 12 obtained from healthy donors and 86 obtained cryostatic sections OCT-embedded affected by MF. Relative quantification of mRNA CD27 expression was achieved by means of TaqMan (Thermo Fisher Scientific, Waltham, MA, USA) amplification and normalization to glyceraldehyde-3-phosphate dehydrogenase (GAPDH). RESULTS: Housekeeping gene was detectable in all skin samples and there is no difference between healthy control and MF P value =0.1564. CD27 mRNA sequences were found in 3 of 12 (25%) of skin obtained from healthy donors and in 59 of 86 (68%) of skin obtained from cryostatic sections OCT-embedded affected by MF. The χ2 statistic with Yates correction is 6.8413 and the P value is 0.0089. When we compared the CD27 expression in MF and controls the RQ analysis showed a value of 9.12±14.13. A RQ of 9.12 means that this gene is 9.12 times more expressed in MF skin samples then in the healthy skin samples. No difference was observed in the MF clustered by stages. CONCLUSIONS: Our findings indicates that CD27 can be used as diagnostic/prognostic markers, and whether anti-CD27 antibodies can be used in therapy.

Functional study of TNF-α as a promoter of polymorphisms in psoriasis.

BACKGROUND: TNF-α is an important mediator in the pathogenesis of psoriasis and polymorphisms influence its transcription and could be implicated in psoriasis risk and modify certain aspects of disease, such as age at onset of psoriasis vulgaris and disease severity. Six TNF-α single nucleotide polymorphisms (SNPs) in promoter region has been identified and studied but with discordant results. The aim of this study was to evaluate whether the polymorphisms in TNF-α (-238 [rs361525], -308 [rs1800629], -857 [rs1799724], -1031 [rs1799964]) are associated with severity, itch, early onset or response to drug therapy in psoriasis in Caucasian Italian patients. METHODS: Fifty-eight psoriasis patients from Turin PSOCARE, 23 with psoriasis vulgaris and 35 with psoriatic arthritis were studied. Ready-to-use master mix for allelic discrimination of rs1800629, rs361525 and rs1799964 respectively. RESULTS: Our data showed a significant association between the -857(G) variant and both VAS-itch (P=0.03) and VAS-pain index (P=0.006), OR=0.2 (0.04-0.98) and OR=0.12 (0.02-0.59). No significant association between the genotypes or alleles of TNF-α SNPs has been observed with other clinic-pathologic parameters or etanercept response. CONCLUSIONS: Our data suggest that -857 CC genotype could be involved in pain and itch severity in psoriasis patients.

Misuse, consequences and phototoxic skin-related effects of Rutaceae.

Ruta is a common plant growing in Italy and in the Mediterranean area. It has been used in popular tradition with different aims, ranging from therapeutic to esoteric purposes. However, the plant is still used as a common remedy in some of present-day rural and urban communities and it can be found in gardens all over Europe. Ruta's photosensitizing effect has been described in the literature and seems to be mediated by furanocoumarins. We collected data from the 18 case-reports for a total of 32 patients that we included in our analysis, assessing demographic variables, clinical findings, diagnosis, time of onset of lesions, time of resolution and therapy. The main aim of this work was to outline the clinical presentation, therapeutic management and demography of phytophototoxic reactions from contact with Ruta in order to suggest the correct diagnostic approach and disease recognition, as well as its possible prevention.

Therapeutic management of chronic spontaneous urticaria in clinical practice: results from a pilot survey.

BACKGROUND: The therapeutic approaches to patients with chronic spontaneous urticaria (CSU) differ among health care professionals and may be influenced by many factors. This cross-sectional survey was aimed at evaluating physicians' attitudes regarding therapeutic management of CSU in clinical practice. METHODS: A study-specific questionnaire was administered to a group of physicians (N.=21) with a specialist interest in CSU from different areas of Italy (group A) and also to other physicians (N.=25) who manage CSU only occasionally in their clinical activity (group B). RESULTS: In case of ineffectiveness of second-generation antihistamines at standard doses, higher doses of the same drug were always or frequently prescribed by most physicians in both groups, and 64% in group B and one third in group A usually increased the dose up to twice. Old-generation antihistamines were never used in clinical practice by 14% of survey participants in group A and 24% in group B, with the remaining physicians reporting rare or occasional uses. The prescription of systemic corticosteroids appeared to be more common among physicians in group B. The question concerning the use of alternative drugs in refractory CSU produced different answers between the two groups. Costs and access to specialist reference centers were indicated as the most important barriers to the use of medications different from antihistamines. CONCLUSIONS: These preliminary results suggest that therapeutic approaches to CSU seem to be heterogeneous in clinical practice and could be at least in part conditioned by the different medical settings where physicians usually work.

Chronic spontaneous urticaria in clinical practice: a pilot survey about attitudes and perceptions on assessment, diagnostic work-up and dietary management.

BACKGROUND: Chronic spontaneous urticaria (CSU) is a heterogeneous condition whose management can be complex and challenging. The aim of this study is to evaluate physicians' attitudes regarding practical aspects of CSU management, including adherence to international guidelines, criteria and instruments for CSU assessment, prescription of laboratory investigations and role of dietary measures. METHODS: A cross-sectional survey was conducted using a study-specific questionnaire. It was administered to a group of physicians with a specialist interest in CSU from different areas of Italy definable as "CSU experts" (group A; N.=21) and subsequently to other physicians who managed CSU only occasionally in their clinical activity (group B; N.=25). RESULTS: The EAACI/GA2LEN/EDF/WAO guidelines were considered very or moderately useful by the majority of participants. Significantly more physicians in group A reported that such guidelines were always followed in clinical practice (P=0.0008). Instruments for the assessment of CSU severity/activity and quality of life were used in clinical practice significantly more often by CSU experts as compared to group B. Dietary measures were frequently suggested for CSU patients by nearly three quarters of group B members and by only 5% of CSU experts (P<0.00001). When physicians were asked to indicate the type of laboratory examinations that were commonly performed in patients with longstanding and/or uncontrolled CSU, regardless of history, the investigations most frequently reported were full blood count and thyroid autoantibodies, followed by erythrocyte sedimentation rate and/or C-reactive protein and thyroid function tests. CONCLUSIONS: The results of the present pilot survey seem to suggest the heterogeneity of the approaches used for CSU management in clinical practice.

Genetic mutations in primary malignant melanoma of the esophagus: case report and literature review.

The most frequent genetic aberrations in mucosal melanoma are activating mutations of c-KIT. Primary malignant melanomas of esophagus (PMME) are uncommon entities, with aggressive biological behavior and poor prognosis. The better definition of their genotype could improve therapeutic options. We report a case of a 66 years old man with a PMME in the lower third of the esophagus. Analysis of c-kit, KRAS, NRAS and BRAF genes resulted negative for mutations. On the basis of a computerized (PuMed/Medline) bibliography search we retrieved a total of other 35 cases of PMME analyzed for genetic alterations in RAS, BRAF, and KIT. When we compared mutations frequency of PMME with those of other mucosal melanomas, it appeared that PMME are characterized by a relative higher percentage of NRAS mutations. PMME seem to show a specific pattern of genetic alterations suggesting that they could represent a distinct entity among mucosal melanomas.

A meta-analysis of melanoma risk in industrial workers.

Industrial workers are exposed to occupational pollutants, which may cause diseases such as cancer, but links to melanoma are not established. The identification of industry-related risk factors for melanoma incidence and mortality might be of importance for workers, health providers, and insurance companies. To assess melanoma incidence and mortality among oil/petroleum, chemical, and electrical industry workers. All studies reporting standardized mortality ratios (SMR) and/or standardized incidence ratios (SIR) of melanoma in workers employed in oil/petroleum, chemical, and electrical industries were included. Random-effect meta-analyses were carried out to summarize SIR and SMR for melanoma among oil/petroleum, chemical, and electrical industry workers. Heterogeneity was assessed using χ and I statistics. Possible source bias and quality were assessed using the Strengthening the Reporting of Observational Studies in Epidemiology checklist and a modified version of the Newcastle-Ottawa scale. Of 1878 citations retrieved, we meta-analyzed 21, 6, and 9 studies for the oil/petroleum, electrical, and chemical industry, respectively. Oil/petroleum industry: summary standardized incidence ratio (SSIR) = 1.23 [95% confidence interval (CI): 1.11-1.36, I = 45%]; summary standardized mortality ratio (SSMR) = 1.02 (95% CI: 0.81-1.28, I = 48%); subgroups: SSIR = 1.16 (95% CI: 1.01-1.32, I = 15%), SSMR = 1.19 (95% CI: 1.00-1.42, I = 20%). Electrical industry: SSIR = 1.00 (95% CI: 0.93-1.11, I = 72%); SSMR = 1.16 (95% CI: 0.74-1.81, I = 11%). Chemical industry: SSIR = 2.08 (95% CI: 0.47-9.24, I = 73%); SSMR = 2.01 (95% CI: 1.09-3.72, I = 33%). Our meta-analysis suggests a slightly increased risk of developing melanoma among oil/petroleum industry workers and an increased melanoma mortality among oil/petroleum and chemical industry workers. No increased risks were found among electrical industry workers.

Lack of detection of Cutavirus DNA using PCR real time in cutaneous T-cell lymphomas.

BACKGROUND: A novel human protoparvovirus named Cutavirus has been discovered. We investigated the presence of Cutavirus in a sample of Cutaneous T-cell lymphomas by using PCR real time TaqMan® (Thermo Fisher Scientific, Waltham, MA, USA). METHODS: In total, 55 CTCL samples were analyzed using a TaqMan® Real time PCR on a 7500 ABI instrument. All of these shown internal control amplification. RESULTS: The presence of Cutavirus DNA corresponding was examined. CuV DNA sequences were not detected in any skin specimen. CONCLUSIONS: The role of Cutaviruses in cutaneous cancers remains to be investigated.

Gender differences in genital lichen sclerosus: data from a multicenter Italian study on 729 consecutive cases.

BACKGROUND: Studies specifically conducted to assess gender differences in genital lichen sclerosus (GLS) are not available. This multicenter study aimed to identify possible gender-related differences on GLS clinical features, history and course, through collecting data from a large mixed-sex sample of patients. 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 specifically collected: clinical features and severity of symptoms related to GLS, extragenital involvement, previous therapies, diagnostic suspicion at referral, type of referring physicians, development of genital squamous-cell carcinoma (SCC). RESULTS: Females complained of symptoms more frequent and severe than men; pallor and scarring-sclerosis-atrophy were the most frequent features without gender differences; itching-related signs were more frequent in females than in males as well as extragenital involvement; prior to receiving a definitive diagnosis, females received treatment more frequently than males; 40% of patients were referred with a misdiagnosis; the highest rate of correct suspected diagnosis at referral came from dermatologists than from other physicians; duration of the disease was found to predispose to SCC development. CONCLUSIONS: Our findings highlighted several gender differences on clinical presentation and symptom profile of GLS. In spite of some characteristic features, misdiagnosis at referrals was frequent.

Efficacy of dupilumab in prurigo nodularis in elderly patient.

Prurigo nodularis (PN) is a chronic disorder, affecting adults, with multiple nodules, typically on the limbs. The treatment is challenging, especially in elderly patients. An 85-year-old woman had developed in the last 3 years itch with nodular lesions and erythematous scaly patches and excoriations. The extension of the lesions was evaluated by body surface area (BSA) score and the patient's itch and disease-related sleep disorders by a Numeric Rating Scale (NRS) from 0 to 10. The Dermatology Life Quality Index (DLQI) and blood chemistry were performed before and during the therapy. At the baseline, the BSA score was 56%. Itch and disease-related sleep disorders were, respectively, NRS 10 and 5 and DLQI was 9. Total IgE count and lactate dehydrogenase were increased. After starting dupilumab, there was a rapid improvement, especially in pruritus. The patient reported the maximum peak of pruritus every day for 6 months. At this time, the itch almost disappeared and clinically only postinflammatory lesions appreciated, with normalization of the blood tests and without any side effects.

Is HERV-K and HERV-W expression regulated by mir-155 in Sézary Syndrome?

BACKGROUND: According to the latest update, 2578 unique mature miRNAs are currently annotated in the human genome and participate in the regulation of multiple events, such as cellular proliferation or apoptosis. A previous study analyzing global miRNA expression patterns in GH cells (high HERV-K versus low) showed that two miRNAs (miR-663 and miR-638) are differentially regulated and exhibit expression parallel to that of HERV-K. The aim of this study was to evaluate HERV-K and -W pol gene and mir-155 expression in SS patients and possible relationship between them. METHODS: The comparison between SS patients and healthy donor showed a significant difference in terms of mir-155 expression P=0.0003 as previously reported by our groups. RESULTS: We demonstrated that HERV-K and -W pol gene expression was significantly higher in SS patients vs. healthy donor as previously reported by our groups. Our correlation data suggest that miR-155 are not directly involved in regulating the HERVs. CONCLUSIONS: Furthermore, further studies including other cohorts of pathology with mir-155 and HERVs involvement such as inflammatory diseases are needed to investigate the role of mir-155 in the cross-activations of HERVs.

Autoimmune connective tissue diseases and pregnancy.

Autoimmune connective tissue-diseases are more frequent in women and deserve a multidisciplinary approach in which the dermatologist play a major role together with other physicians. Pregnancy in these patients has to be considered a high-risk situation, because of possible worsening of the mother's disease and increased morbility and mortality for the fetus; also, therapies have to be chosen carefully because some drugs cannot be used during pregnancy. For all these reasons, the decision to become pregnant needs to consider the type of disease, stage of disease, age and clinical condition, and requires a multidisciplinary approach. A correct counselling, a close monitoring, a specific approach based on the risks involved and the use of appropriate therapies are the keys to obtain optimal pregnancy outcomes.

Primary cutaneous B-cell lymphoma: narrative review of the literature.

Primary cutaneous B-cell lymphomas comprehend a group of lymphoproliferative disorders characterized by being monoclonal proliferations of B-cell primarily involving the skin. Despite being recognized as autonomous and distinct clinico-pathologic entities since the late 80s, their classification is still an ongoing matter of debate. At the moment, WHO classification recognizes three disorders: primary cutaneous marginal zone lymphoma, primary cutaneous follicle center lymphoma and primary cutaneous diffuse large b-cell lymphoma (leg type). Primary cutaneous diffuse large b-cell lymphoma (other) has been used to define rare cases which show histologically an infiltrate with diffuse pattern composed by large b-cell, but not fitting with criteria for follicle center lymphoma nor for primary cutaneous diffuse large b-cell lymphoma (leg type). Aim of this review was to briefly describe all recognized and provisional entities included in the primary cutaneous b-cell lymphomas and to discuss recent acquisitions that may influence their future classifications.

The large spectrum of Spitzoid tumors: a retrospective survival study.

BACKGROUND: There is no universally-accepted classification of Spitzoid tumors. This makes it difficult to assign a correct diagnosis and select a treatment that minimizes the risk of overestimating, or worse, underestimating, the malignant potential of these tumors. The aim of this study was to describe the clinical-pathological and epidemiological features of Spitzoid tumors, as well as to assess mortality in these patients. METHODS: This retrospective cohort study looked at data on Spitzoid tumors excised in 1999-2012 at the Dermatologic Clinic of the Turin University Hospital. Spitzoid melanoma specific survival curves were generated with the Kaplan-Meier method and compared using the log-rank test. RESULTS: In this time period, 1663 lesion were described at the pathologic report as Spitzoid. 262 (15.75%) were Spitz nevi, 307 (18.46%) Reed nevi, 827 (49.73%), 810 (48.71%) Spitzoid dysplastic nevi, 17(1.02%) atypical Spitzoid tumors, and 267 (16.06%) Spitzoid melanomas. Median follow-up time was 9 years. Out of the entire cohort only 24 patients died from melanoma. All of them received a diagnosis of Spitzoid melanoma. None of the patients with a diagnosis of not melanoma Spitz tumor died for melanoma during the follow-up. CONCLUSIONS: In the large majority of the cases, Spitz tumor should be considered as benign lesion and excised only if melanoma features are seen. The used clinical pathological classification avoid misdiagnoses, inappropriate treatment and the risk of death for melanoma.

Sentinel lymph node biopsy versus observation in thick melanoma: A multicenter propensity score matching study.

The clinical value of sentinel lymph node (SLN) biopsy in thick melanoma patients (Breslow >4 mm) has not been sufficiently studied. The aim of the study is to evaluate whether SLN biopsy increases survival in patients with thick cutaneous melanoma, and, as a secondary objective, to investigate correlations between survival and lymph node status. We included 1,211 consecutive patients with thick melanomas (>4 mm) registered in the participating hospitals' melanoma databases between 1997 and 2015. Median follow-up was 40 months. Of these patients, 752 were matched into pairs by propensity scores based on sex, age, tumor location, histologic features of melanoma, year of diagnosis, hospital and adjuvant interferon therapy. The SLN biopsy vs. observation was associated with better DFS [adjusted hazard ratio (AHR), 0.74; 95% confidence interval (CI) 0.61-0.90); p = 0.002] and OS (AHR, 0.75; 95% CI, 0.60-0.94; p = 0.013) but not MSS (AHR, 0.84; 95% CI, 0.65-1.08; p = 0.165). SLN-negative patients had better 5- and 10-year MSS compared with SLN-positive patients (65.4 vs. 51.9% and 48.3 vs. 38.8%; p = 0.01, respectively). As a conclusion, SLN biopsy was associated with better DFS but not MSS in thick melanoma patients after adjustment for classic prognostic factors. SLN biopsy is useful for stratifying these patients into different prognostic groups.