Strabismus in Bronzino's paintings: a hallmark of a realistic painter?

The present article analyses eleven paintings of Bronzino, one of the major painters of the late Italian Mannerism, in which the sitters are portrayed with deviating eyes. The reasons why Bronzino may have included a truant eye in his subjects are herein discussed. We consider the 'wandering' eye as a hallmark of Bronzino's style. The inclusion of strabismus may be part of the Mannerism tendency of using exaggerated hallmarks but pursuing at the same time an increasing realism that was typical of the 15th and 16th century movements.

Clinical and instrumental evaluation of the efficacy of an emollient cream and a cleansing cream in the management of mild to moderate adulthood atopic dermatitis.

BACKGROUND: Atopic dermatitis (AD) is a chronic, recurrent, inflammatory skin disorder which may persist or directly start in adults. This is an open-label prospective study to clinically and instrumentally evaluate the effects of an emollient glycerin and paraffin-based cream and a gentle refatting cleanser in the management of mild to moderate adulthood AD. METHODS: Fifty adult patient with mild to moderate AD were recruited at the Professional Dermatology and Allergology Outpatient Clinic of the San Gallicano Dermatological Institute of Rome, between November 2016 and January 2018. The patients applied the emollient cream twice daily for 2 months. To assess the efficacy of the cream, two different areas of treatment were identified in each patient's limbs. The outcome was evaluated at 30 days (T1) and 60 days (T2) of treatment comparing to baseline (T0) by means of clinical evaluation, Dermatology Life Quality Index (DLQI) questionary, transepidermal waterloss (TEWL) and corneometry measurements. RESULTS: Clinical evaluation showed significative improvement of skin xerosis, fissuring, itching and erythema. Consistently, a significative reduction of TEWL and an improvement in skin hydration was also detected. A significative improvement of DLQI score was also detected. CONCLUSIONS: Study treatment was well tolerated and showed significative improvement of clinical and instrumental parameters evaluated. The topical daily use of an emollient glycerin and paraffin-based cream and a gentle refatting cleanser seems to be a useful tool in the treatment of mild to moderate adulthood AD improving quality of life.

Measuring disability of women with systemic sclerosis: validation of the italian version of the systemic sclerosis questionnaire.

BACKGROUND: The aim of this study was to validate the Italian version of Systemic Sclerosis Questionnaire (SySQ) and to evaluate its psychometric characteristics on a sample of inpatient and outpatient women with systemic sclerosis (SSc). METHODS: Internal and external validity of the Italian version of SySQ were analyzed. Internal validity included: 1) construct validity by means of factor analysis; 2) internal consistency for each category of SySQ through Cronbach's alpha; and 3) reproducibility over time with test-retest using both Pearson's correlation and Intraclass Correlation Coefficient. External validity included: 1) concurrent validity, i.e. correlation with Skindex-17; and 2) discriminant validity, through comparison of scores for different groups of patients. RESULTS: We obtained data on 115 patients with SSc: 68 had the limited clinical form (lSSc) and 47 had the diffuse clinical form (dSSc). The structure of SySQ was confirmed by factor analysis. The questionnaire showed optimal internal consistency for all SySQ categories (Cronbach's alpha >0.84) and very good reproducibility over time (0.79-0.93, P<0.001). Regarding external validity, SySQ showed good correlation with Skindex-17 (P<0.01) and a satisfactory power of discrimination between groups affected by different clinical conditions. CONCLUSIONS: The study confirmed that the SySQ maintains good psychometric properties also in a language different from the original. It is a disease-specific tool that can be routinely used in clinical practice for the evaluation of the level of disability in patients with SSc.

Increased risk of venous thromboembolism in patients with bullous pemphigoid. The INVENTEP (INcidence of VENous ThromboEmbolism in bullous Pemphigoid) study.

Activation of blood coagulation has been demonstrated in bullous pemphigoid (BP), a rare autoimmune blistering disease, potentially leading to a prothrombotic state. In order to evaluate the incidence of venous thromboembolism (VTE) in BP, a cohort study was carried out on 432 BP patients (59% females; median age 76 years, interquartile range [IQR]: 68-82). At diagnosis, autoimmune bullous skin disorder intensity score (ABSIS) was calculated. VTE incidence was standardised with rates of the general population. Multivariable Cox proportional hazard model was used to estimate the hazard ratio of VTE according to ABSIS and concomitant risk factors. During a median follow-up of 4.2 years, 31 objectively-diagnosed VTE events were recorded. The incidence rate of VTE (per 1000 patient-years) was 17.2 overall (95% confidence interval [CI]: 11.1-23.2), 56.7 (95%CI: 33.0-80.4) during acute phase (22 VTE) and 6.3 (95%CI: 2.8-11.3) during remission (9 VTE). The standardised incidence ratio was 4.06 (95%CI: 2.73-5.65), higher during the acute phase (14.86, 95%CI: 9.20-21.88) than during remission (1.48, 0.66-2.63). The adjusted hazard ratio of VTE was 2.74 (95%CI: 1.07-7.04) for ABSIS > 48 vs ABSIS < 28, and 2.56 (95%CI: 1.00-6.70) in patients with ≥ 2 concomitant risk factors. In conclusion, BP patients have a 15-fold increased VTE risk during acute phase, proportional to disease severity and heightened by concomitant risk factors.

The pathogenic activity of anti-desmoglein autoantibodies parallels disease severity in rituximab-treated patients with pemphigus vulgaris.

BACKGROUND: Pemphigus vulgaris (PV) is an autoimmune blistering disease mediated by IgG autoantibodies targeting desmogleins (Dsgs). The anti-CD20 monoclonal antibody rituximab is increasingly used in corticosteroid-resistant PV patients. In a subset of rituximab-treated patients in remission, high ELISA index values have been reported; however, their significance remains so far unclear. OBJECTIVE: To address the discrepancy between anti-Dsg3 serum antibody titers and disease severity. MATERIALS & METHODS: 6 rituximab-treated PV patients were prospectively followed-up for two years and anti-Dsg3 autoantibodies levels and pathogenic activity were measured. RESULTS: All patients achieved complete remission without any serious side effects. Both anti-Dsg3 autoantibodies (p = 0.031) and their pathogenic activity (p = 0.003) were significantly related to disease severity. However, in selected patients, the dissociation index was a more sensitive indicator for PV clinical activity than the ELISA index. CONCLUSION: Our findings have demonstrated the existence of non-pathogenic autoantibodies in PV patients in remission, establishing the basis for the design of a system able to precisely monitor the course of disease.

Definitions and outcome measures for mucous membrane pemphigoid: recommendations of an international panel of experts.

Mucous membrane pemphigoid encompasses a group of autoimmune bullous diseases with a similar phenotype characterized by subepithelial blisters, erosions, and scarring of mucous membranes, skin, or both. Although knowledge about autoimmune bullous disease is increasing, there is often a lack of clear definitions of disease, outcome measures, and therapeutic end points. With clearer definitions and outcome measures, it is possible to directly compare the results and data from various studies using meta-analyses. This consensus statement provides accurate and reproducible definitions for disease extent, activity, outcome measures, end points, and therapeutic response for mucous membrane pemphigoid and proposes a disease extent score, the Mucous Membrane Pemphigoid Disease Area Index.

Pemphigus autoantibodies generated through somatic mutations target the desmoglein-3 cis-interface.

Pemphigus vulgaris (PV) is an autoimmune blistering disease of skin and mucous membranes caused by autoantibodies to the desmoglein (DSG) family proteins DSG3 and DSG1, leading to loss of keratinocyte cell adhesion. To learn more about pathogenic PV autoantibodies, we isolated 15 IgG antibodies specific for DSG3 from 2 PV patients. Three antibodies disrupted keratinocyte monolayers in vitro, and 2 were pathogenic in a passive transfer model in neonatal mice. The epitopes recognized by the pathogenic antibodies were mapped to the DSG3 extracellular 1 (EC1) and EC2 subdomains, regions involved in cis-adhesive interactions. Using a site-specific serological assay, we found that the cis-adhesive interface on EC1 recognized by the pathogenic antibody PVA224 is the primary target of the autoantibodies present in the serum of PV patients. The autoantibodies isolated used different heavy- and light-chain variable region genes and carried high levels of somatic mutations in complementary-determining regions, consistent with antigenic selection. Remarkably, binding to DSG3 was lost when somatic mutations were reverted to the germline sequence. These findings identify the cis-adhesive interface of DSG3 as the immunodominant region targeted by pathogenic antibodies in PV and indicate that autoreactivity relies on somatic mutations generated in the response to an antigen unrelated to DSG3.

Therapy with rituximab for autoimmune pemphigus: results from a single-center observational study on 42 cases with long-term follow-up.

BACKGROUND: Rituximab induces depletion of B cells and has shown efficacy in antibody-mediated autoimmune disorders. In studies on small series of patients with pemphigus, rituximab administration results in significant improvement. However, differences in inclusion criteria, treatment protocols, and follow-up make it difficult to derive uniform conclusions. OBJECTIVES: We sought to test the efficacy and tolerability of rituximab as adjuvant therapy to corticosteroids in the treatment of pemphigus. METHODS: In all, 42 patients with pemphigus were treated with rituximab and followed up for up to 5 years. No additional immunosuppressive agents were used. Steroids were rapidly tapered. Outcomes were the proportion of patients who achieved a complete response on or off therapy, the rate of discontinuation of corticosteroid within 6 months, length of remission, time to relapses, and occurrence of adverse events. RESULTS: In all, 36 of 42 patients (86%; 95% confidence interval 75%-96%) achieved a complete response on or off therapy and discontinued steroids within 6 months from induction therapy. Six patients had a complete response off therapy with an additional infusion of rituximab 6 months after initial treatment. Twenty patients experienced a total of 34 relapses; the time to relapse was 8 to 64 months. Every relapse was treated with rituximab (500 mg) without corticosteroids, which induced a new complete response. No serious adverse events were observed. LIMITATIONS: Lack of a control group is a limitation. CONCLUSIONS: Rituximab therapy induces prolonged clinical remission in patients with pemphigus. Coadministration of other immunosuppressive agents is not necessary. Relapses can be managed with additional infusions administered on demand.

Definitions and outcome measures for bullous pemphigoid: recommendations by an international panel of experts.

Our scientific knowledge of bullous pemphigoid (BP) has dramatically progressed in recent years. However, despite the availability of various therapeutic options for the treatment of inflammatory diseases, only a few multicenter controlled trials have helped to define effective therapies in BP. A major obstacle in sharing multicenter-based evidences for therapeutic efforts is the lack of generally accepted definitions for the clinical evaluation of patients with BP. Common terms and end points of BP are needed so that experts in the field can accurately measure and assess disease extent, activity, severity, and therapeutic response, and thus facilitate and advance clinical trials. These recommendations from the International Pemphigoid Committee represent 2 years of collaborative efforts to attain mutually acceptable common definitions for BP and proposes a disease extent score, the BP Disease Area Index. These items should assist in the development of consistent reporting of outcomes in future BP reports and studies.

Quality-of-life assessment in patients with pemphigus using a minimum set of evaluation tools.

BACKGROUND: Pemphigus is a rare but severe autoimmune disease caused by autoantibodies directed against desmosomes, and clinically characterized by bullae and painful erosions of the skin and mucous membranes. The two major subtypes, vulgaris and foliaceus, are distinguished by the depth of the cleavage plane in the epidermis. Very few studies have investigated the quality of life (QoL) of patients with pemphigus, all reporting a strong impact on physical and emotional status. OBJECTIVES: We sought to achieve an exhaustive description of health status in a large sample of patients with pemphigus, assess the impact on QoL, and define a minimum set of QoL tools for clinical practice. METHODS: In all, 139 patients with pemphigus enrolled at our bullous skin diseases department from February 2007 to February 2008 were given the Medical Outcome Study 36-item short form health survey questionnaire to assess the health status, the Skindex-29 to evaluate the impact of dermatologic-specific aspects, and the 12-item General Health (GH) Questionnaire to detect patients with psychological problems. Clinical severity of the disease was assessed by a dermatologist by the Physician Global Assessment index and the Ikeda index. RESULTS: A strong impact of pemphigus on health status was observed, especially in women and older patients, and in patients with mucocutaneous involvement. A significant association between disease severity and lower Medical Outcome Study 36-item short-form questionnaire values was also observed. Patients with pemphigus showed a markedly impaired overall QoL compared with healthy control subjects on all 3 Skindex-29 scales (symptoms mean scores 37 vs 8, in patients and control subjects, respectively; emotions 37 vs 14; functioning 33 vs 4; P < .001); disease severity was also significantly associated with Skindex-29 scores, on all 3 scale scores for both Physician Global Assessment and Ikeda values (P < .05). GH Questionnaire positivity, reflecting probable minor psychiatric nonpsychotic conditions, such as depression and anxiety, was detected in 39.7% of patients. LIMITATIONS: The small sample size in the different treatment groups prevented a more detailed analysis, failing to highlight an association between treatment type and QoL impairment. CONCLUSIONS: In this study we described a strong impact of pemphigus on patients' QoL both for the dermatology-specific and the GH aspects. The prevalence of patients with GH Questionnaire positivity was also very high (almost 40%). The introduction of the proposed minimal set of QoL evaluation tools would provide additional useful information to guide clinicians in the treatment of these patients.

Consensus statement on definitions of disease, end points, and therapeutic response for pemphigus.

Our scientific knowledge of pemphigus has dramatically progressed in recent years. However, despite the availability of various therapeutic options for the treatment of inflammatory diseases, only a few multicenter controlled trials have helped to define effective therapies in pemphigus. A major obstacle in comparing therapeutic outcomes between centers is the lack of generally accepted definitions and measurements for the clinical evaluation of patients with pemphigus. Common terms and end points of pemphigus are needed so that experts in the field can accurately measure and assess disease extent, activity, severity, and therapeutic response, and thus facilitate and advance clinical trials. This consensus statement from the International Pemphigus Committee represents 2 years of collaborative efforts to attain mutually acceptable common definitions for pemphigus. These should assist in development of consistent reporting of outcomes in future studies.

Treatment of severe pemphigus with rituximab: report of 12 cases and a review of the literature.

BACKGROUND: Treatment of pemphigus vulgaris can be challenging. Systemic steroids associated with other immunosuppressant agents are the mainstay of therapy and have dramatically reduced morbidity and mortality from pemphigus vulgaris. In some patients, however, these agents are not able to control the disease or have severe adverse effects. Rituximab (MabThera; Roche, Basel, Switzerland), a chimeric monoclonal anti-CD20 antibody, induces depletion of B cells in vivo and has shown efficacy in patients with refractory antibody-mediated autoimmune disorders. We report 10 cases of pemphigus vulgaris and 2 cases of pemphigus foliaceous treated with rituximab--to our knowledge the largest series of patients so far--and review the existing literature on the topic. OBSERVATION: The 12 patients were selected for treatment with the anti-CD20 antibody. Rituximab was administered intravenously at a dosage of 375 mg/m(2) once weekly for 4 weeks. The treatment was well tolerated, and all 12 patients showed a good clinical response during an 18-month follow-up period, along with a consensual decline of the serum antidesmoglein titers. No infectious complications were observed. CONCLUSIONS: Rituximab is able to induce a prolonged clinical remission in patients with both pemphigus vulgaris and pemphigus foliaceous after a single course of 4 treatments. The preliminary experiences worldwide make rituximab a promising therapeutic option for patients with autoimmune diseases. The high costs and the limited knowledge of long-term adverse effects, however, limit its use to selected patients with treatment-resistant or life-threatening disease.

Pemphigus foliaceus induced by radiotherapy and responsive to dapsone.

Pemphigus foliaceus induced by ionizing radiation therapy is a rare condition. We describe the case of a 70-year-old female who developed pemphigus foliaceus after X-ray treatment for an adenocarcinoma of the left breast. The eruption started at the portal of irradiation and only subsequently spread to other cutaneous areas. Mucosal membranes were not affected. Skin lesions were completely responsive to dapsone therapy.

Randomized controlled trial of adjuvant oral dexamethasone pulse therapy in pemphigus vulgaris: PEMPULS trial.

OBJECTIVE: To determine the therapeutic effect of adjuvant dexamethasone pulse therapy when given in addition to conventional treatment of pemphigus vulgaris. DESIGN: A randomized, placebo-controlled trial. SETTING: International European, multicenter outpatient and inpatient study. PATIENTS: Of the 20 enrolled patients, 11 were randomized to the dexamethasone pulse (DP) group and 9 to the placebo pulse (PP) group. INTERVENTIONS: Oral dexamethasone in 300-mg pulses or PPs 3 days per month. During the intervention, the DP and PP groups received conventional treatment with prednisolone, 80 mg/d, which was tapered across 19 weeks, and azathioprine sodium, 3 mg/kg per day, until the end of the study. Monthly pulses were continued until prednisolone treatment was tapered to 0 mg. MAIN OUTCOME MEASURES: Number of patients in remission, time to and duration of remission, cumulative prednisolone dose, and occurrence of adverse events during 1 year of follow-up. RESULTS: Eight of the 11 DP-treated patients and all 9 PP-treated patients achieved remission. Mean time to remission was 173 days with DP and 176 days with PP. The mean duration of remission within the first year was 151 days for DP and 141 days for PP. Mean cumulative prednisolone dose was 5300 mg for DP and 4882 mg for PP. Weight gain (>5% of baseline) occurred in 8 DP-treated patients compared with 1 PP-treated patient (P<.01). We found no statistically significant difference (P>.05) of an adjuvant effect of DP on remission of pemphigus vulgaris. CONCLUSION: In patients with new pemphigus vulgaris disease activity, there was no benefit of oral DP therapy given in addition to conventional treatment. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00127764.

Cutaneus pseudolymphoma: a case report.

The authors report on a case of pseudolymphoma cutis in a 48-year-old man. The clinical and histopathological characteristics of this benign skin disorder, especially regarding the differential diagnosis with cutaneous B or T cell lymphomas, are reviewed. Finally, the use of hydroxychloroquine sulfate is suggested for the therapy of pseudolymphoma cutis, especially when the causal factor is unknown.

Increased expression of eotaxin and its specific receptor CCR3 in bullous pemphigoid.

Several skin infiltrating inflammatory cells, such as eosinophils, neutrophils and activated T lymphocytes, are involved in bullous pemphigoid (BP) blister formation. The presence of CD4+ T cells able to produce IL-4 and IL-5 suggests Th2 involvement in the disease. The role of eotaxin in the recruitment of eosinophils into inflammatory sites has been recently described and the specific eotaxin receptor, CCR3, has been documented to be expressed on eosinophils, basophils, and Th2 cells. In this study, we analyzed by immunohistochemistry the expression of both eotaxin and CCR3 in lesional skin from patients with active BP (n = 10) and control subjects affected with pemphigus vulgaris (PV) (n = 3); furthermore eotaxin concentration in BP sera and blister fluids was also evaluated by enzyme-linked immunosorbent assay (ELISA), in comparison to sera from PV and normal donors (n = 10) and to suction blisters from 3 healthy volunteers. A strong immunostaining for eotaxin and CCR3 in BP skin specimens in lesional and, to a lesser extent, in perilesional skin was observed. CCR3 expression was documented on both eosinophils and T cells infiltrating skin lesions. Eotaxin serum levels were significantly higher in BP patients when compared to healthy donors (p = 0.003) and PV patients (p = 0.01). The highest eotaxin concentration was detected in BP blister fluids, in respect to both corresponding BP sera and blister fluids from normal donors (p = 0.003). These results account for the role of eotaxin in the recruitment of activated cells at inflammatory sites during BP and the expression of CCR3 on infiltrating T lymphocytes further supports the involvement of Th2 cells in the pathogenesis of BP.