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.

In-Depth Metallurgical and Microstructural Analysis of Oneshape and Heat Treated Onecurve Instruments.

OBJECTIVE: To define surface, mechanical, microstructural and metallurgical features of conventional One-Shape (OShape) and heat-treated OneCurve (OCurve) nickel-titanium instruments. METHODS: Instruments were analysed by scanning electron microscopy (SEM) on new instruments and after simulated clinical use (SCU). Cyclic fatigue testing was performed and the number of cycles to fracture (NCF) and the length of the fractured instruments were measured (Mann-Whitney test). Fractured instruments during cyclic fatigue testing were then inspected by SEM fractographic analysis. Field emission gun scanning scanning electron microscopy (FEG-SEM), energy-dispersive X-ray spectroscopy (EDX) and micro-Raman spectroscopy were used to assess alloy surface chemistry. Focused ion beam (FIB) was performed to analyse the oxide layer on the surface of OCurve before and after SCU. X-Ray diffraction (XRD), metallographic evaluation and differential scanning calorimetry (DSC) were used to determine martensitic/austenitic phase transformation temperatures. RESULTS: SEM observations on new instruments revealed a smooth regular surface with flattened milling grooves. No wear features were detected after SCU. OCurve exhibited a higher cyclic fatigue resistance (P<0.05), slower crack propagation and a surface layer of TiO2. Metallographic analysis and XRD showed the prevalence of martensitic grains on OCurve instruments that were stable at body temperature as confirmed by DSC analysis. Furthermore, DSC demonstrated a shift in the temperature transformation ranges suggesting an increase of martensite phase in autoclaved OCurve instruments. CONCLUSION: Heat treatment processes were confirmed as a valid enhancement of the properties of the new generation NiTi instruments. OCurve presented a significant improvement over OShape regarding both mechanical and metallurgical characteristics.

Mechanical Properties and Metallurgical Features of New Green NiTi Reciprocating Instruments.

To evaluate the properties of two nickel-titanium (NiTi) reciprocating endodontic instruments (commercially known as Procodile and Reziflow), a total of 40 size 25 and 0.06 taper new Procodile and Reziflow instruments (n = 20) were subjected to cyclic fatigue tests (60° angle of curvature, 5-mm radius) at 20 °C and 37 °C and a torsional test based on ISO 3630-1. The fracture surface of each fragment was examined. The morphological, mechanical, chemical, thermal, and phase composition characteristics of the files were investigated by field-emission gun scanning electron microscopy (FEG-SEM) equipped with an energy-dispersive X-ray (EDX) detector, focused ion beam analysis (FIB), micro-Raman spectroscopy, X-ray diffraction (XRD), differential scanning calorimetry (DSC), and Auger electron spectroscopy (AES). Reziflow showed higher cyclic fatigue resistance than Procodile at 37 °C (p < 0.05). The maximum torsional strength of Procodile was lower than that of Reziflow (p < 0.05). No difference was found between their angular rotations to fracture (p > 0.05). SEM, FIB, Micro-Raman, and AES analyses revealed the presence of an Nb/Nb2O5 coating on the Procodile surface. DSC and XRD analysis confirmed that both files consist of an almost austenitic phase structure at 37 °C. The cyclic fatigue resistance of Procodile and Reziflow significantly decreases upon exposure to body temperature.

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.

Melanoma computer-aided diagnosis: reliability and feasibility study.

BACKGROUND: Differential diagnosis of melanoma from melanocytic nevi is often not straightforward. Thus, a growing interest has developed in the last decade in the automated analysis of digitized images obtained by epiluminescence microscopy techniques to assist clinicians in differentiating early melanoma from benign skin lesions. PURPOSE: The aim of this study was to evaluate diagnostic accuracy provided by different statistical classifiers on a large set of pigmented skin lesions grabbed by four digital analyzers located in two different dermatological units. EXPERIMENTAL DESIGN: Images of 391 melanomas and 449 melanocytic nevi were included in the study. A linear classifier was built by using the method of receiver operating characteristic curves to identify a threshold value for a fixed sensitivity of 95%. A K-nearest-neighbor classifier, a nonparametric method of pattern recognition, was constructed using all available image features and trained for a sensitivity of 98% on a large exemplar set of lesions. RESULTS: On independent test sets of lesions, the linear classifier and the K-nearest-neighbor classifier produced a mean sensitivity of 95% and 98% and a mean specificity of 78% and of 79%, respectively. CONCLUSIONS: In conclusion, our study suggests that computer-aided differentiation of melanoma from benign pigmented lesions obtained with DB-Mips is feasible and, above all, reliable. In fact, the same instrumentations used in different units provided similar diagnostic accuracy. Whether this would improve early diagnosis of melanoma and/or reducing unnecessary surgery needs to be demonstrated by a randomized clinical trial.

Activation of nickel-specific CD4+ T lymphocytes in the absence of professional antigen-presenting cells.

Allergic contact dermatitis ensues from exaggerated T cell responses to haptens. Dendritic cells are required for the initiation of hapten sensitization, but they may not be necessary for disease expression. Here we investigated the antigen-presenting cell requirement of nickel-specific CD4+ lymphocytes isolated from the blood of six allergic individuals. A significant proportion (42 out of 121; 35%) of the T cell clones proliferated in vitro to nickel also in the absence of professional antigen-presenting cells, suggesting a direct T-T hapten presentation. Antigen-presenting-cell-independent T cells showed a predominant T helper 1 phenotype. Nickel recognition by these T cells was major histocompatibility complex class II restricted, not influenced by CD28 triggering, independent from their state of activation, and did not require processing. The capacity of this T cell subset to be directly stimulated by nickel was not due to unique antigen-presenting properties, as both antigen-presenting-cell-dependent and antigen-presenting-cell-independent clones displayed comparable levels of HLA-DR, CD80, and CD86, and were equally capable of presenting nickel to antigen-presenting-cell-independent clones. In contrast, neither T cell types activated antigen-presenting-cell-dependent T lymphocytes. T-T presentation induced T cell receptor downregulation, CD25, CD80, CD86, and HLA-DR upregulation, and interferon-gamma release, although to a lesser extent compared to those induced by dendritic cell-T presentation. Following T-T presentation, the clones did not undergo unresponsiveness and maintained the capacity to respond to dendritic cells pulsed with antigen. In aggregate, our data suggest that antigen-presenting-cell-independent T cell activation can effectively amplify hapten- specific immune responses.

Expression of transglutaminase 5 in normal and pathologic human epidermis.

To explore the expression and gain more information on the function of transglutaminase 5 enzyme in normal and defective human epidermis, we generated a rat antihuman transglutaminase 5 antiserum elicited against a purified active recombinant protein expressed in the baculovirus system. By use of Western blotting and immunofluorescence methods, the immunospecificity of the antibodies for transglutaminase 5 was tested; no crossreactivity with other transglutaminases (types 1, 2, and 3) was observed, thus allowing histochemistry studies. By indirect immunofluorescence analysis the antibodies decorated the upper layers of normal human epidermis, with consistent staining in the spinous and granular layers. We evaluated transglutaminase 5 expression in comparison with proliferating (keratin 14) and differentiating (transglutaminase 3) markers in different diseases, such as psoriasis, ichthyosis vulgaris, lamellar ichthyosis, and Darier's disease. We observed that transglutaminase 5 contributes, as a secondary effect, to the hyperkeratotic phenotype in ichthyosis (both vulgaris and lamellar) and in psoriasis. In Darier's disease, transglutaminase 5 expression, as well as transglutaminase 3, is completely missregulated, being overexpressed or totally absent in different areas of the same lesion.

Eotaxins and CCR3 receptor in inflammatory and allergic skin diseases: therapeutical implications.

Cell migration is mediated by a group of chemotactic cytokines called chemokines: low molecular weight molecules that have been shown as important leukocyte chemical attractants to sites of inflammation and infection. Eotaxin-1, also called CCL11, was first described in 1994, as a highly specific eosinophils chemokine. Many cell types including lymphocytes, macrophages, bronchial smooth muscle cells, endothelial cells and eosinophils, are able to produce this chemokine, predominantly after cytokine stimulation, however little is known about its expression in human skin in vivo. Eotaxin-1 also regulates the chemiotaxis and, in some conditions, activation of basophils, mast cells and T lymphocytes. Chemokine receptors are named from their ligand families, thus the CC chemokine eotaxin-1 binds to the CCR3 receptor which is expressed on eosinophis, mast cells, Th2 type lymphocytes and even on keratinocytes. It seems that eotaxin-1 is one of the most important cytokines involved in tissue inflammation playing a central role in the pathogenesis of allergic airway diseases (asthma and rhinitis), in inflammatory bowel disease and gastrointestinal allergic hypersensitivity and recently it has been proposed as a therapeutical target for these conditions. Our group has studied the role of eotaxin-1 in the pathogenesis of two skin conditions: dermatitis herpetiformis and AIDS-associated eosinophilic folliculitis, demonstrating that this chemokine, together with Th2 type cytokines (IL-13 and IL-4) is important in cell recruitment, inflammation and tissue damage; moreover eotaxin has proven to paly an important role in other skin conditions such as, bullous pemphigoid, pemphigoid gestationis, atopic dermatitis and allergic drug reactions Recent advances in the understanding of eotaxin-1-mediated mechanisms of chemotaxis in allergic and inflammatory conditions may predict that therapeutic antagonism is achievable. This paper will focus on the role that eotaxin and its receptor play in the pathogenetical mechanism in a number of dermatologic diseases, some of which, like atopic dermatitis, may benefit from the introduction of novel and more selective therapeutic options.

Association of dissatisfaction with care and psychiatric morbidity with poor treatment compliance.

OBJECTIVES: To examine factors associated with compliance with dermatologic treatment. DESIGN: Longitudinal study. Quality of life and psychological well-being were measured before the dermatologic visit with a self-completed questionnaire. Telephone interviews were performed 3 days and 4 weeks after the visit to evaluate patient satisfaction and medication adherence, respectively. SETTING: Outpatient clinics of a large dermatologic hospital in Rome, Italy. PATIENTS: A total of 1389 outpatients were contacted and 722 (52%) agreed to participate. Among them, 424 responded to the inclusion criteria and were enrolled in the study. Of these, 396 (93%) completed the telephone interviews. MAIN OUTCOME MEASURE: Self-reported compliance with dermatologic treatment. RESULTS: The dermatologists' prescriptions were not exactly followed by 44% of patients. In multiple logistic regression analysis, treatment adherence was strongly associated with complete satisfaction. Poor quality of life on the emotions scale (indicating mainly high levels of shame and embarrassment) was also associated with medication adherence. On the contrary, a strong negative association was observed between psychiatric morbidity and compliance. CONCLUSIONS: This is the first longitudinal study on dermatologic patients showing that dissatisfaction with care and psychiatric morbidity are significantly and independently associated with poor medication adherence. To improve medication adherence, particular attention should be dedicated to the physician's interpersonal skills, which emerged as a major component of patient satisfaction. Moreover, our results highlight the need for a timely identification and appropriate management of psychiatric disorders in everyday dermatologic practice.

Lipophilic antioxidants in human sebum and aging.

Skin surface lipids (SSL), a very complex mixture of sebum mixed to small amounts of epidermal lipids, mantle the human epidermis, thus representing the outermost protection of the body against exogenous oxidative insults. The present work is a systematic and quantitative analysis of upper-chest SSL and their content in antioxidants in 100 healthy volunteers, divided into five age groups using TLC, HPLC, and GC-MS methods. Further, the effect of exposing SSL in vitro to increasing doses of UV irradiation was examined. Straight monounsaturated and diunsaturated as well as branched monounsaturated fatty acids of triglycerides and pooled fractions were found to be higher at maturity than in childhood and in advancing age. Diunsaturated fatty acids were below 3% of the total and constituted exclusively of C18:2delta5,8, C20:2delta7,10, C18:2delta9,12. Squalene, vitamin E (vit. E) and Coenzyme Q10 (CoQ10) were found to increase from childhood to maturity to decrease again significantly in old age. Vitamin E and CoQ10 were the only known lipophilic antioxidants present in SSL. In spite of their low levels they were found to synergically inhibit the UV induced depletion of squalene, cholesterol and of unsaturated fatty acids of SSL. In fact, exposure of SSL to increasing amounts of UV irradiation led preferentially to lowering of the levels of vit. E and CoQ10. Four minimal erythema dose (MED) (5.6J/cm2) were able to deplete 84% vit. E and 70% ubiquinone, and only 13% squalene. Diunsaturated and monounsaturated fatty acids as well as cholesterol were unaffected even following 10 MED UV exposures, which produced a 26% loss of squalene. The same UV dose when applied in the absence of vit. E and CoQ10 produced a 90% decrease of squalene.

Dermoscopic patterns of cutaneous melanoma metastases.

Although the long experience acquired with the widespread use of dermoscopy has allowed the establishment of criteria for the recognition of benign and malignant skin lesions, very few data are available on cutaneous melanoma metastases. As the characteristic clinical aspects are multiform and even histological evaluation may sometimes be difficult, we have studied and characterized the patterns of cutaneous melanoma metastases in dermoscopy. In this paper, we report dermoscopic data on 130 histologically confirmed metastases observed in 32 patients affected by melanoma, with particular emphasis on dermoscopic features. Nine dermoscopic elements (homogeneous, saccular, amelanotic, polymorphic and vascular patterns, colour, perilesional erythema, pigmentary halo, peripheral grey spots) were studied in 130 cutaneous melanoma metastases and compared with those of 350 melanomas, 150 common naevi, 40 blue naevi, 40 haemangiomas and 50 basal cell carcinomas. The saccular and vascular patterns (especially polymorphic atypical vessels and winding vessels), as well as pigmentary halo and peripheral grey spots, seem to be the most significant elements suggestive of cutaneous melanoma metastases. The interest in and importance of the dermoscopic aspects of cutaneous melanoma metastases cannot be neglected if the American Joint Committee has determined that microsatellitosis and micrometastases are fundamental in the new TNM staging classification for cutaneous melanoma.

The role of chemokines in allergic contact dermatitis.

Chemokines are important mediators of immune-mediated skin diseases. Allergic contact dermatitis (ACD) is the most thoroughly investigated T cell-mediated disorder because of the ability to easily reproduce the lesions in humans and the availability of an excellent mouse model. Migration of dendritic cells from the skin to lymph nodes is absolutely required for induction of hapten sensitization, and depends upon expression of CCR7 by mature dendritic cells and SLC in the lymph nodes. During expression of ACD, recruitment of T lymphocytes is driven by chemokines exposed on the surface of endothelial cells or released by activated resident skin cells such as mast cells, fibroblasts and keratinocytes. Chemokines are produced in a coordinated and sequential manner, with IL-8 and RANTES induced by TNF-alpha during early stages, and MCP-1, IP-10, Mig, I-TAC, I-309 and MDC induced by IFN-gamma during later stages. Infiltrating monocytes, dendritic cells and T cells are additional sources of chemokines for further leukocyte accumulation. Distinct T cell subsets express different chemokine receptors, with type 2 cells mostly attracted by eotaxin, MDC, TARC and I-309, and type 1 cells sensitive to IP-10, Mig, I-TAC, RANTES and MIP-1beta. MCP-1 is effective on both subsets. T regulatory cells, which inhibit dendritic cell function and are probably involved in the termination of ACD, are sensitive to MCP-1, MIPs and TARC, but express high levels of CCR8 and are more specifically attracted by I-309. Targeting chemokines and chemokine receptors may offer new opportunities for therapeutic interventions in ACD and other chronic inflammatory skin diseases.

Pruritic eosinophilic papular eruption revealing HIV infection.

Eosinophilic folliculitis (EF) is a rare follicular pruritic papular eruption observed in association with human immunodeficiency virus (HIV). The diagnosis of eosinophilic folliculitis is based on the histologic findings consisting of a sterile inflammatory infiltrate rich in eosinophils involving hair follicles. EF in HIV patients is believed to be an immunoinflammatory response directed either at follicular or skin flora antigens in the late-stage of HIV infection. In this stage, immune response is characterized by a shift from a Th1- to a Th2-dominant cytokine profile and an increased secretion of interleukin-4 and interleukin-5, both known to promote eosinophilia. We describe a case of HIV-associated eosinophilic folliculitis in a 30-year-old black woman referred to us for a pruritic follicular eruption without any other clinical symptom related to the acquired immunodeficiency syndrome. HIV infection presenting with EF has been rarely reported and its occurrence in women is also very rare.

Satisfaction with health care among dermatological inpatients.

Measuring patient satisfaction is regarded as one of the principal methods for obtaining patients' evaluation of services they receive. During the last decades more interest has been devoted to inpatients' preferences and needs. Surveys on patient satisfaction may provide information to hospitals about areas where improvement is needed. In this survey, 648 questionnaires were completed by dermatological inpatients and were analyzed for overall satisfaction and seven satisfaction determinants. Background factors and clinical parameters were considered. Emotional support was recognized as a critical area. "Coordination of care" and "information and education" were identified as the most relevant determinants for overall patient satisfaction. The Hospital Management, taking into account the results, planned training in order to improve personnel's communication skills. This study confirms that patient satisfaction analysis is a useful instrument also among dermatological inpatients, and satisfaction is a valid measure of quality of health care.

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.

Usefulness of erythrocyte sedimentation rate as tumor marker in cancer associated dermatomyositis.

Dermatomyositis is an inflammatory myopathy characterized by proximal symmetrical muscle weakness with a characteristic cutaneous eruption. Population-based cohort studies provide evidence of an increased frequency of cancer in dermatomyositis patients. Many signs and serology tests have been suggested as markers for malignancy in dermatomyositis. We performed a case-control study on the patients admitted in our institutions for dermatomyositis. Clinical and laboratory data were collected and statistical analysis was performed to reveal important predictive signs of malignancy in dermatomyositis. We found no statistical difference in the clinical or laboratory parameters between the dermatomyositis patients with or without malignancy, with the exception of the erythrocyte sedimentation rate. In our study group an erythrocyte sedimentation rate higher than 35 mm/hr was very strongly associated with the presence or the development of a malignancy. Given the high positive and negative predictive values observed in our study, erythrocyte sedimentation rate evaluation using this cut-off point could be very useful in alerting dermatologists to the need for more in-depth diagnostic procedures in dermatomyositis patients.