The Role of Intramolecular Epitope Spreading in the Pathogenesis of Endemic Pemphigus Foliaceus (Fogo Selvagem)

We report here a relationship between intramolecular epitope spreading and the clinical onset of the endemic form of pemphigus foliaceus in a Brazilian community with a high prevalence and incidence of the disease. Also known as Fogo Selvagem (FS), this disease is characterized by severe skin blistering and pathogenic anti–desmoglein-1 (Dsg1) autoantibodies. These autoantibodies bind the Dsg1 ectodomain and trigger keratinocyte cell detachment, the hallmark of FS. We show that (a) sera from FS patients in the preclinical stage recognized epitopes on the COOH-terminal EC5 domain of Dsg1, (b) disease onset was associated with the emergence of antibodies specific for epitopes on the NH2-terminal EC1 and EC2 domains, (c) all sera from FS patients with active disease recognized the EC1 and/or EC2 domains, and (d) sera from FS patients in remission showed reactivity restricted to EC5. These results suggest that anti-Dsg1 autoantibodies in FS are initially raised against the COOH-terminal EC5 domain of Dsg1 in individuals without skin disease; in genetically predisposed subjects the autoimmune response may then undergo intramolecular epitope spreading toward epitopes on the NH2-terminal EC1 and EC2 domains of Dsg1 leading to disease onset. Moreover, intramolecular epitope spreading may also modulate remissions and relapses of FS

A qualidade de vida é muito comprometida em pacientes adultos com dermatite atópica no Brasil, especialmente devido a fatores emocionais

PURPOSE: to measure the quality of life (QoL), either by a specific dermatology or generic self applied questionnaire, in Atopic dermatitis adult Brazilian patients, looking for selected affected groups. METHODS: We studied the quality of life of 75 Brazilian ambulatory adults with atopic dermatitis using two types of self-answered instruments: a quality of life generic questionnaire (SF-36) and a 10-item Dermatology Life Quality Index (DLQI) questionnaire. All patients had been treated for at least 6 months, and their disease status was determined by Eczema Area and Severity Index scores. RESULTS: Quality of life and disease control were found to be related but with low scores both in DLQI (r²=0.26) and in SF-36 (r²=0.20), but with greater correlation for SF-36 mental components. Using the 75% percentile distribution of SF36 mean score and the 75% value of disease severity score, we sorted patients into four groups: I, referring good QoL and mild atopic disease (14/75), II, referring bad QoL and with mild atopic disease (19/75), III referring good QoL despite severe atopic disease (5/75) and IV referring bad QoL and severe atopic disease (37/75); all groups presented similar age, education, family income and time of disease progression. There was a higher frequency of women in group II, but without sleep disturbance or increased pruritus, which was present in group IV, with intense itching and sleep disturbances. Analyzing the physical or mental components of the SF36 generic test, discrepant groups II and III presented higher differences related to the mental components of the test, which was also related to DLQI scores, with a similar distribution for the 2 groups and a higher relation to the mental component of the generic test. CONCLUSION: The quality of life is affected in adult atopic patients, both related to disease severity and also to mental components, but with diverse effects in patient subgroups. Our data show some components that may mask the exact relationship between QoL results and disease severity.OBJETIVOS: Medir a qualidade de vida (QoL), por questionários tanto genéricos como dermatológicos específicos, em pacientes adultos brasileiros com dermatite atópica, procurando por grupos afetados selecionados. MÉTODOS: Nós estudamos a qualidade de vida em 75 pacientes brasileiros adultos em tratamento ambulatorial de dermatite atópica, usando dois tipos de questionários de auto-resposta, previamente padronizados: um questionário genérico de qualidade de vida de 36 questões (SF-36) e um questionário de 10 questões para determinação do índice dermatológico de qualidade de vida (DLQI). Todos os pacientes estavam em tratamento por pelo menos seis meses e o seu estágio de doença clinico definido quantitativamente pelo índice padronizado de gravidade e áreas de eczema (EASI). RESULTADOS: A QoL e o controle da doença estavam relacionados mas com baixa relação tanto avaliados pelo DLQI (r²=0.26) ou pelo SF-36 (r²=0.20), mas com maiores relações com os componentes emocionais do SF-36. Usando a distribuição do percentil 75% para o SF36 e os valores de 75% do escore de gravidade clínica EASI, os pacientes foram distribuídos em quatro grupos: I que referia boa QoL e doença atópica leve (14/75), II referindo má QoL e doença atópica leve (19/75), III referindo boa QoL apesar de doença atópica mais grave (5/75) e IV concordando uma má QoL referida e uma doença atópica mais grave (37/75); todos os grupos apresentavam mesma distribuição etária, educação e nível social, renda familiar e tempo de doença. Havia uma maior freqüência de mulheres no grupo II, mas sem distúrbios de sono ou prurido intenso, fatores presentes intensamente no grupo IV. Dissecando os componentes físicos e emocionais do SF36, os grupos discrepantes II e II apresentavam maior diferença relativa aos componentes emocionais do teste, que também estavam relacionados aos valores do teste DLQI, o qual apresentava uma distribuição similar entre os grupos e maior relação aos componentes emocionais do teste genérico. CONCLUSÕES: A qualidade de vida é afetada em pacientes adultos com dermatite atópica, relacionada tanto com a gravidade da doença clinica como com os componentes emocionais, que são diferentes em subgrupos de pacientes. Estes dados mostram componentes que podem mascarar o exato impacto da severidade da doença sobre a qualidade de vida destes pacientes

A new highly bioactive composite for scaffold applications: a feasibility study

Hydroxyapatite (HA) has been widely investigated as scaffolding material for bone tissue engineering, mainly for its excellent biocompatibility. Presently, there is an increasing interest in the composites of hydroxyapatite with bioactive glasses, with the aim to obtain systems with improved bioactivity or mechanical properties. Moreover, modifying the ratio between bioactive glass and hydroxyapatite results in the possibility of controlling the reaction rate of the composite scaffold in the human body. However, high temperature treatments are usually required in order to sinter HA-based composites, causing the bioactive glass to crystallize into a glass-ceramic, with possible negative effects on its bioactivity. In the present research work, a glass composition belonging to the Na2O-CaO-P2O5-SiO2 system, with a reduced tendency to crystallize, is applied to realize HA-based composites. The novel samples can be sintered at a relative low temperature (750 °C) compared to the widely studied HA/45S5 Bioglass® composites. This fact greatly helps to preserve the amorphous nature of the glass, with excellent effects in terms of bioactivity, according to in vitro tests. As a first application, the obtained composites are also tested to realize highly porous scaffolds by means of the standard burning out method

Patient-reported burden in adults with atopic dermatitis: an international qualitative study

The objective was to study a large, international, ethnically diverse population of patients with atopic dermatitis (AD) to support the creation of patient-centric recommendations for AD management. Qualitative data were generated from 45-min, 1:1 telephone interviews conducted across 15 countries in each patient’s native language. Interviews explored the impact of AD on patients’ lives, patients’ most important symptoms, treatment expectations, and treatment decision-making. Participants were also questioned on their current knowledge of AD scoring systems and what was most important to include in these tools. In total, 88 adult patients (≥ 18 years old) receiving treatment for AD were recruited through a market research database, clinician referrals, and local advertising. All patients were screened to ensure a balanced and diverse sample in terms of age, gender, educational level, employment status, geographic location, and AD severity. Patients involved in market research or activities supporting advocacy groups within the previous 6 months or affiliated with or employed by pharmaceutical companies were excluded. AD had a substantial impact on patients’ lives. Itch, skin redness, and dry/flaky skin were the most frequently reported symptoms, with > 75% of patients experiencing these symptoms every 1–3 days. Mental health issues were common and resulted in the greatest negative impact on patients’ daily lives. Patients perceived clinicians to underestimate the burden of their AD. Patients had little awareness of AD scoring systems and indicated a preference for these to be more clearly incorporated in clinical practice. For an ideal scoring system, patients favored using a combination of patient-reported and clinician-reported outcomes to reflect disease burden and ensure consistency across all settings. This global study generated diverse patient perspectives on the disease burden of AD, their expectations of treatment, and their views on AD scoring methods. These data provide evidence to support the development of patient-centric recommendations for AD management

Update on fogo selvagem, an endemic form of pemphigus foliaceus

Pemphigus are organ-specific autoimmune diseases, where autoantibodies (mainly IgG) directed against epidermal targets (glycoproteins of the desmosomal core) are detected. Endemic pemphigus foliaceus or fogo selvagem (FS) is one of the variants of pemphigus foliaceus (PF) that shares the same clinical and immunopathological features of the classic nonendemic PF form, including pathogenic IgG (mainly IgG4) autoantibodies directed against the ectodomain of desmoglein 1 (Dsg1), that lead to acantholysis. Pathogenesis of FS is complex, involving genetic, environmental and immunological factors. HLADRB1 alleles DRB1*0404, *1402, *1406 or *0102 have been previously identified as risk factors for FS (relative risk > 14). Individuals exposed to hematophagous insects are more susceptible to develop the disease. Nonpathogenic anti-Dsg1 antibodies of the IgG1 subclass, directed against the extra-cellular 5 domain of Dsg1 are detected in patients in the preclinical stage of the disease, and also in healthy controls living in endemic areas. In counterpart, patients with FS show pathogenic anti-Dsg1 IgG4 auto-antibodies that bind the pathogenic extracellular 1 and 2 domains of Dsg 1, emphasizing the intramolecular epitope spreading hypothesis. A possible explanation for the development of the autoimmune process would be antigenic mimicry, initiated by environmental stimuli in those genetically predisposed individuals. Characterization of the pathogenesis of FS will allow the development of specific therapeutic targets, and the elucidation of other autoimmune processes

Gastrointestinal cytomegalovirus disease in a patient with pemphigus vulgaris treated with corticosteroid and mycophenolate mofetil

Pemphigus vulgaris is an autoimmune disease characterized by the formation of suprabasal intra-epidermal blisters on the skin and mucosal surfaces. Infectious diseases are the main cause of death in patients with pemphigus due to the disrupture of the physiological skin barrier, immune dysregulation, and the use of immunosuppressive medications leaving the patient prone to acquire opportunistic infections. We report the case of a 67-year-old woman diagnosed with pemphigus vulgaris, who was irregularly taking prednisone and mycophenolate mofetil. She was hospitalized because of a 1-month history of watery diarrhea and oral ulcers. Unfortunately, the patient died suddenly on the ward. The autopsy revealed a bilateral saddle pulmonary embolism, Gram-positive cocci bronchopneumonia, and gastrointestinal cytomegalovirus infection, causing extensive gastrointestinal mucosal ulcer

Prevalence of Anti-Desmoglein-3 Antibodies in Endemic Regions of Fogo Selvagem in Brazil

Fogo selvagem (FS), the endemic form of pemphigus foliaceus (PF), is an autoimmune blistering disease characterized by autoantibodies against desmoglein 1. The Terena reservation of Limao Verde in Mato Grosso do Sul, Brazil, is a previously identified focus of disease. Autoantibodies against desmoglein 3 (Dsg3) have also been detected in sera from patients with FS. In an effort to further characterize the serological, geographical, and clinical epidemiology of the disease, we sought to determine the prevalence of anti-Dsg3 autoantibodies in sera from normal subjects living outside of and in an endemic area using an ELISA. Anti-Dsg3 antibodies were detected in 53 of 146 normal subjects from Limao Verde (36%), and in eight of 140 normal subjects from surrounding areas (6%). A significant trend was observed in the proportion of positive tests relative to distance from the endemic area (

The IgM Anti-Desmoglein 1 Response Distinguishes Brazilian Pemphigus Foliaceus (Fogo Selvagem) from Other Forms of Pemphigus

Fogo selvagem (FS) and pemphigus foliaceus (PF) possess pathogenic IgG anti-desmoglein 1-(Dsg1) autoantibodies. Although PF occurs sporadically, FS is endemic in Limao Verde (LV), Brazil (3.4% prevalence). IgM anti-Dsg1 were detected in 58% FS LV patients (n=31), 19% of FS patients from Hospital-Campo Grande (n=57), 19% from Hospital-Goiania (n=42), 12% from Hospital-Sao Paulo (n=56), 10% of PF patients from United States (n=20), and 0% of PF patients from Japan (n=20). Pemphigus vulgaris (n=40, USA and Japan), bullous pemphigoid (n=40, USA), and healthy donors (n=55, USA) showed negligible percentages of positive sera. High percentages of positive IgM anti-Dsg1 were found in healthy donors from four rural Amerindian populations (42% of 243) as compared with urban donors (14% of 81; P<0.001). More than 50% of healthy donors from LV (n = 99, age 5-20 years) possess IgM anti-Dsg1 across ages, whereas IgG-anti-Dsg1 was detected in 2.9% (age 5-10 years), 7.3% (age 11-15 years), and 29% of donors above age 16. IgM anti-Dsg1 epitopes are Ca2+and carbohydrate-independent. We propose that IgM anti-Dsg1 are common in FS patients in their native environment and uncommon in other pemphigus phenotypes and in FS patients who migrate to urban hospitals. Recurrent environmental antigenic exposure may lead to IgM and IgG responses that trigger FS

Nomenclature and clinical phenotypes of atopic dermatitis

Atopic dermatitis is a heterogeneous disease and resists classification. In this review, we discuss atopic dermatitis nomenclature and identify morphologic phenotypes, which will facilitate correct diagnoses and development of treatment strategies. We support using the term 'atopic dermatitis' rather than eczema, because it describes the allergic background and inflammation ('itis') as drivers of the disease. Atopic dermatitis has many morphologic manifestations that vary by topographic area affected, age, or race and require consideration in differential diagnosis. Different phenotypes based on morphology and topographic location, ethnicity, and age are discussed. A better-defined phenotype identification for atopic dermatitis will facilitate earlier and correct diagnosis of this complex condition and inform selection of the most appropriate treatment choice in an era in which targeted therapies may generate more individualized patient care

Overlapping IgG4 Responses to Self- and Environmental Antigens in Endemic Pemphigus Foliaceus

The etiology of human autoimmune diseases in general remains largely unknown, although the genetic and environmental interplay may be relevant. This applies to the autoimmune diseases of the skin such as the pemphigus phenotypes and others. In this group, there is an endemic form of pemphigus foliaceus [also known as Fogo Selvagem (FS)] where the pathogenic IgG4 autoantibody response to the self-antigen, Desmoglein 1 (Dsg1) cross-react with the LJM11 sand fly salivary gland antigen. In this investigation we dissected the IgG4 autoantibody repertoires utilized by FS patients in response to endogenous self Dsg1 and exogenous LJM11 sand fly antigen. Based on analyses of the genetic clonal signatures of these antibodies, our results indicate that there is a significant overlap between these two responses as all identified IgG4 monoclonal antibodies cross-react to both Dsg1 and LJM11 antigens. Germline H and L chain V gene antibodies generated according to mutated cross-reactive monoclonal antibodies preserved their reactivity to both antigens. Our findings suggest that both Dsg1 autoantigen and LJM11 environmental antigen could be the initial antigenic stimulants for the IgG4 autoimmune responses in FS. These results support our hypothesis that LJM11 antigen plays a substantial role in triggering the IgG4 autoantibody development in FS, and provide new insights on how non-infectious environmental antigen(s) may drive the generation of autoantibodies in IgG4-related autoimmune diseases