Pênfigo foliáceo: análise comparativa de aspectos epidemiológicos, clínicos e imunológicos em duas populações (brasileira e holandesa)
Data
2015-08-31
Autores
Maehara, Laura de Sena Nogueira 
Orientadores
Tomimori, Jane
Tipo
Tese de doutorado
Título da Revista
ISSN da Revista
Título de Volume
Resumo
Introdução: O pênfigo foliáceo é uma doença cutânea bolhosa auto-imune caracterizada pela presença de autoanticorpos antidesmogleína 1. A variante endêmica ocorre em certas regiões do Brasil - onde é chamada fogo selvagem - e outros países das Américas e África, enquanto a forma não-endêmica (tipo Cazenave) ocorre em todo o mundo. A participação da genética no desenvolvimento do pênfigo foliáceo foi demonstrada através da associação do alelo HLA-DRB1*04 do complexo HLA (antígeno leucocitário humano) de classe II em diversas populações. Objetivo: Descrever e comparar características epidemiológicas, clínicas e terapêuticas, em dois grupos de pacientes: fogo selvagem no Brasil e pênfigo foliáceo Cazenave, na Holanda. Em seguida, verificar a possível associação dos alelos HLA de classe I e II nestes pacientes. Métodos: Na primeira fase do estudo, realizou-se um estudo retrospectivo com revisão de prontuários médicos dos pacientes nos dois grupos. Posteriormente, uma entrevista foi realizada para completar dados clínicos. Na segunda fase, procedeu-se à avaliação dos alelos HLA, comparando-se 42 pacientes brasileiros com 478 controles, e 17 pacientes holandeses com controles (7554, 6559 e 447, dependendo do alelo estudado). As amostras de DNA foram obtidas pela técnica de salting-out. Os alelos HLA de classe I (locus A*, B*, C*), e de classe II (locus DRB1* e DQB1*) foram determinados em baixa resolução por meio da técnica de reação em cadeia da polimerase com sequências específicas de oligonucleotídeos (PCR-SSO) empregando-se o kit Labtype-SSO (One Lambda, CA, USA). Resultados: A média da idade de início da doença nos pacientes brasileiros foi de 32,0 anos e, nos holandeses, de 56,1 anos. A diferença de idades foi estatisticamente significante (p<0,0001). A ocupação rural foi predominante no Brasil (p<0,0001), enquanto os holandeses mais frequentemente estavam aposentados no início da doença (p<0,0001). Apenas brasileiros relataram antecedente familiar ou epidemiológico de pênfigo foliáceo (p=0,0387). Os demais dados analisados não apresentaram diferença significante: gênero, forma da doença (localizada/generalizada) e antecedentes pessoais e/ou familiares de outras doenças auto-imunes. Os alelos HLA-DRB1*04, DRB1*16 e DQB1*05 associaram-se a suscetibilidade ao fogo selvagem no Brasil (p<0,0001, p=0,0325 e p<0,0001, respectivamente). Na amostra holandesa, apenas o HLA-DRB1*04 conferiu suscetibilidade xi ao pênfigo foliáceo (p= 0,0058). Quando o alelo HLA-DRB1*04 foi comparado entre as duas populações, um maior risco foi atribuído à população brasileira em relação a holandesa (OR 6,46 e 3,17, respectivamente; p=0,0498). No Brasil, a proteção ao fogo selvagem foi associada aos alelos HLA-DRB1*07 e DQB1*02 (p= 0,0448 e 0,0012, respectivamente). Conclusão: No Brasil, o fogo selvagem afetou indivíduos jovens trabalhadores rurais ativos, contrastando com o pênfigo foliáceo na Holanda, que acometeu mais aposentados. Entre os brasileiros, os alelos HLA-DRB1*04, DRB1*16 e DQB1*05 foram associados a suscetibilidade ao FS, enquanto os alelos DRB1*07 e DQB1*02 promoveram proteção contra a doença. A associação do alelo HLA-DRB1*04 foi demonstrado pela primeira vez na população holandesa, conferindo suscetibilidade ao pênfigo foliáceo. Não foi encontrado alelo de proteção entre os holandeses. Não foi encontrada associação da doença com os alelos HLA de classe I nas duas populações. O risco conferido pelo HLA-DRB1*04 foi maior na população brasileira.
INTRODUCTION: Pemphigus foliaceus is a cutaneous autoimmune skin disease characterized by the presence of autoantibodies anti-desmoglein 1. The endemic variant occurs in certain regions of Brazil and other countries in America and Africa, whereas the non-endemic variant (named Cazenave) is present worldwide. In Brazil, the endemic variant is called fogo selvagem. The genetic factor include HLA-DRB1*04 class II allele (human leukocyte antigen) as susceptibility to PF in different populations. OBJECTIVE: To describe and compare epidemiological, clinical and therapeutic characteristics in two groups of patients: fogo selvagem in Brazil and pemphigus foliaceus Cazenave, in the Netherlands. Next, to determine HLA alleles in Brazilian and Dutch patients. METHODS: In the first phase of the study, a retrospective analysis, medical records from patients in the two groups were reviewed. The patients were then invited for an interview for additional clinical data. In the second study phase, we determined HLA alleles in fogo selvagem patients in Brazil and pemphigus foliaceus patients in the Netherlands, by comparing 42 Brazilian patients with 478 controls, and 17 Dutch patients with controls (7554, 6559 and 447, depending on the alleles). DNA samples were obtained by salting-out technique. The HLA class I alleles (locus A*, B*, C*), and class II (locus DRB1* and DQB1*) were determined in low resolution by Polymerase Chain Reaction--SequenceSpecific Oligonucleotide Probe (PCR-SSOP) hybridization with Labtype-SSO kit (One Lambda, CA, USA). RESULTS: The mean age of disease onset in Brazilian patients was 32.0 years, and for Dutch, 56.1 years. The difference in these means was statistically significant (p<0.0001). Rural occupation was predominant in Brazil (p<0.0001), whereas Dutch patients more frequently were retired at disease onset (p<0.0001). Only Brazilian patients reported familymembers or members of the surrounding community as affected by pemphigus foliaceus (p=0.0387). The remaining analyzed data did not present significant difference: gender, disease presentation (localized/generalized forms) and personal and/or family history of autoimmune diseases, excluding pemphigus. HLA-DRB1*04, DRB1*16 and DQB1*05 alleles were associated with susceptibility to FS in Brazil (p<0.0001, p=0.0325 and p<0.0001, respectively). In the Dutch group, HLA-DRB1*04 was also associated with susceptibility to PF (p= 0.0058). HLA-DRB1*04 allele was associated with a higher risk for FS in Brazil than PF in the Netherlands (OR 6.46 and 3.17, respectively; p=0.0498). In Brazil, protection against FS was associated with HLA-DRB1*07 and DQB1*02 alleles (p= 0.0448 and 0.0012, respectively). CONCLUSION: In Brazil, fogo selvagem affected young rural active workers, contrasting to retired pemphigus foliaceus patients in the Netherlands. In Brazil, HLA class II alleles DRB1*04, DRB1*16 and DQB1*05 were associated with susceptibility to fogo selvagem, whereas DRB1*07 and DQB1*02 protected against the disease. HLA-DRB1*04 as a susceptibility allele for pemphigus foliaceus was demonstrated for the first time in Dutch population. Protection alleles were not found among Dutch. HLA class I alleles were not associated with fogo selvagem or pemphigus foliaceus. The risk conferred by HLA-DRB1*04 was higher in Brazilian group.
INTRODUCTION: Pemphigus foliaceus is a cutaneous autoimmune skin disease characterized by the presence of autoantibodies anti-desmoglein 1. The endemic variant occurs in certain regions of Brazil and other countries in America and Africa, whereas the non-endemic variant (named Cazenave) is present worldwide. In Brazil, the endemic variant is called fogo selvagem. The genetic factor include HLA-DRB1*04 class II allele (human leukocyte antigen) as susceptibility to PF in different populations. OBJECTIVE: To describe and compare epidemiological, clinical and therapeutic characteristics in two groups of patients: fogo selvagem in Brazil and pemphigus foliaceus Cazenave, in the Netherlands. Next, to determine HLA alleles in Brazilian and Dutch patients. METHODS: In the first phase of the study, a retrospective analysis, medical records from patients in the two groups were reviewed. The patients were then invited for an interview for additional clinical data. In the second study phase, we determined HLA alleles in fogo selvagem patients in Brazil and pemphigus foliaceus patients in the Netherlands, by comparing 42 Brazilian patients with 478 controls, and 17 Dutch patients with controls (7554, 6559 and 447, depending on the alleles). DNA samples were obtained by salting-out technique. The HLA class I alleles (locus A*, B*, C*), and class II (locus DRB1* and DQB1*) were determined in low resolution by Polymerase Chain Reaction--SequenceSpecific Oligonucleotide Probe (PCR-SSOP) hybridization with Labtype-SSO kit (One Lambda, CA, USA). RESULTS: The mean age of disease onset in Brazilian patients was 32.0 years, and for Dutch, 56.1 years. The difference in these means was statistically significant (p<0.0001). Rural occupation was predominant in Brazil (p<0.0001), whereas Dutch patients more frequently were retired at disease onset (p<0.0001). Only Brazilian patients reported familymembers or members of the surrounding community as affected by pemphigus foliaceus (p=0.0387). The remaining analyzed data did not present significant difference: gender, disease presentation (localized/generalized forms) and personal and/or family history of autoimmune diseases, excluding pemphigus. HLA-DRB1*04, DRB1*16 and DQB1*05 alleles were associated with susceptibility to FS in Brazil (p<0.0001, p=0.0325 and p<0.0001, respectively). In the Dutch group, HLA-DRB1*04 was also associated with susceptibility to PF (p= 0.0058). HLA-DRB1*04 allele was associated with a higher risk for FS in Brazil than PF in the Netherlands (OR 6.46 and 3.17, respectively; p=0.0498). In Brazil, protection against FS was associated with HLA-DRB1*07 and DQB1*02 alleles (p= 0.0448 and 0.0012, respectively). CONCLUSION: In Brazil, fogo selvagem affected young rural active workers, contrasting to retired pemphigus foliaceus patients in the Netherlands. In Brazil, HLA class II alleles DRB1*04, DRB1*16 and DQB1*05 were associated with susceptibility to fogo selvagem, whereas DRB1*07 and DQB1*02 protected against the disease. HLA-DRB1*04 as a susceptibility allele for pemphigus foliaceus was demonstrated for the first time in Dutch population. Protection alleles were not found among Dutch. HLA class I alleles were not associated with fogo selvagem or pemphigus foliaceus. The risk conferred by HLA-DRB1*04 was higher in Brazilian group.
Descrição
Citação
MAEHARA, Laura de Sena Nogueira. Pênfigo foliáceo: análise comparativa de aspectos epidemiológicos, clínicos e imunológicos em duas populações (brasileira e holandesa). 2015. 111 f. Tese (Doutorado em Medicina Translacional) - Escola Paulista de Medicina, Universidade Federal de São Paulo (UNIFESP), São Paulo, 2015.