Diss. (sammanfattning) Stockholm : Karol. inst. / Härtill 5 uppsatser.

Myasthenia Gravis (MG) is an autoimmune disorder of neuromuscular transmission. Clinically, the disease is manifested by abnormal muscle fatigue with recovery on resting. Circulating nicotinic acetylcholine receptor antibodies (nAchR Ab) are highly characteristic of myasthenia gravis. These antibodies have been shown to be directly pathogenic at the muscle endplate and are responsible for impaired neuromuscular transmission through several mechanisms. While it is clear that the immune system does not function normally in MG, the mechanisms by which the response to nAchR is initiated and perpetuated remain unknown. Moreover, it is not clear whether immunoregulatory defects actually precede development of MG or are secondary features of the disease. The overall goal of the present investigation has been to more clearly define the nature of the immune regulatory defects existing in MG, both at the cellular level and in terms of possible relationship to disease progression. To begin these studies it was necessary to develop an assay that could be used to measure nAchR Ab secreted by lymphocytes in culture. Thus, we modified the original nAchR Ab immunoassay described by Lindstrom (1976) for this purpose. Additionally, in order to gain access to an appropriate patient base for our study, we established a further modification with improved sensitivity for detection of serum nAchR Ab. This important diagnostic test had not been available in this country. Therefore, our assay was made available in Canada for clinical purposes. Through the study of in vitro nAchR Ab and polyclonal IgG secretion by peripheral blood mononuclear cells (PBMNC), we were able to identify two previously unrecognized subgroups of seropositive, generalized MG patients. PBMNC from patients with long disease duration had low capacity for in vitro Ab production (Nonsecretors). Among patients of short disease duration, PBMNC produced nAchR Ab and also secreted higher than normal levels of polyclonal IgG (Secretors). The data suggested that there were nonspecific abnormalities affecting the immune response in myasthenia gravis. Moreover, regulation of B lymphocyte mediated immune function appeared to be related to disease progression. It was hypothesized that circulating auto-antibody may contribute to deregulation of the immune response at certain stages of disease through direct interactions with leukocyte determinants. Separation/reconstitution experiments with CD4+ enriched, T-helper/inducer lymphocytes and B enriched (E- cells) lymphocytes suggested that the control of antibody production in myasthenia gravis was operative at the T-helper/inducer level. Preliminary studies with serum pretreated, CD4+ enriched, T-helper/inducer lymphocytes suggested that serum of Secretor MG patients indeed contained a factor(s) which interfered with the function of a CD4+ lymphocyte subset. We further hypothesized that nAchR Ab would have the potential to behave as anti-lymphocyte Ab if nAchR were expressed on lymphocytes. Accordingly, direct binding studies, using the nicotinic antagonist, alpha-bungarotoxin, were carried out to look for such receptors on PBMNC. Specific, saturable binding of alpha-bungarotoxin to the rhabdomyosarcoma cell line, TE671, was confirmed and characterized. However, in parallel studies, alpha-bungarotoxin binding to PBMNC of healthy individuals or MG patients was not detected. These results suggested that nicotinic acetylcholine receptors, of the type expressed by muscle endplate, do not occur on human peripheral blood mononuclear cells. / Medicine, Faculty of / Pathology and Laboratory Medicine, Department of / Graduate

INTRODUÇÃO: A Miastenia gravis (MG) é uma desordem imunológica com antígenos alvos conhecidos, com produção de anticorpos contra o receptor nicotínico de acetilcolina, AAChR e Musk, na junção neuromuscular, dificultando a transmissão do impulso nervoso e provocando fadiga e fraqueza flutuantes na musculatura ocular, facial, dos membros e respiratória. A terapêutica sintomática com inibidores de acetilcolinesterase e a etiopatogênica como a timectomia, corticosteróides, agentes citostásticos e imunoglobulinas são utilizadas e indicadas em acordo com a incapacidade e gravidade clínicas. A qualidade de vida (QV) é uma ferramenta utilizada para quantificar a eficácia e a resposta às terapêuticas adotadas, avaliar a efetividade e custos econômicos de novas estratégias terapêuticas, contribuir para planejar e aplicar os recursos para a saúde na comunidade. OBJETIVO: Avaliar a influência da terapêutica na QV e evolução clínica dos pacientes com MG. CASUÍSTICA: Foram avaliados 51 pacientes com MG, 38 submetidos a tratamento conservador e 13 timectomizados. MÉTODOS: Os instrumentos genéricos quantitativos de QV como WHOQOL, qualidade de vida relacionada à saúde (QVRS) SF-36, e depressão (BDI) foram utilizados. ESTATÍSTICA: Empregou-se análise univariada com os testes de Wilcoxon, U-Mann-Whitney, Fisher e razão de chance para avaliar a evolução clínica, a QV e QVRS e depressão; análise multivariada para a caracterização dos dois grupos de terapêutica considerando a interação de múltiplos fatores. RESULTADOS: O grupo submetido à terapêutica conservadora foi constituído por 16 pacientes do sexo masculino e 22 do feminino, com média de idade de 33,71±2,76 anos; o grupo timectomizado foi constituído por 6 homens e 7 mulheres, média de idade de 32,23±4,16 anos. Os pacientes do grupo conservador apresentaram melhora clínica estatisticamente significante (p <0,05) dos aspectos clínicos, da QV, da QVRS e depressão. Os timectomizados apresentaram melhora estatisticamente significante dos aspectos físicos e psicológicos da QV e QVRS e depressão, e melhora clínica evidente e não significante (p = 0,06). A análise multivariável mostrou r=0,65 para comparação das áreas; Wilks? Lambda para analisar as distâncias, X2 = 22,67; gl = 7; p = 0,05; as medidas centrais mostraram média = -0,42 dp = 1,0 para o grupo conservador; e média = 1,22, dp = 1,0 para o grupo timectomizado. CONCLUSÕES: Nesta amostra e no período avaliado constatamos que: 1) Os pacientes submetidos ao tratamento conservador apresentaram diferenças significantes com melhora clínica acentuada, de QV, de QVRS e depressão; 2) os timectomizados apresentaram melhora clínica, da QV e QVRS em seus aspectos físicos e psicológicos, e efetiva e significante melhora dos índices de depressão; 3) a análise multivariada revelou que a timectomia produziu efeito benéfico e significativo na recuperação da saúde e bem estar nos pacientes. / INTRODUCTION: Myasthenia gravis (MG) is an immune mediated disease with production of antibodies against post-synaptic acetylcholine receptor of neuromuscular junctions (AAChR,Musk) and orders in nervous impulse transmission. The disease´s clinical characteristics include fatigability and fluctuating weakness of voluntary muscles. Acetylcholinesterase inhibitors, thymectomy, corticosteroids, cytostatic agents and immunoglobulin are widely used and are indicated according to the patient´s disability and severity. Clinical manifestations, Quality of life (Qol), health-related (HRQol) analysis are used to evaluate response to therapy. Nowadays, Qol index is an important tool to evaluate the medical outcome, treatment efficacy, cost effectiveness and net benefit of new therapeutic strategies to determine whether their cost can be justified in the planning and application of health policies. OBJECTIVE: To evaluate the influence of conservative treatment and thymectomy on Qol and clinical response of myasthenic patients. SUBJECTS: Fifty-one myasthenic patients were chosen; 38 were submitted to conservative therapy and 13 to thymectomy. METHODS: Quantitative Qol tools such as WHOQOL, SF-36 and BDI were employed to evaluate Qol, HRQol and depression. STATISTICS: Univariate analysis by means of the Wilcoxon, U-Mann Whitney and Fisher tests, Chi-Square, odd ratio were used to follow the patient?s clinical status, evolution of Qol, HRQol and depression. Discriminant analysis was used to analyze the interation of multiple factors in the characterization of conservative and thymectomized groups. RESULTS: The conservative group of patients was constituted of 16 males and 22 females average age 33.71±2.76 years; the thymectomized group was composed of 6 males, 7 females, average age 32.23±4.16 years. Patients submitted to conservative therapy improved significantly in clinical progress, Qol, HRQol and depression. The follow-up of thymectomized patients showed a strong trend for clinical progress and significant improvement in physical and psychological Qol domains as well as in depression index. Discriminant analysis showed r = 0.65, p <0.05; Wilk?s Lambda X2 = 22.67, gl = 7; mean = -0.42, SD = 1.0 for conservative group; and mean = 1.22, SD = 1.0 for timectomized group. CONCLUSIONS: A prospective evaluation of a myasthenic patients sample revealed: 1) conservative treatment was found to have a strong and significant impact on clinical progress, Qol, HRQol and depression; 2) Thymectomy partly influenced Qol, specially physical and psychological aspects. There was also improvement in depression and clinical progress; 3) the evaluation of multiple parameters pointed to a strong and positive influence of thymectomy in the recovery of the patients.

INTRODUÇÃO: A Miastenia gravis (MG) é uma desordem imunológica com antígenos alvos conhecidos, com produção de anticorpos contra o receptor nicotínico de acetilcolina, AAChR e Musk, na junção neuromuscular, dificultando a transmissão do impulso nervoso e provocando fadiga e fraqueza flutuantes na musculatura ocular, facial, dos membros e respiratória. A terapêutica sintomática com inibidores de acetilcolinesterase e a etiopatogênica como a timectomia, corticosteróides, agentes citostásticos e imunoglobulinas são utilizadas e indicadas em acordo com a incapacidade e gravidade clínicas. A qualidade de vida (QV) é uma ferramenta utilizada para quantificar a eficácia e a resposta às terapêuticas adotadas, avaliar a efetividade e custos econômicos de novas estratégias terapêuticas, contribuir para planejar e aplicar os recursos para a saúde na comunidade. OBJETIVO: Avaliar a influência da terapêutica na QV e evolução clínica dos pacientes com MG. CASUÍSTICA: Foram avaliados 51 pacientes com MG, 38 submetidos a tratamento conservador e 13 timectomizados. MÉTODOS: Os instrumentos genéricos quantitativos de QV como WHOQOL, qualidade de vida relacionada à saúde (QVRS) SF-36, e depressão (BDI) foram utilizados. ESTATÍSTICA: Empregou-se análise univariada com os testes de Wilcoxon, U-Mann-Whitney, Fisher e razão de chance para avaliar a evolução clínica, a QV e QVRS e depressão; análise multivariada para a caracterização dos dois grupos de terapêutica considerando a interação de múltiplos fatores. RESULTADOS: O grupo submetido à terapêutica conservadora foi constituído por 16 pacientes do sexo masculino e 22 do feminino, com média de idade de 33,71±2,76 anos; o grupo timectomizado foi constituído por 6 homens e 7 mulheres, média de idade de 32,23±4,16 anos. Os pacientes do grupo conservador apresentaram melhora clínica estatisticamente significante (p <0,05) dos aspectos clínicos, da QV, da QVRS e depressão. Os timectomizados apresentaram melhora estatisticamente significante dos aspectos físicos e psicológicos da QV e QVRS e depressão, e melhora clínica evidente e não significante (p = 0,06). A análise multivariável mostrou r=0,65 para comparação das áreas; Wilks? Lambda para analisar as distâncias, X2 = 22,67; gl = 7; p = 0,05; as medidas centrais mostraram média = -0,42 dp = 1,0 para o grupo conservador; e média = 1,22, dp = 1,0 para o grupo timectomizado. CONCLUSÕES: Nesta amostra e no período avaliado constatamos que: 1) Os pacientes submetidos ao tratamento conservador apresentaram diferenças significantes com melhora clínica acentuada, de QV, de QVRS e depressão; 2) os timectomizados apresentaram melhora clínica, da QV e QVRS em seus aspectos físicos e psicológicos, e efetiva e significante melhora dos índices de depressão; 3) a análise multivariada revelou que a timectomia produziu efeito benéfico e significativo na recuperação da saúde e bem estar nos pacientes. / INTRODUCTION: Myasthenia gravis (MG) is an immune mediated disease with production of antibodies against post-synaptic acetylcholine receptor of neuromuscular junctions (AAChR,Musk) and orders in nervous impulse transmission. The disease´s clinical characteristics include fatigability and fluctuating weakness of voluntary muscles. Acetylcholinesterase inhibitors, thymectomy, corticosteroids, cytostatic agents and immunoglobulin are widely used and are indicated according to the patient´s disability and severity. Clinical manifestations, Quality of life (Qol), health-related (HRQol) analysis are used to evaluate response to therapy. Nowadays, Qol index is an important tool to evaluate the medical outcome, treatment efficacy, cost effectiveness and net benefit of new therapeutic strategies to determine whether their cost can be justified in the planning and application of health policies. OBJECTIVE: To evaluate the influence of conservative treatment and thymectomy on Qol and clinical response of myasthenic patients. SUBJECTS: Fifty-one myasthenic patients were chosen; 38 were submitted to conservative therapy and 13 to thymectomy. METHODS: Quantitative Qol tools such as WHOQOL, SF-36 and BDI were employed to evaluate Qol, HRQol and depression. STATISTICS: Univariate analysis by means of the Wilcoxon, U-Mann Whitney and Fisher tests, Chi-Square, odd ratio were used to follow the patient?s clinical status, evolution of Qol, HRQol and depression. Discriminant analysis was used to analyze the interation of multiple factors in the characterization of conservative and thymectomized groups. RESULTS: The conservative group of patients was constituted of 16 males and 22 females average age 33.71±2.76 years; the thymectomized group was composed of 6 males, 7 females, average age 32.23±4.16 years. Patients submitted to conservative therapy improved significantly in clinical progress, Qol, HRQol and depression. The follow-up of thymectomized patients showed a strong trend for clinical progress and significant improvement in physical and psychological Qol domains as well as in depression index. Discriminant analysis showed r = 0.65, p <0.05; Wilk?s Lambda X2 = 22.67, gl = 7; mean = -0.42, SD = 1.0 for conservative group; and mean = 1.22, SD = 1.0 for timectomized group. CONCLUSIONS: A prospective evaluation of a myasthenic patients sample revealed: 1) conservative treatment was found to have a strong and significant impact on clinical progress, Qol, HRQol and depression; 2) Thymectomy partly influenced Qol, specially physical and psychological aspects. There was also improvement in depression and clinical progress; 3) the evaluation of multiple parameters pointed to a strong and positive influence of thymectomy in the recovery of the patients.