Thesis (Ph. D.)--Ohio State University, 2007. / Full text release at OhioLINK's ETD Center delayed at author's request

Section A: This paper reviews the literature surrounding cognitive functioning in patients with Antiphospholipid syndrome (APS) in the context of quality of life as an indicator of adaptation to chronic illness. The review focuses on cognitive functioning in APS patients and related clinical populations, describing and critiquing the empirical research literature exploring the evidence for cognitive deficits in these populations. Psychological theories of adaptation to chronic illness are discussed in relation to the concept of quality of life and research examining the relationship between cognitive dysfunction in APS and related clinical populations and health- related quality of life (HRQoL) is summarised. The limitations of previous research examining these factors are highlighted, demonstrating the need for empirical studies that address cognitive functioning and quality of life in patients with primary APS (PAPS). Section B: Objective: To explore the relationship between cognitive functioning and health related quality of life (HRQoL) in patients with PAPS. Method: Cross sectional comparisons of PAPS patients (PAPS thrombosis; n = 15; PAPS pregnancy; n = 15) and healthy controls (n = 15) on a battery of neuropsychological assessments and a measure of HRQoL. Results: PAPS thrombosis patients were twice as likely to be designated as cognitively impaired compared to PAPS pregnancy patients. PAPS thrombosis patients demonstrated lower performance on measures of memory and executive functioning compared to controls. PAPS pregnancy patients also performed more poorly on these measures compared to controls although not significantly. Both groups demonstrated poor HRQoL across physical and mental subscales. Both groups were significantly more impaired in all physical domains and one mental domain of HRQoL compared to controls. Neuropsychological outcomes in general intellectual abilities, memory and executive functioning were significantly associated with mental HRQoL subscales in PAPS thrombosis and executive functioning and memory were significantly associated with physical HRQoL subscales in PAPS pregnancy. Conclusions: Cognitive impairment is associated with and is more prevalent in PAPS thrombosis patients when compared with PAPS pregnancy patients. Both PAPS groups demonstrate poor HRQoL which is associated with executive functioning and memory. Section C: The critical review is structured to address four specific questions providing a reflective account of how the involvement in this project has contributed to the researcher’s skills and abilities and highlighted areas where further learning is necessary. The review also discusses further clinical applications and research for cognitive functioning and HRQoL in patients with PAPS.

B-lymphocytes have traditionally been thought to contribute to immunity and autoimmune disease through terminal differentiation into plasma cells that secrete antibody. However, studies in mice and recent clinical studies have demonstrated that genetically altered B-cell function and B-cell-targeted therapies can significantly affect autoimmune diseases that were predominantly thought to be T-cell-mediated. B-cell depletion in mouse models of disease has also led to the identification of alternative B-cell effector functions that regulate normal immune responses and autoimmune disease. This review highlights multiple B-cell effector mechanisms, including the promotion of cellular immunity, the negative regulation of immune responses, and the production of pathogenic antibodies. / Dissertation

<p>Dysregulated inflammation underlies the pathogenesis of a myriad of human diseases ranging from cancer to autoimmunity. As coordinators, executers and sentinels of host immunity, T cells represent a compelling target population for immune-modulation. In fact, the antigen-specificity, cytotoxicity and promise of long-lived of immune-protection make T cells ideal vehicles for cancer immunotherapy. Interventions for autoimmune disorders, on the other hand, aim to dampen T cell-mediated inflammation and promote their regulatory functions. Although significant strides have been made in targeting T cells for immune-modulation, current approaches remain less than ideal and leave room for improvement. In this dissertation, I seek to improve on current T cell-targeted immunotherapies, by identifying and preclinically characterizing their mechanisms of action and in vivo therapeutic efficacy.</p><p>CD8+ cytotoxic T cells have potent antitumor activity and therefore are leading candidates for use in cancer immunotherapy. The application of CD8+ T cells for clinical use has been limited by the susceptibility of ex vivo-expanded CD8+ T cells to become dysfunctional in response to immunosuppressive microenvironments. To enhance the efficacy of adoptive cell transfer therapy (ACT), we established a novel microRNA-targeting approach that augments CTL cytotoxicity and preserves immunocompetence. Specifically, we screened for miRNAs that modulate cytotoxicity and identified miR-23a as a strong functional repressor of the transcription factor Blimp-1, which promotes CTL cytotoxicity and effector cell differentiation. In a cohort of advanced lung cancer patients, miR-23a was upregulated in tumor-infiltrating CD8+ T cells, and its expression correlated with impaired antitumor potential of patient CD8+ T cells. We determined that tumor-derived TGF-&#946; directly suppresses CD8+ T cell immune function by elevating miR-23a and downregulating Blimp-1. Functional blockade of miR-23a in human CD8+ T cells enhanced granzyme B expression; and in mice with established tumors, immunotherapy with just a small number of tumor-specific CD8+ T cells in which miR-23a was inhibited robustly hindered tumor progression. Together, our findings provide a miRNA-based strategy that subverts the immunosuppression of CD8+ T cells that is often observed during adoptive cell transfer tumor immunotherapy and identify a TGF&#946;-mediated tumor immune-evasion pathway.</p><p>Having established that miR-23a-inhibition can enhance the quality and functional-resilience of anti-tumor CD8+ T cells, especially within the immune-suppressive tumor microenvironment, we went on to interrogate the translational applicability of this strategy in the context of chimeric antigen receptor (CAR)-modified CD8+ T cells. Although CAR T cells hold immense promise for ACT, CAR T cells are not completely curative due to their in vivo functional suppression by immune barriers &#8210; such as TGF&#946; &#8210; within the tumor microenvironment. Since TGF&#946; poses a substantial immune barrier in the tumor microenvironment, we sought to investigate whether inhibiting miR-23a in CAR T cells can confer immune-competence to afford enhanced tumor clearance. To this end, we retrovirally transduced wildtype and miR-23a-deficient CD8+ T cells with the EGFRvIII-CAR, which targets the PepvIII tumor-specific epitope expressed by glioblastomas (GBM). Our in vitro studies demonstrated that while wildtype EGFRvIII-CAR T cells were vulnerable to functional suppression by TGF&#946;, miR-23a abrogation rendered EGFRvIII-CAR T cells immune-resistant to TGF&#946;. Rigorous preclinical studies are currently underway to evaluate the efficacy of miR-23a-deficient EGFRvIII-CAR T cells for GBM immunotherapy. </p><p>Lastly, we explored novel immune-suppressive therapies by the biological characterization of pharmacological agents that could target T cells. Although immune-suppressive drugs are classical therapies for a wide range of autoimmune diseases, they are accompanied by severe adverse effects. This motivated our search for novel immune-suppressive agents that are efficacious and lack undesirable side effects. To this end, we explored the potential utility of subglutinol A, a natural product isolated from the endophytic fungus Fusarium subglutinans. We showed that subglutinol A exerts multimodal immune-suppressive effects on activated T cells in vitro: subglutinol A effectively blocked T cell proliferation and survival, while profoundly inhibiting pro-inflammatory IFN&#947; and IL-17 production by fully-differentiated effector Th1 and Th17 cells. Our data further revealed that subglutinol A might exert its anti-inflammatory effects by exacerbating mitochondrial damage in T cells, but not in innate immune cells or fibroblasts. Additionally, we demonstrated that subglutinol A significantly reduced lymphocytic infiltration into the footpad and ameliorated footpad swelling in the mouse model of Th1-driven delayed-type hypersensitivity. These results suggest the potential of subglutinol A as a novel therapeutic for inflammatory diseases.</p> / Dissertation

A hepatite auto-imune (HAI) é doença necroinflamatória crônica do fígado que provoca destruição progressiva do parênquima e, na ausência de tratamento imunossupressor, evolui para óbito. Estudos prévios demonstraram algumas particularidades clínicas e genéticas dessa doença no Brasil. O objetivo desse trabalho foi avaliar aspectos clínicos, laboratoriais, histológicos, evolução da gestação e a resposta ao tratamento de 268 pacientes com diagnóstico provável ou definitivo de HAI atendidos no período de 20 anos, com tempo médio de seguimento de 6,2 anos. A relação sexo F:M foi de 5,7:1, a idade média ao diagnóstico de 29,1 anos, 28,4% apresentaram doença auto-imune extra-hepática concomitante, a mais freqüente foi tireoidiana. A forma de apresentação da doença foi aguda em 56%. Antes do tratamento 81,4% tinham diagnóstico definitivo de HAI. 78,4% tinham HAI tipo 1, 7,1% tipo 2, 9% HAI sem marcador e 5,6% HAI com antimitocôndria. 80,6% submeteram-se à biópsia hepática inicial, 56% com cirrose hepática (45,1% da casuística). O tratamento inicial foi azatioprina e prednisona em 70,9%, com 57,5% de efeitos colaterais e necessidade de troca do esquema terapêutico em 33%. O efeito colateral documentado mais freqüente foi desmineralização óssea. 51,5% dos pacientes atingiram remissão bioquímica e apenas 36,2% remissão histológica em tempo médio de cinco anos; em 22% foi necessário o uso do ácido ursodesoxicólico como tentativa de normalização bioquímica. As doses médias de corticóide e azatioprina usadas para remissão histológica foram 8,3mg/dia e 84,3mg/dia. A recidiva após suspensão do tratamento ocorreu em 58,7%, 75,7% nos primeiros seis meses. A sobrevida em cinco anos foi de 91,4%, 9,7% necessitaram de transplante hepático, com 26,9% de recidiva da HAI em seguimento médio de quatro anos após o transplante. A principal etiologia de mortalidade foi infecção. Para avaliação da gestação foram consideradas 54 gestações ocorridas em 39 patientes (71,8% com HAI tipo 1, 15,4% tipo 2 e 12,8% formas variantes), com idade média à gestação de 24 anos e 68,4% de cirrose hepática. 48,1% usavam azatioprina e prednisona na concepção e início da gestação e 48,1% tomaram prednisona 20mg/d após o seu diagnóstico. A taxa de perda fetal foi de 29,4%, a de abortos espontâneos 24%, de prematuridade 11,8%. Ocorreram 3,9% malformações fetais e uma gestação ectópica. Aparentemente não houve relação entre o uso de azatioprina e eventos gestacionais desfavoráveis. Embora em quatro gestações houvesse complicações maternas, não se observaram óbitos. Em 55% das gestações ocorreram aumentos das enzimas hepáticas, mas recidiva da HAI ocorreu em 31,4%, apenas no período puerperal. Concluímos que a HAI no Brasil é doença mais grave, com idade mais precoce de início, maior porcentagem de cirrose hepática à apresentação. Há necessidade de maiores doses de medicação para remissão e menores taxas de resposta completa e recidiva após a suspensão do tratamento. A gestação na HAI é geralmente segura, com necessidade de monitorização rigorosa principalmente no puerpério e o uso de azatioprina é aparentemente desprovido de complicações. / Autoimmune hepatitis (AIH) is a chronic liver disease in which there is a progressive destruction of the hepatic parenchyma, leading to cirrhosis without treatment. Previous publications reported some regional and racial differences in clinical, laboratorial, histologic features and treatment response of this disease, probably related to genetic backgrounds and environmental factors. The aim of this study was to analyze clinical, laboratorial and histologic features, pregnancy outcomes and treatment response of 268 patients with definite or probable diagnosis of AIH followed-up for 20y (median time - 6.2y). Women were more affected than men; gender ratio of 5.7:1. Median age at diagnosis was 29.1y. 28.4% had a concomitant autoimmune extra-hepatic disease, more frequently a thyroid disease. Clinical presentation was acute in 56% of patients. Before treatment, 81.4% had a definite diagnosis of AIH, 78.4% type 1, 7.1% type 2, 9% seronegative and 5.6% with antimitochondrial antibodies. 80.6% had initial histologic evaluation, 56% of them with liver cirrhosis. Initial treatment included azathioprine and prednisone in 70.9% of patients; 57.5% had side effects and 33% of them needed to change the medication regimen. The most frequent documented side effect was bone disease. 51.5% of patients entered biochemical remission but only 36.2% had a complete response in 5 years. In 22% of patients ursodeoxycholic acid was added to improve biochemical remission. Median doses of azathioprine and prednisone for histological remission were 84.3mg/day and 8.3mg/day respectively. Relapses after treatment withdrawal occurred in 58.7%, mostly in the first six months. Five-year survival was 91.4%, 9.7% of patients underwent liver transplantation and 26.9% had AIH recurrence in 4-year follow-up. The main cause of death was infection. We analyzed 54 pregnancies of 39 patients with AIH (71.8% type 1, 15.4% type 2 and 12.8% variant forms). Median age at pregnancy was 24 years, 68.4% of patients had liver cirrhosis. In 48.1% of pregnancies, patients were taking azathioprine and prednisone at conception and early pregnancy. In 48.1% of pregnancies 20mg/day prednisone was administered alone, after the diagnosis of gestation. The fetal loss rate was 29.4%, spontaneous abortions occurred in 24% and premature labors in 11.8%. There were 3.9% of congenital malformation and one ectopic pregnancy. Apparently there was no relationship between adverse pregnancy outcomes and azathioprine use. In 4 pregnancies there were maternal complications, but no mortalities. In 55% of pregnancies there were elevation of aminotransferase levels, 31.4% had a relapse of AIH, only in the postpartum period. We concluded that AIH in Brazil occurred in a younger age, had more cirrhosis at presentation and medication doses for histologic remission were higher than those previously reported. Patients had lower rates of complete response and of relapse after drug withdrawal. Pregnancy is safe, but a close monitoring is important especially in the postpartum period. Azathioprine administration during pregnancy apparently had no toxic effects.

A origem das doenças autoimunes é multifatorial, sendo que envolve condições ambientais e predisposição genética, dificultando sua identificação. Muitos pesquisadores têm estudado a associação entre agentes infecciosos e autoimunidade, a qual pode ser disparada pelo processo conhecido por mimetismo molecular. Neste caso, respostas imunes cruzadas envolvendo antígenos próprios têm sido documentadas. O presente projeto tem como objetivo a busca in silico por associações entre epítopos de microrganismos e autoantígenos humanos. Iniciaram-se as análises pela identificação de semelhanças de sequências de aminoácidos entre epítopos de microrganismos e autoantígenos humanos por meio do alinhamento local de sequências efetuado pelo programa BLASTP. As sequências de epítopos dos microrganismos e autoantígenos humanos foram previamente adquiridas nos bancos de dados Immune Epitope Database and Analysis Resource (IEDB) e no Genbank, respectivamente. Foram também realizadas modelagens de estruturas proteicas para o antígeno e o autoantígeno que obtiveram melhores valores de alinhamento, com base no valor do E-value, por meio dos programas Modeller e Rosetta. Por fim, a predição de epítopos foi executada, pelo uso dos softwares NetMHC e NetMHCII, para avaliar a possibilidade de epítopos de microrganismos e de autoantígenos humanos se associarem aos mesmos alelos de HLA. Como resultado, foram encontradas similaridades tanto de sequências proteicas quanto de afinidade a 4 tipos de alelos de HLA entre um epítopo do antígeno LSA-1 de Plasmodium falciparum e o autoantígeno de miosina, o que sugere uma associação entre eles, atingindo o objetivo deste trabalho. / The origin of autoimmune diseases is multifactorial. It involves environmental conditions and genetic predisposition that difficulties its identification. Several researchers have studied the association between infectious agents and autoimmunity, which can be initiated by a process named molecular mimicry. In this case, cross immune responses involving self antigens have been documented. This project aims to search in silico for associations between microorganisms epitopes and human autoantigens. The first step was the identification of similarities in amino acid sequences between microorganisms epitopes and human autoantigens by use of sequence local alignment performed by the program blastp. The sequences of the microorganisms epitope and the human autoantigens had been previously acquired in the Immune Epitope Database and Analysis Resource (IEDB) and Genbank, respectively. The modeling of protein structures for the antigen and autoantigen was also carried out to show the best alignment values, based on the E-value, using the programs Modeller and Rosetta. Finally, the prediction of epitopes was performed by use of NetMHC and NetMHCII softwares to evaluate the possibility of microorganisms epitopes and human autoantigens join the same HLA alleles. Similarities of protein sequences was found for both. It was possible to observe affinity of 4 HLA alleles between an epitope from LSA-1 Plasmodium falciparum antigen and the myosin, suggesting an association between them, reaching the goal of this work.

Este estudo avaliou a eficácia do propionato de clobetasol a 0,05% em pomada, com uso de moldeiras individuais de silicone, em 22 pacientes com lesões gengivais de doenças mucocutâneas auto-imunes e inflamatórias, por meio de um estudo duplo-cego, cruzado, placebo-controlado. Os pacientes foram distribuídos em dois grupos: grupo 1, que consistiu de 5 pacientes em uso de corticosteróide e/ou imunossupressor sistêmico para controle de lesões cutâneas e/ou gengivais associadas às doenças mucocutâneas; grupo 2, que consistiu de 17 pacientes sem utilização de corticosteróide e/ou imunossupressor sistêmico. Os pacientes de cada grupo receberam a bisnaga 1, e foram orientados a utilizá-la no preenchimento das moldeiras. Em seguida, foram instruídos a aplicar a pomada com a moldeira 3 vezes ao dia, durante 20 minutos, por um período de duas semanas. A freqüência de uso da pomada foi reduzida na 3 a semana para 1 vez ao dia (pela manhã), em dias alternados. Após esta fase, foi estabelecido um intervalo de 2 semanas sem tratamento após o qual houve a inversão das pomadas (bisnaga 2), e os pacientes passaram a utilizá-la da mesma maneira que a bisnaga 1. As consultas de avaliações foram realizadas na 2 a , 5 a , 7 a , e na 10 a semana após o início do teste, e a resposta terapêutica foi baseada no percentual da remissão dos sinais classificada como completa (100%), excelente (75% a 99%), boa (50% a 74%), regular (1% a 49%), inalterada e piorada; e da remissão dos sintomas classificada como completa, parcial, inalterada e piorada. Durante as consultas de retorno, os pacientes foram monitorados quanto à ocorrência de efeitos colaterais. Com relação à remissão dos sinais, nos pacientes do grupo 1, 4 pacientes (80%) mostraram resposta regular; e 1 paciente (20%) apresentou piora do quadro clínico após o uso do propionato de clobetasol. Nos pacientes do grupo 2, 13 pacientes (76,5%) apresentaram alguma melhora durante o uso do propionato de clobetasol, e 4 pacientes (23,5%) apresentaram piora do quadro clínico. Com relação aos sintomas, durante o uso do propionato de clobetasol, 3 (60%) pacientes do grupo 1, apresentaram melhora parcial, 1 paciente (20%) não verificou mudança na sintomatologia, e 1 paciente (20%) referiu piora dos sintomas. Nos pacientes do grupo 2, completa melhora dos sintomas foi verificado em 2 pacientes (11,8%) e resposta parcial em 9 pacientes (52,9%) durante o uso do propionato de clobetasol. A diferença dos resultados obtidos entre o período de uso do propionato de clobetasol e placebo, nos dois grupos de pacientes e para os parâmetros analisados, não foi estatisticamente significante (Teste exato de Fisher; p > 0,05). Apenas 2 pacientes (11,8 %) do grupo 2 desenvolveram candidose após o uso do propionato de clobetasol. Os resultados deste estudo demonstraram que a aplicação do propionato de clobetasol 0,05% em pomada, com o auxílio de moldeiras de silicone, apresenta eficácia boa a moderada no controle das lesões gengivais de doenças mucocutâneas, causando mínimo de efeitos colaterais. / This study evaluated the efficacy of 0.05% clobetasol propionate in ointment administered with trays in 22 patients with gingival lesions of autoimmune and inflammatory mucocutaneous diseases. The patients were subdivided into two groups: group 1, which was composed by 5 patients treated systemically with corticosteroid and/or other immunosuppressive drug for control of skin and/or gingival lesions associated to mucocutaneous diseases; and the group 2, which was composed by 17 patients not being under systemic corticotherapy. The patients of each group received the container number 1 and they were instructed to apply the ointment with the tray for 20 minutes, 3 times daily, for 2 weeks. The frequency of use of ointment was reduced in the third week for once a day on alternate days. After that, the patients were instructed to discontinue the treatment for 2 weeks (washout period), and then were given the container number 2, to be used in the same way as that of the container 1. Each patient was examined in the weeks 2, 5, 7, and 10 after the beginning of the study. The therapeutic response was determined according to remission of signs on percentage, and assessed as follow: complete (100%), excellent (75% to 99%), good (50% to 74%), poor (1% to 49%), failed and worsened; and on remission of symptoms assessed as complete, partial, failed and worsened. At every visit, the patients were also examined for the presence of side-effects. In group 1, 4 patients (80%) had a poor response, and 1 patient (20%) had a worse of clinical presentation after the use of clobetasol propionate. In patients of group 2, 13 (76.5%) presented some improvement after the use of clobetasol propionate, and 4 patients (23.5%) presented worse of signals. For symptoms, 3 patients (60%) of the group 1 showed partial improvement while 1 (20%) presented no response, and 1 (20%) had symptoms worsened after the use of corticosteroid. In the group 2, complete improvement of symptoms was observed in 2 (11.8%) and partial in 9 (52.9%) after the use of clobetasol. There was no statistical difference when compared the results obtained with clobetasol propionate and placebo in the two groups of patients for the parameters evaluated (Fisher test; P > 0.05). Only 2 patients (11.8%) of group 2 developed candidosis after the use of clobetasol propionate. This study showed that clobetasol propionate ointment present good to moderate efficacy, with minimal side-effects, in the treatment of gingival lesions of mucocutaneous diseases.

The purpose of this study was 1) to examine the significance of a patient’s active or passive role in terms of his/her health management; 2) to determine if a relationship exists between one’s active and passive scores and his/her self-directed learning readiness, and 3) to identify if his/her view of one’s self as a patient (when diagnosed with a chronic disease) impacted his/her own personal health management. Utilizing the quantitative analysis of The Self-Directed Learning Readiness Scale and the Vanderbilt Pain Management Inventory, 81 individuals’ descriptive statistics were analyzed. Self-directed learning was found to positively influence an individual’s ability to be an active patient. The moderated demographic characteristics of age, ethnicity, education level, and gender did not have a direct relationship between selfdirected learning readiness and active/passive coping groups. Further, it was established that the majority of the participants within the study, 83.75%, considered themselves an active patient managing their lupus diagnosis. However, 16.25% of the participants did not believe that they were actively managing their illness. Self-directed learning characteristics were examined through the responses to an open-ended question. The two most prevalent themes pertained to active coping and control. Characteristics of self-directed learning readiness appeared predominant amongst the responses, particularly goal-orientation and accepting responsibility for learning. Minimal themes regarding planning and enjoying learning were provided within the data. These characteristics were identified throughout the study in hopes of further research and program implementations that will help to develop leadership abilities and activity levels of self-health management in chronically ill patients. This will enable lupus patients to have a more positive outcome, it will help them successfully manage their own health, and it will improve their overall quality of life. / Includes bibliography. / Dissertation (Ph.D.)--Florida Atlantic University, 2016. / FAU Electronic Theses and Dissertations Collection

Este estudo avaliou a eficácia do propionato de clobetasol a 0,05% em pomada, com uso de moldeiras individuais de silicone, em 22 pacientes com lesões gengivais de doenças mucocutâneas auto-imunes e inflamatórias, por meio de um estudo duplo-cego, cruzado, placebo-controlado. Os pacientes foram distribuídos em dois grupos: grupo 1, que consistiu de 5 pacientes em uso de corticosteróide e/ou imunossupressor sistêmico para controle de lesões cutâneas e/ou gengivais associadas às doenças mucocutâneas; grupo 2, que consistiu de 17 pacientes sem utilização de corticosteróide e/ou imunossupressor sistêmico. Os pacientes de cada grupo receberam a bisnaga 1, e foram orientados a utilizá-la no preenchimento das moldeiras. Em seguida, foram instruídos a aplicar a pomada com a moldeira 3 vezes ao dia, durante 20 minutos, por um período de duas semanas. A freqüência de uso da pomada foi reduzida na 3 a semana para 1 vez ao dia (pela manhã), em dias alternados. Após esta fase, foi estabelecido um intervalo de 2 semanas sem tratamento após o qual houve a inversão das pomadas (bisnaga 2), e os pacientes passaram a utilizá-la da mesma maneira que a bisnaga 1. As consultas de avaliações foram realizadas na 2 a , 5 a , 7 a , e na 10 a semana após o início do teste, e a resposta terapêutica foi baseada no percentual da remissão dos sinais classificada como completa (100%), excelente (75% a 99%), boa (50% a 74%), regular (1% a 49%), inalterada e piorada; e da remissão dos sintomas classificada como completa, parcial, inalterada e piorada. Durante as consultas de retorno, os pacientes foram monitorados quanto à ocorrência de efeitos colaterais. Com relação à remissão dos sinais, nos pacientes do grupo 1, 4 pacientes (80%) mostraram resposta regular; e 1 paciente (20%) apresentou piora do quadro clínico após o uso do propionato de clobetasol. Nos pacientes do grupo 2, 13 pacientes (76,5%) apresentaram alguma melhora durante o uso do propionato de clobetasol, e 4 pacientes (23,5%) apresentaram piora do quadro clínico. Com relação aos sintomas, durante o uso do propionato de clobetasol, 3 (60%) pacientes do grupo 1, apresentaram melhora parcial, 1 paciente (20%) não verificou mudança na sintomatologia, e 1 paciente (20%) referiu piora dos sintomas. Nos pacientes do grupo 2, completa melhora dos sintomas foi verificado em 2 pacientes (11,8%) e resposta parcial em 9 pacientes (52,9%) durante o uso do propionato de clobetasol. A diferença dos resultados obtidos entre o período de uso do propionato de clobetasol e placebo, nos dois grupos de pacientes e para os parâmetros analisados, não foi estatisticamente significante (Teste exato de Fisher; p > 0,05). Apenas 2 pacientes (11,8 %) do grupo 2 desenvolveram candidose após o uso do propionato de clobetasol. Os resultados deste estudo demonstraram que a aplicação do propionato de clobetasol 0,05% em pomada, com o auxílio de moldeiras de silicone, apresenta eficácia boa a moderada no controle das lesões gengivais de doenças mucocutâneas, causando mínimo de efeitos colaterais. / This study evaluated the efficacy of 0.05% clobetasol propionate in ointment administered with trays in 22 patients with gingival lesions of autoimmune and inflammatory mucocutaneous diseases. The patients were subdivided into two groups: group 1, which was composed by 5 patients treated systemically with corticosteroid and/or other immunosuppressive drug for control of skin and/or gingival lesions associated to mucocutaneous diseases; and the group 2, which was composed by 17 patients not being under systemic corticotherapy. The patients of each group received the container number 1 and they were instructed to apply the ointment with the tray for 20 minutes, 3 times daily, for 2 weeks. The frequency of use of ointment was reduced in the third week for once a day on alternate days. After that, the patients were instructed to discontinue the treatment for 2 weeks (washout period), and then were given the container number 2, to be used in the same way as that of the container 1. Each patient was examined in the weeks 2, 5, 7, and 10 after the beginning of the study. The therapeutic response was determined according to remission of signs on percentage, and assessed as follow: complete (100%), excellent (75% to 99%), good (50% to 74%), poor (1% to 49%), failed and worsened; and on remission of symptoms assessed as complete, partial, failed and worsened. At every visit, the patients were also examined for the presence of side-effects. In group 1, 4 patients (80%) had a poor response, and 1 patient (20%) had a worse of clinical presentation after the use of clobetasol propionate. In patients of group 2, 13 (76.5%) presented some improvement after the use of clobetasol propionate, and 4 patients (23.5%) presented worse of signals. For symptoms, 3 patients (60%) of the group 1 showed partial improvement while 1 (20%) presented no response, and 1 (20%) had symptoms worsened after the use of corticosteroid. In the group 2, complete improvement of symptoms was observed in 2 (11.8%) and partial in 9 (52.9%) after the use of clobetasol. There was no statistical difference when compared the results obtained with clobetasol propionate and placebo in the two groups of patients for the parameters evaluated (Fisher test; P > 0.05). Only 2 patients (11.8%) of group 2 developed candidosis after the use of clobetasol propionate. This study showed that clobetasol propionate ointment present good to moderate efficacy, with minimal side-effects, in the treatment of gingival lesions of mucocutaneous diseases.

Made available in DSpace on 2014-07-29T15:25:24Z (GMT). No. of bitstreams: 1 tese Jozelia rego.pdf: 289983 bytes, checksum: 81f90ad780122cbecb664ab66f6306c0 (MD5) Previous issue date: 2009-12-17 / Autoimmune diseases are a clinical syndrome caused by the activation of T and/or B cells. They are multifactorial in nature and characterized by the presence of autoantibodies directed against cellular components. These autoantibodies can act as diagnostic markers or as predictors for these diseases. The ANA test is a very useful tool in the investigation of autoimmune diseases. OBJECTIVES: a) establishing a correlation between clinical diagnoses and fluorescence patterns in ANA tests on HEp-2 cells; b) determining the frequency of fluorescence patterns; c) establishing a correlation between clinical diagnosis and fluorescence titers; d) establishing possible correlations of changes in fluorescence patterns. CASES AND METHODS: All the ANA requests sent to the Immunorheumatology Laboratory of the Teaching Hospital of the Federal University of Goias, from January / 2000 to December / 2007 were analyzed and those with positive results were selected. For the ANA research, the investigator used the IFI technique and HEp-2 cells as substrate. To classify the fluorescence patterns decision trees proposed by the Brazilian Consensus for Standardization of ANA in HEp-2 cells were used. RESULTS: Among the 8,631 ANA requests, 1,167 presented positive results (13,52%). These positive tests were divided into two groups: Group I (tests requested in one occasion) and Group II (tests requested in more than one occasion). In Group I, nuclear patterns were more prevalent (89,41%). Speckled nuclear patterns were seen more frequently (78,81%), with special notice to fine speckled nuclear patterns (32,74%), coarse speckled nuclear patterns (29,86%) and fine dense speckled nuclear patterns (9,79%). Among the clinical diagnoses, rheumatic autoimmune diseases were the most prevalent (59,87%) and they correlated mostly with speckled nuclear patterns. A positive ANA was noted in 216 cases (34,67%) of non-immune conditions and in 22 cases (3,53%) of undetermined diagnosis. Cases with moderate (1:160) and high (1:640 and > 1:640) titers presented a high association with autoimmune diseases (54,25%; 73,23%; 83,91%, respectively). In Group II, the analytic clinical diagnosis and fluorescence titer factors showed a significant association with the change in the fluorescence pattern. CONCLUSIONS: 1) ANA was found to be positive in autoimmune (61,80%) and in non-autoimmune diseases (34,67%). 2) The most frequently found positive ANA correlation was seen with a diagnosis of lupus erythematosus (38,04%), mainly with coarse speckled nuclear pattern (32,91%), fine speckled nuclear pattern (25,73%), homogeneous nuclear pattern (19,40%) and fine dense speckled nuclear pattern (10,12%). 3) Nuclear patterns were more frequently found (89,41%), and among them, speckled patterns were prevalent (78,81%). 4) Low titers can be found in rheumatic autoimmune diseases and, therefore, can not be interpreted as an exclusion criteria for autoimmune disease, as long as there are clinical indications. 5) High titers can be found in non-autoimmune diseases and, therefore, can not be interpreted as specific to autoimmune diseases. 6) When the ANA test was requested in more than one occasion for the same patient, the clinical diagnosis (especially SLE) and the fluorescence titer (1:40 and 1:160) showed an association with the change of the fluorescence pattern. 7) A correct valuation of the ANA test should associate information from positive results to the clinical history and the physical examination of the patient when they are suggestive of an autoimmune disease, most notably, of rheumatic autoimmune diseases / As doenças autoimunes são síndromes clínicas causadas pela ativação de células T e/ou B, de origem multifatorial, caracterizadas pela presença de autoanticorpos dirigidos contra componentes celulares. Os autoanticorpos podem atuar como marcadores diagnósticos ou como marcadores preditores destas doenças. O teste de FAN é um exame útil na investigação de doenças autoimunes. OBJETIVOS: a) verificar a correlação entre os diagnósticos clínicos e os padrões de fluorescência na pesquisa de FAN em células HEp-2; b) determinar a freqüência dos padrões de fluorescência; c) verificar a correlação entre os diagnósticos clínicos e os títulos de fluorescência; d) verificar as possíveis correlações da mudança dos padrões de fluorescência. CASUÍSTICA E MÉTODOS: Foram analisadas todas as solicitações de FAN encaminhadas ao Laboratório de Imuno-Reumatologia do Hospital das Clínicas da Universidade Federal de Goiás, durante o período de jan./ 2000 a dez./ 2007, e selecionadas as solicitações com resultados positivos. A pesquisa do FAN foi realizada pela técnica de IFI, utilizando-se como substrato células HEp-2. Para a classificação dos padrões de fluorescência utilizou-se as árvores de classificação definidas pelo I Consenso Nacional para padronização dos laudos de FAN em células HEp-2. RESULTADOS: Das 8631 solicitações de FAN, 1167 apresentaram resultados positivos (13,52%). Os testes positivos foram divididos em dois grupos: Grupo I (exames solicitados em uma ocasião) e Grupo II (exames solicitados em mais de uma ocasião). No Grupo I, os padrões encontrados em maior freqüência foram os nucleares (89,41%). Os padrões nucleares pontilhados foram observados em maior freqüência (78,81%), destacando-se os padrões nuclear pontilhado fino (32,74%), nuclear pontilhado grosso (29,86%) e nuclear pontilhado fino denso (9,79%). Dentre os diagnósticos clínicos descritos, as doenças autoimunes reumáticas foram observadas em maior freqüência (59,87%) e correlacionaram-se, principalmente, com os padrões nucleares pontilhados. FAN positivo foi observado em 216 casos (34,67%) de situações não-autoimunes e em 22 casos (3,53%) de diagnóstico não definido. Os casos com títulos moderados (1:160) e elevados (1:640 e > 1:640) apresentaram maior associação com enfermidades autoimunes (54,25%; 73,23%; 83,91%, respectivamente). No Grupo II, os fatores analíticos diagnóstico clínico e título de fluorescência mostraram associação significativa com a mudança do padrão de fluorescência. CONCLUSÕES: 1) A positividade do teste de FAN foi observada em doenças autoimunes (61,80%) e em doenças não-autoimunes (34,67%). 2) A correlação mais freqüente do FAN positivo foi observada com o diagnóstico de lupus eritematoso (38,04%), principalmente com os padrões nuclear pontilhado grosso (32,91%), nuclear pontilhado fino (25,73%), nuclear homogêneo (19,40%) e nuclear pontilhado fino denso (10,12%). 3) Os padrões nucleares foram observados em maior freqüência (89,41%), sendo os pontilhados os mais comuns (78,81%). 4) Títulos baixos podem ser encontrados em doenças autoimunes reumáticas e, portanto, não devem ser interpretados como critério para exclusão de doença autoimune, desde que exista suspeita clínica. 5) Títulos altos podem ser encontrados em doenças não-autoimunes e, portanto, não devem ser interpretados como específicos de doença autoimune. 6) Quando o teste de FAN foi solicitado em mais de uma ocasião, para o mesmo paciente, o diagnóstico clínico (principalmente de LES) e o título de fluorescência (1:40 e 1:160) mostraram associação com a mudança do padrão de fluorescência. 7) A valorização correta do teste de FAN deve associar as informações fornecidas pelo resultado positivo à história clínica e exame físico do paciente, quando sugestivos de doença autoimune, principalmente de doenças autoimunes reumáticas.