by Ho Cheong-Yip. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2001. / Includes bibliographical references (p. 198-222). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Mode of access: World Wide Web. / Abstracts in English and Chinese.

INTRODUÇÃO: Lúpus eritematoso (LE) é uma doença inflamatória crônica, autoimune. A presença de citocinas do tipo 1 nas lesões cutâneas discoides sugere que estas sejam críticas para a indução, desenvolvimento e manutenção destas manifestações. As citocinas do tipo 2 em combinação com Interferon- local podem estar relacionadas com a fisiopatologia do lúpus cutâneo. O perfil das citocinas ainda é desconhecido nas lesões orais do LE. MÉTODOS: Foram investigadas e comparadas as expressões das citocinas Th1 e Th2, representadas por IL-4, IL-5, IL-6, IL-10, IL-12, fator de necrose tumoral alfa (TNF-) e interferon gama (IFN-), de 29 biopsias de LE de mucosa intraoral (área não exposta ao sol) e semimucosa labial (área exposta) por meio da técnica de imuno-histoquímica. RESULTADOS: O infiltrado inflamatório das lesões de LE foi fortemente positivo para IFN- (97%) e TNF- (90%), ambas citocinas Th1. Interleucina 10 (IL-10), citocina Th2, foi fortemente expressa. Outras citocinas foram apenas moderadamente positivas. O padrão de citocinas foi semelhante nas lesões orais do LE na mucosa intraoral (área não exposta) e na semimucosa labial (área exposta). CONCLUSÕES: As lesões orais de LE estão associadas tanto a citocinas Th1 quanto a citocinas Th2, caracterizadas por expressão forte de IFN-, TNF- e IL-10. Além disso, os achados sugerem que apesar da radiação ultravioleta estar envolvida na indução das lesões de LE, os mecanismos de formação das lesões podem ser similares nas áreas expostas e não expostas ao sol. / Lupus erythematosus (LE) is a chronic inflammatory disease, autoimune. Presence of type 1 cytokines in cutaneous discoid lesions suggests that they may be critical for induction, development and maintenance of these manifestations. Type 2 cytokines in combination with local interferon (IFN-) are thought to be related to the physiopathology of cutaneous LE. Cytokines profiles are still unknown in oral LE lesions. Material and Methods: Expression of Th1 and Th2 cytokines (including IL-4, IL-5, IL-6, IL-10, IL-12, tumor necrosis factor (TNF-) and IFN- was investigated and compared in 29 biopsies of intra-oral (sun-protected) and labial lesions (sun-exposed) of LE using immunohistochemistry. Results: Inflammatory infiltrate of LE lesions was strongly positive for IFN- (97%) and TNF- (90%), both Th1 type cytokines. Interleukin-10, a Th2 cytokine was also strongly expressed. Other cytokines were only mildly positive. Cytokines patterns were similar in intra-oral (sun-covered) and labial (sun-exposed) LE lesions Conclusions: Oral LE lesions are associated with both type 1 and type 2 cytokines, characterized by stronger expression of IFN-, TNF- and IL-10. These findings suggest that although ultraviolet light is involved in the induction of LE lesions, mechanisms of lesions formation may be similar in sun-exposed as well as sun-covered areas.

Lupus is a complex, poorly understood long-term disease in which the body's immune system mistakenly attacks healthy tissues of any part of the body. The disease mainly affects young women of childbearing age. Studies from developed countries show that the condition affects individuals physically, emotionally and socially. However, nothing is known about how having lupus has affected individuals living with the condition in the African continent. I explored how lupus had affected individuals living with the condition in Kenya from the time individuals began to feel unwell. I interviewed three groups of participants. 10 individuals who attended the public rheumatology clinic, 11 individuals who attended a private rheumatology clinic and 6 doctors who worked in the rheumatology clinics. The study found that some individuals delayed in getting medical help for their lupus. It appears to take a long time for individuals to get their lupus diagnosed due to organisation and staffing of the Kenyan health system. It was also perceived by individuals with lupus that treatment for the condition was difficult to access and it was also costly. Some individuals believed that their lupus had a supernatural cause. Often there appeared to be a lack of understanding of lupus by individuals who suffered from the condition; and also by others, some having experienced disapproval or negative feelings from others. Individuals with lupus reported lacking the financial resources and social support to manage their condition better. Lupus was affecting them physically, emotionally and had an impact on their social lives. There are a number of challenges in living with lupus in Kenya, including individuals' and others perception of the condition, but also how healthcare is provided to these individuals.

Systemic lupus erythematosus is an autoinflammatory disorder driven by the development of autoantibodies to self-nucleic acids, in particular to DNA and to chromatin. Loss-of-function mutations of the secreted deoxyribonuclease DNASE1L3 have been implicated in the development of aggressive familial lupus. In addition, recent genome-wide association studies have linked a hypomorphic variant of DNASE1L3 to sporadic lupus. Studies in the lab determined that Dnase1l3-deficient mice develop rapid autoantibody responses against dsDNA and chromatin, and at older ages this leads to a lupus-like inflammatory disease. These disease manifestations were completely independent of the intracellular DNA sensor STING, which has been implicated in other examples of self-DNA driven autoinflammatory diseases. My project focused on developing assays to track the activity of DNASE1L3, as well as identifying the endogenous source of self-DNA normally processed by DNASE1L3. Using mouse models that allow the depletion of specific cell populations, we found that circulating DNASE1L3 is produced by hematopoietic cells, in particular by CD11c+ dendritic cells and by tissue macrophages. Taking into account the unique properties of DNASE1L3, we discovered that this enzyme is uniquely able to digest chromatin contained within and on the surface of apoptotic microparticles. Loss of DNASE1L3 activity in circulation results in elevated levels of DNA in plasma, in particular within microparticles. Microparticles are extensively bound by anti-chromatin autoantibodies isolated from both murine models of lupus as well as prototypical human clones. In addition, Dnase1l3-deficient mice have high levels of circulating IgG that bind to microparticles from young ages, and these titers increased as disease progressed in aged animals. Pretreatment of microparticles with DNASE1L3 largely abrogated this binding, demonstrating that DNASE1L3 directly reduces the immunogenicity of microparticles. We also studied two human patients with null mutations in DNASE1L3, and observed increased DNA circulating in plasma and, in particular, in their microparticles, demonstrating a conserved role for DNASE1L3 in mice and humans. Finally, we obtained plasma samples from a cohort of patients with sporadic SLE, and found that roughly 80% had circulating IgG that avidly bound microparticles. Roughly half of this group failed to bind to microparticles that had been pretreated with DNASE1L3, and this DNASE1L3-sensitive group also presented with lower levels of DNASE1L3 activity. We conclude that extracellular chromatin associated with microparticles acts as a potential self-antigen capable of causing loss of tolerance to self-DNA and inflammatory disease in both mice and humans. The secretion of a DNA-processing enzyme thus represents a novel, conserved tolerogenic mechanism by which dendritic cells restrict autoimmunity.

INTRODUÇÃO: Lúpus eritematoso (LE) é uma doença inflamatória crônica, autoimune. A presença de citocinas do tipo 1 nas lesões cutâneas discoides sugere que estas sejam críticas para a indução, desenvolvimento e manutenção destas manifestações. As citocinas do tipo 2 em combinação com Interferon- local podem estar relacionadas com a fisiopatologia do lúpus cutâneo. O perfil das citocinas ainda é desconhecido nas lesões orais do LE. MÉTODOS: Foram investigadas e comparadas as expressões das citocinas Th1 e Th2, representadas por IL-4, IL-5, IL-6, IL-10, IL-12, fator de necrose tumoral alfa (TNF-) e interferon gama (IFN-), de 29 biopsias de LE de mucosa intraoral (área não exposta ao sol) e semimucosa labial (área exposta) por meio da técnica de imuno-histoquímica. RESULTADOS: O infiltrado inflamatório das lesões de LE foi fortemente positivo para IFN- (97%) e TNF- (90%), ambas citocinas Th1. Interleucina 10 (IL-10), citocina Th2, foi fortemente expressa. Outras citocinas foram apenas moderadamente positivas. O padrão de citocinas foi semelhante nas lesões orais do LE na mucosa intraoral (área não exposta) e na semimucosa labial (área exposta). CONCLUSÕES: As lesões orais de LE estão associadas tanto a citocinas Th1 quanto a citocinas Th2, caracterizadas por expressão forte de IFN-, TNF- e IL-10. Além disso, os achados sugerem que apesar da radiação ultravioleta estar envolvida na indução das lesões de LE, os mecanismos de formação das lesões podem ser similares nas áreas expostas e não expostas ao sol. / Lupus erythematosus (LE) is a chronic inflammatory disease, autoimune. Presence of type 1 cytokines in cutaneous discoid lesions suggests that they may be critical for induction, development and maintenance of these manifestations. Type 2 cytokines in combination with local interferon (IFN-) are thought to be related to the physiopathology of cutaneous LE. Cytokines profiles are still unknown in oral LE lesions. Material and Methods: Expression of Th1 and Th2 cytokines (including IL-4, IL-5, IL-6, IL-10, IL-12, tumor necrosis factor (TNF-) and IFN- was investigated and compared in 29 biopsies of intra-oral (sun-protected) and labial lesions (sun-exposed) of LE using immunohistochemistry. Results: Inflammatory infiltrate of LE lesions was strongly positive for IFN- (97%) and TNF- (90%), both Th1 type cytokines. Interleukin-10, a Th2 cytokine was also strongly expressed. Other cytokines were only mildly positive. Cytokines patterns were similar in intra-oral (sun-covered) and labial (sun-exposed) LE lesions Conclusions: Oral LE lesions are associated with both type 1 and type 2 cytokines, characterized by stronger expression of IFN-, TNF- and IL-10. These findings suggest that although ultraviolet light is involved in the induction of LE lesions, mechanisms of lesions formation may be similar in sun-exposed as well as sun-covered areas.

Os antimaláricos, cloroquina e hidroxicloroquina, têm sido usados há décadas com bons resultados terapêuticos para o tratamento do lupus eritematoso e são considerados medicações seguras, muito embora, haja preocupação em relação à retinotoxicidade, notadamente com a cloroquina. O objetivo deste trabalho foi avaliar a ocorrência dos efeitos adversos desencadeados pelo tratamento com 250mg/d de difosfato de cloroquina em doentes com lupus eritematoso, dando ênfase à retinotoxicidade. Foram estudados 350 doentes e reavaliados seus respectivos prontuários, que datavam de 1980 a 2003. Os doentes foram acompanhados no ambulatório de colagenoses da Divisão de Dermatologia do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo. A ocorrência dos efeitos adversos foi de 35,7%, sendo que 17,4% decorreram de alterações oculares. Em 12% dos doentes ocorreu pigmentação retiniana sugestiva de retinopatia antimalárica, em 3,1% depósitos corneanos e, em 2,3%, sintomas visuais agudos. Em 10% dos doentes houve alterações gastrointestinais: epigastralgia (6%), náuseas e vômitos (3,7%) e diarréia (0,3%). Alterações dermatológicas ocorreram em 3,4% dos doentes: rash cutâneo no início do tratamento (2%), exacerbação de quadro de psoríase pré-existente (0,3%) e pigmentação cutânea (1,1%). Ocorreram ainda cefaléia (2,9%), alterações neuromusculares (1,7%) com quadro gripal símile no início do tratamento (1,1%), neuropatia sensitiva (0,3%) e miopatia compatível com miastenia (0,3%) e, sintomas neuropsiquiátricos (0,3%). A droga foi suspensa devido aos efeitos adversos em 22,9% dos doentes, principalmente, em decorrência de alterações oculares, gastrointestinais e dermatológicas. A reavaliação oftalmológica de 12% dos doentes com pigmentação retiniana, confirmou a retinopatia antimalárica em apenas 2,6%, o que demonstrou uma tendência à valorização de alterações retinianas inespecíficas, discretas e unilaterais, com indicação desnecessária da suspensão da droga em 9,4% dos doentes. Não ocorreram casos de retinopatia antimalárica avançada com lesão do tipo bull-eye. Não houve associação estatisticamente significativa entre a ocorrência de efeitos adversos e alterações retinianas com dose diária de difosfato de cloroquina por quilo de peso e com o tipo clínico do lupus eritematoso. As alterações retinianas foram estatisticamente significativas nos doentes acima de cinqüenta anos quando comparado ao grupo abaixo dos cinqüenta anos, possivelmente pela dificuldade em diferenciar as alterações iniciais da retinopatia antimlárica daquelas decorrentes da degeneração macular senil. O controle oftalmológico foi realizado em intervalo médio de 10,5 meses, demonstrando que o controle anual foi eficaz para o acompanhamento dos doentes. Nove doentes foram expostas durante o primeiro trimestre gestacional, não ocorrendo casos de mal formação fetal / Antimalarial agents, chloroquine and hydroxichloroquine, have been used for decades leading to good therapeutic outcomes at treatment approach for lupus erythematosus and are considered safe medication; however, the main concern is retina toxicity, especially with chloroquine. The purpose of the present study was to conduct analysis of the occurrence of adverse effects, triggered by use of 250 mg/d of chloroquine diphosphate at treatment for lupus erythematosus, especially retina toxicity. We analyzed 350 patients and reviewed their medical charts, from 1980 to 2003. The patients were followed up by the outpatient unit of collagenosis, Division of Dermatology, Hospital das Clinicas, Medical School, University of São Paulo. The occurrence of adverse effects was 35.7%, and eye affections were detected in 17.4% of patients. Impairment of retina pigmentation suggestive of antimalarial retinopathy occurred in 12%, cornea deposits in 3,1%, and acute visual symptoms in 2.3%. Gastrointestinal affections were detected in 10% of patients: epigastralgia (6%), nausea and vomiting (3.7%) and diarrhea (0.3%). Dermatological affections occurred in 3.4% of patients: skin rash in the beginning of treatment (2%), exacerbation of preexisting psoriasis (0.3%) and skin pigmentation (1.1%). We also detected headache (2.9%), neuromuscular disorders (1.7%) with flu-like episode at the beginning of treatment (1,1%), sensitive neuropathy (0,3%) and myopathy compatible with myasthenia (0.3%) and neuropsychiatric symptoms (0.3%). Discontinuation of drugs owing to side effects occurred in 22.9% of the patients, being that the main affections were eye, gastrointestinal and dermatological occurrences. Ophthalmologic reevaluation of retina pigmentation affections occurred in 12% of the patients, but we confirmed antimalarial retinopathy only in 2.6%, detecting a tendency to value nonspecific, discreet and unilateral affections, which generated unnecessary recommendations for discontinuation of drug in 9.4% of the patients. There were no cases of advanced retinopathy with bull-eye type lesion. There was no statistically significant association between occurrence of adverse effects and retina affections with daily dose per kg of chloroquine diphosphate and the differents types of lupus erythematosus. In patients over the age of 50, there was statistically significant increase in number of retina affections when compared to the group aged below 50 years, possibly owing to difficulty to differentiate between initial affections in antimalarial retinopathy from those resultant from senile macular degeneration. Ophthalmologic control was conducted on average after 10.5 months, showing that annual follow-up was effective to keep track of patients. Nine of the patients were exposed during the first gestational trimester and there were no cases of fetal malformations

Silent mating type Information Regulator 2 homolog 1 (SIRT1) é uma proteína deacetilase que participa em diversos processos fisiológicos, com importância no silenciamento transcricional, apoptose, regulação do sistema imune e inflamação. O lúpus eritematoso sistêmico (LES) é uma doença inflamatória autoimune com etiologia multifatorial, caracterizada pela produção de autoanticorpos, deposição de imunocomplexos e dano tecidual. Já foi demonstrado que existem níveis elevados da expressão de SIRT1 em linfócitos T CD4+ de pacientes com LES, acompanhados de hipoacetilação global das histonas H3 e H4, com correlação entre a hipoacetilação de H3 e maior atividade da doença. Os polimorfismos rs12778366 e rs3758391 do promotor do gene SIRT1 podem exercer influência sobre a expressão diferencial desta molécula e, no presente estudo, foi investigado o papel destas variantes na susceptibilidade ao LES. Não foram encontradas diferenças estatisticamente significativas ao comparar 367 pacientes e 290 controles quanto às frequências alélicas, genotípicas e haplotípicas dos polimorfismos rs12778366 e rs3758391 de SIRT1. Entretanto, o SNP rs3758391 não estava em equilíbrio de Hardy-Weingberg, apresentando um excesso de homozigotos CC e TT em ambos pacientes e controles. Após correções para múltiplas comparações, nossos resultados indicam um papel para o alelo rs3758391 T de SIRT1 na morbidade associada ao lúpus. Pacientes com genótipos TT e CT apresentaram uma maior chance de desenvolvimento de nefrite (Pcorr=0,012, OR=2,04 95% IC 1,32 – 3,14) e um maior índice de atividade da doença (Ranking médio 170,95 vs 137,26, Pcorr=0,006) quando comparados a pacientes homozigotos CC. Nossos resultados sugerem que o polimorfismo rs3758391 modifica a morbidade associada ao LES, sendo o alelo rs3758391 T um fator de risco para nefrite e SLEDAI elevado. Não obstante, ainda deve ser elucidado o mecanismo funcional pelo qual a variante rs3758391 de SIRT1 influencia a severidade de LES. / Silent mating type Information Regulator 2 homolog 1 (SIRT1) is a deacetylase protein that participates in several physiological processes with importance in transcriptional silencing, apoptosis, immune system regulation and inflammation. Systemic lupus erythematosus (SLE) is an inflammatory autoimmune disease with multifactorial etiology, characterized by autoantibody production, immune complex deposition and tissue damage. Upregulated expression of SIRT1 on CD4+ T lymphocytes of active SLE patients was already reported and global hypoacetylation of histones H3 and H4, with H3 hypoacetylation correlated with a higher disease activity index. SIRT1 promoter SNPs rs12778366 and rs3758391 may account for differential expression of this molecule, and in the present study, we investigated the role of these variants in SLE susceptibility. No statistically significant differences were observed comparing 367 SLE patients and 290 healthy controls concerning allelic, genotypic or haplotypic frequencies of SIRT1 rs12778366 and rs3758391 polymorphisms. Nevertheless, SIRT1 rs3758391 SNP was not in Hardy-Weinberg equilibrium, presenting an excess of CC and TT homozygotes in both patients and controls. After correction for multiple-comparisons, our results supported a role for SIRT1 rs3758391 T allele in disease morbidity. SLE patients with TT and CT genotypes displayed a higher chance of developing lupus nephritis (Pcorr=0.012, OR=2.04 95% CI 1.32 – 3.14) and presented a higher disease activity index (Mean rank 170.95 vs 137.26, Pcorr=0.006) when compared with CC homozygotes patients. Our results suggest that SNP rs3758391 modifies SLE morbidity, with rs3758391 T allele being a risk factor for nephritis and a higher SLEDAI. Nevertheless, it remains to be elucidated how the SIRT1 rs3758391 variation functionally influences SLE severity.

Introdução: A prolactina (PRL) exerce efeitos imunoestimulatórios in vitro e in vivo, porém a literatura é controversa quanto ao papel deste hormônio na atividade do Lúpus Eritematoso Sistêmico (LES). A macroprolactina possui menor atividade biológica in vivo e poderia explicar os resultados díspares. Objetivos: avaliar a prevalência de hiperprolactinemia e macroprolactinemia em pacientes lúpicas; analisar a correlação entre a atividade do LES e PRL, e interferência da macroprolactina nesta associação. Casuística e Métodos: Em 73 mulheres com LES ativo foi dosada a PRL pelo Immulite 2000®, e a macroprolactina pelo método do Polietilenoglicol (momento 1); em 62 destas pacientes foi colhida uma segunda amostra com a menor atividade do LES ao longo do tratamento (momento 2). Os controles foram 29 mulheres hígidas no menacme (grupo C) e 34 gestantes no terceiro trimestre (grupo G). Resultados: Houve 15 casos (20,55%) de hiperprolactinemia nas lúpicas, e nenhum entre as mulheres hígidas (p = 0,005). Todas as gestantes apresentaram hiperprolactinemia. A concentração de PRL foi maior (Med = 11,70 ng/ml) (p = 0,01) no LES do que no grupo C (Med = 8,81ng/ml), e correlacionou-se com a atividade da doença pelo SLEDAI (r = 0,41; p = 0,0003) no momento 1. No LES muito ativo os níveis de PRL foram maiores do que na doença inativa (Med = 17,10 ng/ml vs. Med = 8,36 ng/ml) (p< 0,01), e moderadamente ativa (Med = 7,75 ng/ml) (p < 0,05). Dentre as lúpicas hiperprolactinêmicas, 04 casos (26,7%) foram devidos à macroprolactina, e nas gestantes, 02 casos (5,9%). O LES foi tão ativo na macroprolactinemia quanto nos casos pela forma monomérica, porém a correlação entre PRL e SLEDAI foi maior para a PRL livre (r = 0,44; p = 0,0001). O tratamento das pacientes lúpicas hiperprolactinêmicas resultou em diminuição da concentração de PRL (Me momento 1 = 56,71 ± 43,87 ng/ml vs. Me momento 2 = 18,68 ± 24,20 ng/ml) (p = 0,015). Conclusões: pacientes lúpicas apresentam hiperprolactinemia mais frequentemente do que mulheres hígidas, e a PRL correlaciona-se com a atividade do LES. A macroprolactinemia não é marcador de doença inativa/pouco ativa. / Introduction: Prolactin (PRL) is a hormone with widespread influences in the cells of the immune system, which have been demonstrated by several in vitro and in vivo studies. However, the role of this hormone in the pathogenesis of Systemic Lupus Erythematosus (SLE) is controversial within the medical literature. The potentially lower biological activity of macroprolactin could explain the disparity of the results. Methods: PRL levels were determined by chemo luminescence method (Immulite 2000®) in 73 women with active SLE (group L), while the screening for macroprolactinemia was determined by the polyethylene glycol precipitation method (first moment). Sixty two of these patients had their PRL levels determined in a second occasion, when the disease was inactive or with the lowest activity observed after treatment (second moment). The control groups were 29 healthy women (group C) and 34 third-trimester healthy pregnant (group P). The levels of PRL were correlated with the SLE Disease Activity Index (SLEDAI). Results: In the study group there were 15 (20.55%) cases of hyperprolactinemia, while in the group C there were none (p = 0,005). All pregnant women presented hyperprolactinemia. Prolactin levels were higher in group L (Med = 11,70 ng/ml) then in group C (Med = 8,81ng/ml) (p = 0,01) and correlated with the SLEDAI in the first moment (r = 0,41; p = 0,0003). We also detected that PRL levels were higher at highly active SLE (SLEDAI ¡Ý 11) than when the disease was inactive (SLEDAI = 0) (Med = 17,10 ng/ml vs. Med = 8,36 ng/ml) (p< 0,01) or moderately active SLE (6 ¡Ü SLEDAI ¡Ü 10) (Med = 7,75 ng/ml) (p<0,05). In the 15 patients of group L with hyperprolactinemia, there were 04 cases of macroprolactinemia (26.7%), while 02 subjects in group P presented it (5.9%). SLE was as active in the patients with hyperprolactinemia caused by the monomeric form of the hormone, as in the ones with macroprolactinemia. The correlation of the PRL levels and the SLEDAI was, nevertheless, stronger for free PRL (r = 0,44; p = 0,0001). The SLE treatment in the hyperprolactinemic patients reduced PRL levels from 56,71 ng/ml (sd = 43,87) to 18,68 ng/ml (± 24,20) (p = 0,015). Discussion: the frequency of hyperprolactinemia is higher in SLE than in the general population, and the levels of PRL correlate with the activity of the disease. Macroprolactin is also associated to active SLE.

Introducción: Los pacientes con lupus eritematoso sistémico (LES) presentan un riesgo incrementado de morbilidad cardiovascular, relacionado a factores de riesgo cardiovasculares clásicos y factores propios de la enfermedad y del tratamiento. Objetivo: Determinar los factores asociados a síndrome metabólico en pacientes con LES. Diseño: Estudio transversal, observacional, de asociación. Lugar: Servicio de Reumatología, Hospital Guillermo Almenara Irigoyen, EsSalud. Población: Pacientes con diagnóstico de LES, atendidos en el servicio de Reumatología entre enero de 2012 y junio de 2013 que cumplieron los criterios de inclusión y exclusión. Intervenciones: Se realizó una entrevista, examen físico y revisión de historia clínica, para obtener los datos de presencia o ausencia de síndrome metabólico, factores de riesgo cardiovasculares clásicos, evaluación de actividad y daño asociado a LES, y tratamientos recibidos. Principales medidas de resultados: Se realizó el test exacto de Fisher o la u de Mann-Withney para determinar que variables se encuentran asociadas al síndrome metabólico. Posterior a ello, se realizó una regresión logística binaria con método de step-down. Resultados: Fueron incluidos 206 pacientes, 85 (41.3%) pacientes tuvieron síndrome metabólico. Luego del análisis multivariado, las variables que permanecían asociadas con el síndrome metabólico fueron la edad (OR 1.04; p: 0.004), el ácido úrico (OR 1.80, p<0.001) y un mayor porcentaje de grasa subtotal (OR 1.09, p: 0.002). Conclusiones: En el presente estudio se ha encontrado que la edad, el nivel de ácido úrico y el porcentaje de grasa subtotal se encuentran asociados con una mayor prevalencia de síndrome metabólico en pacientes con LES. / Tesis

El objetivo del estudio fue determinar la incidencia de reacciones adversas medicamentosas (RAM) producidas por el uso de ciclofosfamida endovenoso (CFA- EV) en un grupo de 30 pacientes con Lupus Eritematoso Sistémico en el Servicio de Reumatología del Hospital Nacional Guillermo Almenara Irigoyen que iniciaron el tratamiento entre enero de 1999 a diciembre del 2001, los datos se obtuvieron por la evaluación de las historias clínicas entre los meses de junio a septiembre del 2002 determinándose que el 100% de los pacientes presentaron RAM. La leucopenia fue la RAM más frecuente presentándose en el 76,7% de los pacientes durante el tratamiento. Utilizando el Algoritmo de Decisión aplicado por el Centro Nacional de Farmacovigilancia e Información de Medicamentos de la Dirección General de Medicamentos, Insumos y Drogas del Ministerio de Salud (CENAFIM – DIGEMID – MINSA), determinamos que del total de las RAM identificadas el 38,2% fueron de causa definida y el 58,4% corresponde a RAM serias. El medico clínico tuvo que suspender definitivamente el tratamiento con CFA-EV a 9 de los 30 pacientes, por presentar RAM severas. A través de la medida de asociación estadística Odds Ratio se determinó que existe relación entre las dosis administradas por superficie corporal de CFA-EV y la presencia de náuseas, vómitos y leucopenia. Se propone una guía para el manejo de las RAM a CFA-EV en los pacientes con LES, elaborada en base a la experiencia recogida durante nuestro estudio. / The goal of this study was to determine the effect of drug adverse reactions (DAR) produced by the use of intravenous cyclophosphamide in a group of 30 patients with Systemic Lupus Erythematosus (SLE) in the Rheumatology's Service of the National Hospital Guillermo Almenara Irigoyen from Lima-Perú. These patients initiated the treatment between January 1999 to December 2001, the information was obtained by the evaluation of the clinical histories between June to September 2002. We determined that 100 % of the patients presented DAR. The leucopenia was the most frequent DAR appearing in 76,7 % of the patients during the treatment. Using the Algorithm of Decision applied by Farmacovigilancia's National Center and Information of Dirección General de Medicamentos, Insumos y Drogas - Ministerio de Salud (CENAFIM - DIGEMID - MINSA), of the identified DARs, 38,2 % was from definite cause and 58,4 % corresponds to serious DAR The clinical doctor had to suspend definitively the treatment with intravenous cyclophosphamide to 9 of 30 patients, for presenting severe RAM. By the measurement of statistical association Odds Ratio we determined that it exists relation between the administered doses by cyclophosphamide's corporal surface and the presence of nauseas, vomits and leucopenia. We propose a guide for the managing of DAR to intravenous cyclophosphamide in patients with SLE, elaborated on the basis of the experience gathered along the present study. / Tesis