Orientadores: Simone Appenzeller, Lilian Tereza Lavras Costallat / Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas / Made available in DSpace on 2018-08-25T13:51:27Z (GMT). No. of bitstreams: 1 Peres_FernandoAugusto_M.pdf: 1437476 bytes, checksum: a879071e9da761defaf00fb710eaf9b4 (MD5) Previous issue date: 2014 / Resumo: Lúpus Eritematoso Sistêmico (LES) é uma doença autoimune, crônica e mutissistêmica, caracterizada por períodos de atividade e remissão. Manifestações neuropsiquiátricas ocorrem em 12-95% dos pacientes, dependendo dos critérios diagnósticos aplicados e estão associadas a uma elevada morbi-mortalidade. Vários anticorpos têm sido relacionados com manifestações neuropsiquiátricas no LES, os mais frequentemente associados são anticorpo antifosfolípides, um subtipo de dupla-fita DNA e anticorpo anti-P ribossomal. Estudos recentes têm demonstrado a alta especificidade do anti-P ribossomal para o LES podendo ser também um marcador para atividade de doença. Anti-P ribossomal são capazes de se ligar em células neuronais em áreas relacionadas com o sistema límbico que são associadas ao olfato. Os objetivos deste trabalho foram analisar a prevalência de distúrbio olfatório no LES, correlacionar essas alterações olfatórias a alterações de humor, ansiedade, presença de manifestações neuropsiquiátricas e atividade e dano da doença e associar os níveis de anti-P ribossomal com distúrbios olfatórios, presença de manifestações neuropsiquiátricas e atividade da doença. Foram selecionados pacientes com diagnóstico de LES, seguidos no ambulatório de reumatologia do HC-UNICAMP, no período de março de 2011 a dezembro de 2013. O grupo controle foi constituído por voluntários sadios com idade e gênero semelhantes aos do grupo de pacientes com LES, que não apresentavam histórico de doenças autoimunes ou alérgicas, sem alterações de vias aéreas superiores e sem histórico de uso de drogas inalantes. Foram incluídos 120 pacientes com LES, e 135 voluntários sadios. Ansiedade foi encontrada em 67,5% dos pacientes e em 39,2% dos controles e depressão foi identificada em 46,6% dos pacientes e em 28,8% dos controles. Alteração olfatória foi observada em 51,6% dos pacientes e em 29,6% dos controles. O anti-P ribossomal foi identificado exclusivamente em pacientes e estava presente em 13 (10,8%) deles. Alteração olfatória foi associada com LES; pacientes tiveram médias significativamente menores nas três fases da avaliação olfatória e, consequentemente, no somatório total do teste (LDI). A alteração olfatória ainda se associou inversamente com ansiedade (p=0,004; R= -0,18), depressão (p=0,01; R= -0,232), dano da doença (p=0,002; R=-0,282) e maior idade (p<0,001; R= -0.353). Não encontramos associação entre alteração olfatória, sexo ou atividade da doença (p=0,891 e p=0,914, respectivamente). O LDI se correlacionou com histórico de manifestações NP, sendo que pacientes com manifestações NP tinham média de LDI de 28,35 (DP±5,30) pontos, enquanto que pacientes sem manifestações NP tinham média de LDI de 30,8 (DP±4,51) pontos (p<0,05). O Anti-P ribossomal não foi associado com a presença de manifestações NP (p=0,730), porém quando analisamos os subitens classificatórios de manifestações NP separadamente, observamos associação entre anti-P ribossomal positivo e psicose (p<0,05). Observamos ainda associação do anti-P ribossomal com atividade da doença. Não observamos outras associações com anti-P ribossomal. Concluímos que pacientes apresentam uma significativa diminuição do olfato quando comparados a controles sadios, que se associa com histórico de manifestações neuropsiquiátricas, ansiedade, depressão, dano da doença e maior idade. Os anticorpos anti-P ribossomais estavam presentes exclusivamente em pacientes e se associou com psicose e atividade da doença / Abstract: Systemic lupus erythematosus (SLE) is an autoimmune, chronic, multisystemic disorder characterized by periods of activity and remission. Neuropsychiatric manifestations occur in 12-95 % of SLE patients, depending on the diagnostic criteria applied and are associated with a high morbidity and mortality. Several antibodies have been associated with neuropsychiatric manifestations in SLE. These antibodies are more often associated with antiphospholipid antibody, a subtype of double-stranded DNA and antiribosomal P antibodies. Recent studies have demonstrated the high specificity of antiribosomal P antibodies for SLE, suggesting that antiribosomal P antibodies may be a biomarker for disease activity. Antiribosomal P antibodies are able to bind to neuronal cells in areas of the limbic system which are responsible to the olfactory. The objectives of this study were to analyze the prevalence of olfactory disorder in SLE, to correlate olfactory changes to mood disorders, anxiety, presence of neuropsychiatric manifestations, disease activity and damage, and also to associate of the presence of antiribosomal P antibodies with olfactory disorders, presence of neuropsychiatric manifestations and disease activity. One hundred and twenty SLE patients included in the study were followed at the outpatient rheumatology UNICAMP, from March 2011 to December 2013. The control group was consisted of 135 healthy volunteers matched by age and sex. They had no history of autoimmune or allergic diseases, with no changes in upper airway and no history of use of inhalant drugs. Anxiety was observed in 67.5 % SLE patients and in 39.2% controls. Depression was identified in 46.6 % SLE patients and in 28.8% controls. Olfactory changes were observed in 51.6 % SLE patients and in 29.6 % controls. Anti-ribosomal P antibodies were identified exclusively in SLE patients and were present in 13 (10.8%) of them. Olfactory changes had significantly lower averages in all three phases of the olfactory evaluation and, consequently, in the total sum test (LDI). The olfactory also inversely associated with anxiety (p = 0.004, R = -0.18), depression (p = 0.01, R = -0.232), cumulative damage (p = 0.002 R = -0.282) and age (p <0.001 , R = -0.353). We did not observe an association between olfactory changes and gender or disease activity (p = 0.891 and p = 0,914), respectively. The TDI was correlated with a CNS involvement, and patients with NPC [mean of 28.35 (SD ± 5.30] points, whereas patients without CNS involvement had a mean TDI of 30.8 (SD ± 4.51) points (p < 0.05). Antiribosomal P antibodies were not associated with the presence of CNS involvemnt (p = 0.730), but when we analyzed each subitem of CNS involvement separately, we observed an association between the presence of antiribosomal P antibodies and psychosis (p < 0.05). We also observed an association between antiribosomal P antibodies and disease activity (p < 0.05). We concluded that SLE patients show a significant decrease of smell when compared to healthy controls. Olfactory changes are associated with a history of neuropsychiatric symptoms, anxiety, depression, cumulative damage, and older age. Antiribosomal P antibodies were exclusively observed in SLE patients compared to healthy controls and were associated with psychosis and disease activity / Mestrado / Clinica Medica / Mestre em Clinica Medica

published_or_final_version / Social Work / Master / Master of Social Work

published_or_final_version / Social Work / Master / Master of Social Work

published_or_final_version / Medicine / Doctoral / Doctor of Philosophy

Objective: to assess the prevalence of rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) and spondyloarthropathy (SpA) in Vilnius, Lithuania. Methods: 3 prevalence studies were conducted: 1. Registry-based study of the prevalence of RA and SLE; 2. Population-based study of the prevalence of RA and SLE (interview conducted by mail); 3. Poulation-based study of the prevalence of RA and SpA (interview conducted by telephone). Results: according to the Vilnius RA and SLE registry, the prevalence of RA in Vilnius at the end of year 2004 was 0,14% (95% CI 0,13-0,15), and the prevalence of SLE was 0,0174% or 17,4/100 000 (95% CI 0,0137-0,0218). The population-based study, conducted by mail, revealed 15 RA and 2 SLE cases, accounting for a prevalence rate of RA of 0,37% (95% CI 0,21-0,62), and a prevalence of SLE rate of 0,0498% (95% CI 0,006-0,180). The standardized prevalence rate according to age and sex in the Vilnius population showed an RA prevalence of 0,32% (95% CI 0,18-0,57). The population-based study, conducted be telephone, detected 16 RA and 13 SpA cases, resulting in a crude prevalence of 0,76% (95% CI 0,44-1,24) for RA and 0,62% (95% CI 0,33-1,06) for SpA. The standardized prevalence rate according to age and sex in the Vilnius population showed an RA prevalence of 0,51% (95% CI 0,29-0,96) and a SpA prevalence of – 0,75% (95% CI 0,38-1,40). / Darbo tikslas: nustatyti reumatoidinio artrito (RA), seronegatyvių spondiloartropatijų (SpA) bei sisteminės raudonosios vilkligės (SRV) paplitimą Vilniaus mieste. Darbo metodika: Buvo atlikti 3 tyrimai: 1. RA ir SRV paplitimo Vilniaus mieste apskaičiavimas, remiantis Vilniaus miesto RA ir SRV sergančių asmenų duomenų baze; 2. RA ir SRV paplitimo Vilniaus mieste populiacinis tyrimas, apklausiant Vilniaus miesto gyventojus paštu; 3. RA ir SpA paplitimo Vilniaus mieste populiacinis tyrimas, apklausiant Vilniaus miesto gyventojus telefonu. Rezultatai: remiantis Vilniaus miesto RA ir SRV sergančiųjų duomenų baze, RA paplitimas Vilniaus mieste 2004m. pabaigoje buvo 0,14% (95% PI 0,13-0,15). Apskaičiuotas SRV paplitimas Vilniuje 2004m. pabaigoje buvo 0,0174% arba 17,4/100 000 gyventojų (95% PI 0,0137-0,0218). Atlikus RA ir SRV paplitimo tyrimą (apklausą paštu), nustatyta, kad RA paplitimas Vilniuje yra 0,37% (95% PI 0,21-0,62), o SRV paplitimas – 0,0498% (95% PI 0,006-0,180). RA paplitimas buvo standartizuotas pagal amžių ir lytį, remiantis 2004m. pradžios Vilniaus miesto populiacija, apskaičiuotas standartizuotas RA paplitimas yra 0,32% (95% PI 0,18-0,57). Atlikus RA ir SpA paplitimo tyrimą (apklausą telefonu), apskaičiuotas RA paplitimas buvo 0,76% (95% PI 0,44-1,24), o SpA paplitimas - 0,62% (95% PI 0,33-1,06). RA ir SpA paplitimas buvo standartizuotas pagal amžių ir lytį, remiantis 2004m. pradžios Lietuvos populiacija, apskaičiuotas standartizuotas RA paplitimas yra 0,51% (95%... [toliau žr. visą tekstą]

Darbo tikslas: nustatyti reumatoidinio artrito (RA), seronegatyvių spondiloartropatijų (SpA) bei sisteminės raudonosios vilkligės (SRV) paplitimą Vilniaus mieste. Darbo metodika: Buvo atlikti 3 tyrimai: 1. RA ir SRV paplitimo Vilniaus mieste apskaičiavimas, remiantis Vilniaus miesto RA ir SRV sergančių asmenų duomenų baze; 2. RA ir SRV paplitimo Vilniaus mieste populiacinis tyrimas, apklausiant Vilniaus miesto gyventojus paštu; 3. RA ir SpA paplitimo Vilniaus mieste populiacinis tyrimas, apklausiant Vilniaus miesto gyventojus telefonu. Rezultatai: remiantis Vilniaus miesto RA ir SRV sergančiųjų duomenų baze, RA paplitimas Vilniaus mieste 2004m. pabaigoje buvo 0,14% (95% PI 0,13-0,15). Apskaičiuotas SRV paplitimas Vilniuje 2004m. pabaigoje buvo 0,0174% arba 17,4/100 000 gyventojų (95% PI 0,0137-0,0218). Atlikus RA ir SRV paplitimo tyrimą (apklausą paštu), nustatyta, kad RA paplitimas Vilniuje yra 0,37% (95% PI 0,21-0,62), o SRV paplitimas – 0,0498% (95% PI 0,006-0,180). RA paplitimas buvo standartizuotas pagal amžių ir lytį, remiantis 2004m. pradžios Vilniaus miesto populiacija, apskaičiuotas standartizuotas RA paplitimas yra 0,32% (95% PI 0,18-0,57). Atlikus RA ir SpA paplitimo tyrimą (apklausą telefonu), apskaičiuotas RA paplitimas buvo 0,76% (95% PI 0,44-1,24), o SpA paplitimas - 0,62% (95% PI 0,33-1,06). RA ir SpA paplitimas buvo standartizuotas pagal amžių ir lytį, remiantis 2004m. pradžios Lietuvos populiacija, apskaičiuotas standartizuotas RA paplitimas yra 0,51% (95%... [toliau žr. visą tekstą] / Objective: to assess the prevalence of rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) and spondyloarthropathy (SpA) in Vilnius, Lithuania. Methods: 3 prevalence studies were conducted: 1. Registry-based study of the prevalence of RA and SLE; 2. Population-based study of the prevalence of RA and SLE (interview conducted by mail); 3. Poulation-based study of the prevalence of RA and SpA (interview conducted by telephone). Results: according to the Vilnius RA and SLE registry, the prevalence of RA in Vilnius at the end of year 2004 was 0,14% (95% CI 0,13-0,15), and the prevalence of SLE was 0,0174% or 17,4/100 000 (95% CI 0,0137-0,0218). The population-based study, conducted by mail, revealed 15 RA and 2 SLE cases, accounting for a prevalence rate of RA of 0,37% (95% CI 0,21-0,62), and a prevalence of SLE rate of 0,0498% (95% CI 0,006-0,180). The standardized prevalence rate according to age and sex in the Vilnius population showed an RA prevalence of 0,32% (95% CI 0,18-0,57). The population-based study, conducted be telephone, detected 16 RA and 13 SpA cases, resulting in a crude prevalence of 0,76% (95% CI 0,44-1,24) for RA and 0,62% (95% CI 0,33-1,06) for SpA. The standardized prevalence rate according to age and sex in the Vilnius population showed an RA prevalence of 0,51% (95% CI 0,29-0,96) and a SpA prevalence of – 0,75% (95% CI 0,38-1,40).

Autoimmune diseases are clinical manifestations of a loss-of-tolerance of the immune system against the body’s own substances and healthy tissues. Primary Sjögren’s syndrome (pSS) and systemic lupus erythematosus (SLE) are two chronic inflammatory autoimmune diseases characterized by autoantibody production and an activated type I interferon system. Although the precise mechanisms leading to autoimmune processes are not well defined, recent studies suggest that aberrant DNA methylation and gene expression patterns may play a central role in the pathogenesis of these disorders. The aim of this thesis was to investigate DNA methylation and gene expression in pSS and SLE on a genome-wide scale to advance our understanding of how these factors contribute to the diseases and to identify potential biomarkers and novel treatment targets. In study I, differential DNA methylation was analyzed in multiple tissues from pSS patients and healthy controls. We identified thousands of CpG sites with perturbed methylation; the most prominent finding was a profound hypomethylation at regulatory regions of type I interferon induced genes in pSS. In study II, a cases-case study comparing DNA methylation in pSS patients with high fatigue to patients with low fatigue, we found methylation patterns associated to the degree of fatigue. In study III, RNA-sequencing was applied to investigate the transcriptome of B cells in pSS in comparison to controls. Increased expression of type I and type II interferon regulated genes in pSS was observed, indicating ongoing immune activation in B cells. In study IV, the impact of DNA methylation on disease susceptibility and phenotypic variability in SLE was investigated. We identified DNA methylation patterns associated to disease susceptibility, SLE manifestations and different treatments. In addition, we mapped methylation quantitative trait loci and observed evidence for genetic regulation of DNA methylation in SLE.   In conclusion, the results presented in this thesis provide new insights into the molecular mechanisms underlying autoimmunity in pSS and SLE. The studies confirm the central role of the interferon system in pSS and SLE and further suggest novel genes and mechanisms to be involved in the pathogenesis these autoimmune diseases.

Two novel B cell populations were characterized in peripheral blood of patients with common variable immunodeficiency and healthy controls were observed using flow cytometry in the study supported by the grant IGA MZ ČR NKT11414-3. These B cell populations were defined as CD19+ CD27- CD21+ CD38low CD24+ IgM+ FO I and CD19+ CD27- CD21+ CD38low CD24++ IgM++ cells. Since none of found populations has ever been described, the aim of this thesis was to characterize these populations with focus on analysis of variable regions of the heavy chains of immunoglobulins and genes coding proteins participating in the process of VHDHJH formation (Rag 1, Rag 2, and TdT) produced by cells of these populations. Flow cytometry, single cell sorting, single-cell RT-PCR, IgVH, Rag 1, Rag 2, and TdT specific PCR amplification and cycle sequencing were employed to perform the molecular analysis in individual B lymphocytes. Both populations in two patients with common variable immunodeficiency, two healthy controls, and in two patients with autoimmune diseases - rheumatoid arthritis and systemic lupus erythematosus (as the disease control) - were examined. Finally, the statistical analysis was used to evaluate the differences in expression of variable regions of the heavy chains of immunoglobulins and in Rag1 and 2, and...

Introduktion: Systemisk Lupus Erythematosus är en prototypisk autoimmun sjukdom som gör att immunförsvarets antikroppar angriper kroppens egna vävnader, vilket leder till kronisk inflammation i kroppens organsystem. Idag finns ingen verksam behandling för Systemisk Lupus Erythematosus. Syftet med denna studie var att undersöka hur Dvitamintillskott påverkar Systemisk Lupus Erythematosus. Metod: Artiklarna hittades i databasen ”Pubmed” med sökningen ”Systemic Lupus Erythematosus and vitamin D supplementation”. Bland sökresultaten fanns sex relevanta artiklar som hade undersökt effekten av D-vitamintillskott på SLE. Resultat: Mer än hälften av patienterna i samtliga studier nådde serum 25(OH) D-nivåer som ansågs vara tillräckliga. D-vitamintillskottet minskade Th1/Th17-cellerna men ökade också Treg-celler och Th2-celler. Tre studier visade sig ha en signifikant minskning i sjukdomsaktivitet och anti-dsDNA antikroppar. Komplement C3 minskade i studie 2. Diskussion: Fem av studierna tyder på att oral administrering av D-vitamin tillskott har gett positiv inverkan på SLE. Två av de granskade studierna rapporterades inge positiv klinisk effekt hos deltagarna. Slutsats: D-vitamintillskott dämpar immunsystemet genom att öka Treg-celler och Th-2-celler men även minska Th1/Th17-celler och B-celler samt produktionen av autoantikroppar och anti-dsDNA-antikroppar. Effekten av D-vitamintillskott på komplement C3 och C4 är oklar. Det krävs dock fler studier med fler deltagarantal för att dra en slutsats om Dvitamintillskott kan användas som behandling för SLE. / Background: Systemic Lupus Erythematosus is a prototypical autoimmune disease in which antibodies attack healthy tissues in the body, causing inflammation in several organs. Aim: The aim of this literature study was to investigate the effect of Vitamin Dsupplementation on SLE. Method: The articles were searched in the database called ”Pubmed” using the search terms ”Systemic Lupus Erythematosus and Vitamin D supplementation”. Six of the articles which examined the effects of D-vitamin supplementation on SLE were relevant for this study. Result: More than half of the patients in all six studies reached sufficient serum 25(OH)D. Vitamin D-supplement reduced Th1/Th17-cells but increased Tregs-cells and Th2-cells. 3 studies showed a decrease in disease-activity and anti-dsDNA. C3 decreased in study 2. Discussion: Five studies indicated that the oral administration of vitamin-D supplementation had a positive effect on SLE. Two of the examined studies did not observe any clinical effect of the vitamin-D supplement. Conclusion: Vitamin-D supplement suppresses the immunesystem by increasing Treg cells and Th-2 cells but also reducing Th1/Th17-cells and B-cells as well as the production of autoantibodies and anti-dsDNA antibodies. The effect of vitamin D-supplement is unclear. More studies with more participants are required to determine if vitamin-D supplement can be used as a treatment for SLE.

OBJETIVO. Identificar fatores preditivos para o desenvolvimento da osteonecrose (ONA) em pacientes com Lúpus Eritematoso Sistêmico (LES) de diagnóstico recente. METODOLOGIA. Quarenta e seis pacientes consecutivos, de uma coorte informatizada no ambulatório de LES do serviço de Reumatologia do Hospital das Clínicas de São Paulo, participaram deste protocolo que ocorreu entre julho de 2004 e julho de 2005. Os critérios de inclusão foram: pacientes do sexo feminino; menos de cinco anos de diagnóstico de LES; e idade maior que 18 anos. Todas as pacientes foram submetidas à ressonância nuclear magnética (RNM) dos quadris para o diagnóstico de ONA, independente da sintomatologia. Variáveis clínicas foram obtidas através de prontuários médicos, entrevista e exame clínico. Variáveis laboratoriais incluíram: lipoproteínas séricas, auto-anticorpos, fatores trombofílicos e de hipofibrinólise. Densidade mineral óssea foi medida através da densitometria de dupla emissão de raios-X. Fraturas vertebrais foram investigadas através da realização de radiografias da coluna. RESULTADOS. A ONA foi encontrada em 10 das 46 pacientes. Idade, duração de doença e raça não diferiram entre pacientes lúpicas com e sem ONA. Comparações envolvendo as várias manifestações clínicas do LES, perfil lipoprotéico e de auto-anticorpos, freqüência de trombofilia e hipofibrinólise também não foram estatisticamente diferentes entre os grupos. A freqüência de pacientes com SLEDAI ?8 no ano anterior ao diagnóstico clínico de ONA foi significativamente maior (60%) do que no grupo sem ONA considerando-se o ano anterior à entrada no estudo (19,4%), p=0,011. Corroborando com esse achado, a dose cumulativa de glicocorticóide (GC) utilizada no anterior ao diagnóstico de ONA foi maior quando comparada ao ano anterior à entrada no estudo(p=0,045). Não foram observadas diferenças com relação aos dados densitométricos e radiográficos da coluna. Na análise multivariada somente o SLEDAI permaneceu como fator de risco independente para ONA (OR=6,6, IC=1,07-41,29, p=0,042). CONCLUSÃO. Este estudo revela que a atividade de doença no ano anterior ao diagnóstico clínico de ONA é fator de risco preponderante para o desenvolvimento desta complicação no LES recente. / OBJECTIVE. To evaluate predictive factors for osteonecrosis (ON) development in patients with early Systemic Lupus Erythematosus (SLE). METHODS. Forty-six consecutive SLE patients from an electronic cohort in a Lupus Clinic from the Rheumatology Division in the University of São Paulo were enrolled on this study that occurred between July 2004 and July 2005. Inclusion criteria were female gender, age > 18 years-old and less than 5 years of disease duration. All patients underwent magnetic resonance imaging (MRI) of the hips for ON diagnosis irrespective of symptoms. Clinical variables were obtained through medical records, interview and physical examination. Laboratory variables were: serum lipoproteins, autoantibodies profile, trombophilia and hypofibrinolysis factors. Bone mineral density was acquired through dual energy x-ray absorptiometry. Vertebral fractures were investigated by spine X-rays. RESULTS. ON was found in 10 of 46 patients. Age, disease duration and race did not differ between patients with and without ON. The frequency of clinical features, lipoprotein and auto-antibodies profile and frequency of trombophilia and hypofibrinolysis were also alike in the two groups. Importantly, disease activity (frequency of patients with SLEDAI ?8) in the previous year of ON clinical diagnosis was significantly higher when compared to patients without ON in the previous year of study entrance (60.0% vs. 19.4%, p=0.011). Reinforcing this finding, glucocorticoid cumulative dose used in the previous year of ON diagnosis was also higher compared to SLE without ON in the previous year of study entrance (p=0.045). Differences concerning the densitometric and radiographic data were not observed. Remarkably, in the multivariate analysis only SLEDAI remained as an independent risk factor for ON (OR=6.6, CI=1.07-41.29, p= 0.042). CONCLUSION. This study has clearly revealed that disease activity in the previous year of ON clinical diagnosis is the main predictor factor for the development of this complication in early SLE.