Background Rheumatoid arthritis (RA) is a systemic progressive destructive joint disease with an increased risk for co-morbidity and premature death if untreated. Cardiovascular disease (CVD) is the main cause of death but also other co-morbid conditions contribute to the patient’s shorter life expectancy. Inflammation is important for the development of CVD, but knowledge of its relationship with other co-morbidities is sparse. Early disease modifying anti rheumatic drugs (DMARDs) can suppress disease activity and improve the long-term outcome. The aim of this thesis was to evaluate prospectively aspects of disease activity and severity in a large cohort of patients with early RA. Predictive and prognostic markers, e.g., antibodies against citrullinated proteins/peptides (ACPAs), occurring in early disease and with implications for disease outcome and co-morbidity were evaluated. Methods Patients with early RA (i.e., symptomatic for ≤12 months) have, since December 1995, been consecutively included in a large survey of prospective and observational studies on the progression of RA and the development of co-omorbidity. Autoantibodies, inflammatory, genetic markers and radiographs have been analyzed. In paper I, 210 RA patients and 102 controls were followed regularly for two years. The predictive value of four different ACPAs in relation to disease activity and radiological progression was evaluated. In Paper II (n = 700) and in Papers III-IV (n =950), patients with early RA from the four northern-most counties of Sweden were followed regularly for 5 years. Data on risk factors and co-morbidity was collected, according to the study protocol, from clinical records and self-reported questionnaires from patients at inclusion into the study cohort and after five years. The predictive value of traditional and potential disease related risk factors for new cardiovascular events (CVE) was evaluated (II). In Paper III, the impact of age at the onset RA, stratified as being young onset RA (<58 years; YORA) and late onset RA (≥58 years; LORA) on disease activity, severity and chosen treatment, was evaluated. In Paper IV, the development of new co-morbidities after RA onset and their relation to inflammatory activity was assessed. Results The presence of anti-mutated citrullinated vimentin (MCV ) antibodies was associated with a more severe disease course, estimated by disease activity score, erythrocyte sedimentation rate (ESR) and swollen joint count after 24 months, compared with anti-CCP2, anti-CCP3, and anti CCP3.1 antibodies. In Paper II, the incidence of a new CVE during 5 years was explained by several of the traditional CV risk factors, and potentiated by a high disease activity. Treatment with DMARDs decreased the risk. In Paper III, LORA patients were associated with greater disease activity/severity at disease onset and over time compared with YORA who were more often ACPA positive. YORA patients were treated earlier with DMARDs, whilst LORA patients were more often treated with corticosteroids and less so with DMARDs early in the course of their disease. In Paper IV, 53%of patients already had one or more co-morbidities already at the onset of RA. After 5 years, 41% of the patients had developed at least one new co-morbidity. ESR at baseline and accumulated disease activity were associated with a new co-morbidity after five years. Conclusion Early RA patients sero-positive for anti- MCV antibodies appeared to have a higher disease activity over time. The occurrence of a new CVE in early RA patients was predicted by traditional risk factors for CVD which were potentiated by a high disease activity. Treatment with DMARDs decreased the risk. Patients with young onset of RA were associated with a higher frequency of ACPA. Late onset of RA was associated with higher disease activity/severity at inclusion and over time. However, LORA patients were more often treated with corticosteroids and less so with DMARDs early in the disease course. Development of a new co-morbidity during the five years following diagnosis was related to ESR.

<p>In the present studies, aspects of some disease activity measures in rheumatoid arthritis (RA) have been investigated, including the effect of glucocorticoids on this activity. In RA, serum interleukin(IL)-6 levels were elevated and were shown to have a circadian rhythm, with peak levels in the morning, declining towards low or normal levels in the afternoon and evening. In contrast, serum levels of tumour necrosis factor(TNF) alpha were low and stable. In other connective tissue diseases, serum TNF alpha levels were elevated but without circadian variation, while IL-6 levels were low and stable. Nocturnal administration (at 2:00 a.m.) of low-dose prednisolone a few hours before the early morning peak of IL-6 was shown to be significantly more effective in reducing clinical symptoms of disease activity and serum IL-6 levels than the traditional morning administration (at 7:30 a.m.) of the same dose of prednisolone. Circulating monocytes are activated in RA, expressing receptors related to adhesion and phagocytosis. Treatment with glucocorticoids suppressed the expression of these receptors on monocytes, and this may be one mechanism of the beneficial effect of glucocorticoids in RA. Endogenous levels of cortisol seem to play a minor role in expression of monocyte receptors. The different acute phase markers used to assess disease activity in RA showed good corrrelations with each other and with serum IL-6 levels. There were especially strong corrrelations between C-reactive protein (CRP) and Serum amyloid protein A (SAA), and between fibrinogen and erythrocyte sedimentation rate (ESR). Fibrinogen and CRP showed stronger correlation than ESR with the Modified Health Assessment Questionnaire (MHAQ) score and with the neutrophil count. Four simple objective function tests were each compared with the HAQ score a with a radiological joint damage score (Larsen score). The objective function tests correlated with the MHAQ score, and each of these two methods of assessing physical disability correlated with pain, CRP and ESR. In addition, most of the objective function tests correlated significantly with radiological joint damage, while the MHAQ score did not.</p>

In the present studies, aspects of some disease activity measures in rheumatoid arthritis (RA) have been investigated, including the effect of glucocorticoids on this activity. In RA, serum interleukin(IL)-6 levels were elevated and were shown to have a circadian rhythm, with peak levels in the morning, declining towards low or normal levels in the afternoon and evening. In contrast, serum levels of tumour necrosis factor(TNF) alpha were low and stable. In other connective tissue diseases, serum TNF alpha levels were elevated but without circadian variation, while IL-6 levels were low and stable. Nocturnal administration (at 2:00 a.m.) of low-dose prednisolone a few hours before the early morning peak of IL-6 was shown to be significantly more effective in reducing clinical symptoms of disease activity and serum IL-6 levels than the traditional morning administration (at 7:30 a.m.) of the same dose of prednisolone. Circulating monocytes are activated in RA, expressing receptors related to adhesion and phagocytosis. Treatment with glucocorticoids suppressed the expression of these receptors on monocytes, and this may be one mechanism of the beneficial effect of glucocorticoids in RA. Endogenous levels of cortisol seem to play a minor role in expression of monocyte receptors. The different acute phase markers used to assess disease activity in RA showed good corrrelations with each other and with serum IL-6 levels. There were especially strong corrrelations between C-reactive protein (CRP) and Serum amyloid protein A (SAA), and between fibrinogen and erythrocyte sedimentation rate (ESR). Fibrinogen and CRP showed stronger correlation than ESR with the Modified Health Assessment Questionnaire (MHAQ) score and with the neutrophil count. Four simple objective function tests were each compared with the HAQ score a with a radiological joint damage score (Larsen score). The objective function tests correlated with the MHAQ score, and each of these two methods of assessing physical disability correlated with pain, CRP and ESR. In addition, most of the objective function tests correlated significantly with radiological joint damage, while the MHAQ score did not.

Introdução: A artrite reumatoide (AR) é uma doença auto imune e crônica que provoca inflamação articular e sistêmica, afetando cerca de 0,5 a 1% da população adulta. A mesma está associada à alta morbidade e ao aumento da mortalidade principalmente devido à doença cardiovascular. Entende-se por Síndrome Metabólica (SM) um conjunto de distúrbios metabólicos, que se correlaciona com a obesidade e sedentarismo, porém ainda não há uma definição aceita universalmente. Sabe-se que a mesma tem como característica um grupo de aspectos clínicos e laboratoriais, onde estão incluídas a obesidade central, níveis reduzidos de HDL, níveis elevados de triglicerídeos, aumento da pressão arterial e hiperglicemia. Objetivos: Avaliar a prevalência da SM, numa coorte de pacientes com AR e sua relação com fatores específicos da doença. Métodos: Foi estudada uma coorte prospectiva com 283 pacientes portadores de AR, em acompanhamento no Ambulatório de Reumatologia do Hospital de Clínicas de Porto Alegre entre 2008 e 2016. Destes, 187 indivíduos, mantiveram acompanhamento neste mesmo ambulatório e concordaram em serem reavaliados no período entre janeiro e novembro de 2016. A SM foi definida de acordo com o National Cholesterol Education Program (NCEP). A atividade da doença foi avaliada através do Disease Activity Score (DAS28). Além disso, foram realizadas avaliação clínica, bioquímica e antropométrica dos pacientes. Para as análises estatísticas foi utilizado o Statistical Package for Social Sciences (SPSS) versão 21.0, o teste de Kolmogorov-Smirmov, para constatar a normalidade das variáveis quantitativas ,bem como para a definição dos teste paramétricos e não-paramétricos. Foram construídos os deltas das variáveis estudadas, utilizando-se a diferença entre as duas avaliações. A representação das variáveis quantitativas foram analisadas pela média e desvio padrão ou mediana e amplitude interquartílica. O teste de t de Studant foi utilizado para comparar os dois tempos de avaliação para as amostras pareadas. Ocorrendo assimetria o teste de Wilcoxon foi aplicado. As variáveis categóricas foram analisadas pelo teste de Mc Nemar. A Análise de Variância (ANOVA) em conjunto com o teste de Tukey foram utilizados para comparar a média entre os quatro grupos de Síndrome Metabólica. Os testes de Kruskal-Wallis e de Dunn foram usados, respectivamente, em caso de assimetria. Recorremos ao teste do qui-quadrado de Person para a comparação das variáveis categóricas . Para a verificação do grau de relação entre as variáveis aplicamos a Correlação de Pearson. A Regressão de Poisson multivariada foi utilizada para os fatores confundidores, neste estudo, consideramos a idade dos pacientes. Resultados: A prevalência de SM na primeira avaliação era de 43,9% e, e após 8 anos, passou a ser de 59,4%. Diminuição da circunferência da cintura, diminuição das PAs, triglicerídeos elevados e HDL baixo foram os componentes de SM mais freqüentemente.O DAS28 foi significativamente menor na reavaliação (p = 0,006). Conclusão: A prevalência de SM foi maior nos pacientes acompanhados no final de 8 anos, entretanto,a atividade da doença,e os níveis pressórios diminuíram neste período. O uso de corticóide foi menor ao final do acompanhamento e houve aumento do uso de terapia biológica nos pacientes reavaliados. / Background: Rheumatoid arthritis (RA) is a chronic, autoimmune, inflammatory disease that causes joint and systemic inflammation, affecting 0.5 to 1% of the world adult population. It is associated with high morbidity and increased mortality, mainly due to cardiovascular disease. Metabolic Syndrome (MS) is understood as a set of metabolic disorders that correlates with obesity and sedentary lifestyle; however, to this moment there is no definition that is universally accepted. It encompasses a group of clinical and laboratory, features that include central obesity, reduced HDL, high triglycerides, increased blood pressure, and hyperglycemia. Objectives: To evaluate the prevalence of MS in a cohort of patients with RA and its correlation to specific factors of the disease. Methods: A prospective cohort study was conducted with 283 patients with RA, followed at the Rheumatology Outpatient Clinic of the Hospital de Clínicas de Porto Alegre between 2008 and 2016. Of these, 187 continued to be followed in this same clinic and agreed to be reevaluated in the period between January and November 2016. MS was defined according to the National Cholesterol Education Program (NCEP). Disease activity was assessed using the Disease Activity Score (DAS28). Clinical, biochemical, and anthropometric evaluations were conducted. The Statistical Package for Social Sciences (SPSS) version 21.0 was used for the statistical analysis. The Kolmogorov-Smirmov test was used to verify the normality of the quantitative variables, as well as to define the parametric and non-parametric tests. The deltas of the studied variables were constructed using the difference between the two evaluations. The quantitative variables were analyzed by means and standard deviations or medians and interquartile ranges. The Student-t test was used to compare the two evaluation moments for the paired samples. When asymmetry occurred, the Wilcoxon test was applied. Categorical variables were analyzed using the Mc Nemar test. The Analysis of Variance (ANOVA) was used in conjunction with the Tukey test in order to compare the means between the four groups of Metabolic Syndrome. The Kruskal-Wallis and Dunn tests were used, respectively, in case of asymmetry. We used the Person chi-square test in order to compare the categorical variables. For the verification of the degree of relationship between the variables we applied Pearson's correlation. Multivariate Poisson Regression was used for the confounding factors, in this study, we considered the age of the patients. Results: The prevalence of MS in the first evaluation was 43.9% and, after 8 years, 59.4%. Decreased waist circumference, decreased BPs, elevated triglycerides and low HDL were the most frequent features of MS. The DAS28 was significantly lower in the reevaluation (p = 0.006). Conclusion: The prevalence of MS was higher in the patients followed, at the end of 8 years; disease activity, as well as pressure values (SBP and DBP) decreased during this period. Steroid use had decreased at the end of follow-up. There was more use of biological in the patients that were reassessed.

Fadiga é um sintoma subjetivo de difícil definição. Extremamente comum em pacientes com Artrite Reumatoide. O objetivo deste estudo é estudar a fadiga numa amostra de pacientes brasileiros de dois hospitais de grande porte na cidade do Rio de Janeiro e analisar sua correlação com outras variáveis freqüentes da doença como a Qualidade de Vida, Capacidade Funcional, Ansiedade, Depressão e atividade inflamatória da doença.Um protocolo padrão foi prospectivamente aplicado a 371 pacientes como diagnóstico de AR de acordo com os critérios de classificação do American College of Rheumatology de 1987. Achados clínicos, demograficos e laboratoriais foram coletados.Os dados laboratoriais incluíram a velocidade de sedimentação das hemácias e dosagem da proteína C reativa. O número de juntas dolorosas foi obtido atraves do terceiro item do questionário de atividade inflamatória da doença DAS 28. Idade, gênero, índice de massa corporal, tempo de doença, qualidade de vida avaliada pelos domínios físico e mental do questionário Medical Outcomes Study Short-Form 36-item Health Survey (SF-36P e SF-36M), a capacidade funcional avaliada pelo Health Assessment Questionaire - Disability Index (HAQ DI). A ansiedade e a depressão foi mensurada pelo Hospital Anxiety and Depression Scale (HAD a/d). A fadiga foi avaliada pela utilização da subscalaprópria para mensuração das queixas de fadiga do questionário Fatigue Assessment of Chronic Illness Therapy (Facit FS). Foi aplicado o intervalo de confiança de 95% como medida de precisão. O valor médio de fadiga mensurado pelo Facit FS foi 39.88 8.64. O escore da fadiga correlacionou-se com capacidade funcional mensurada pelo HAQ DI (-0.507; p < 0.0000), a ansiedade e depressão mensurada pelo HAD a/d (-0.542 e -0.545; p < 0.0000 respectivamente) e com a qualidade de vida mensuradapor ambos domínios do SF-36, porém predominantemente com o seu domínio físico (SF-36P: 0.584; p < 0.0000 e 0.405; p < 0,05 respectivamente).Não encontramos associação com a velocidade de sedimentação das hemácias (-0.118; p < 0.05), da proteína C reativa (-0.089), da atividade de doença mensurada pelo DAS 28 (-0.250; p < 0.0000) ou com o número de juntas dolorosas (-0.135; p < 0.009). Nesta amostra de pacientes com Artrite reumatoide, sugerimos um novo significado para a fadiga, como um parâmetro independente, não relacionado a atividade inflamatória da doença ou ao número de juntas dolorosas. A fadiga mostrou-se associada principalmente a incapacidade funcional e a sintomas de ansiedade. Estudos adicionais e a adoção de métodos padronizados para seu monitoramento e manejo clínico são necessáriospara melhor compreensão da fadiga. A fadiga mostrou ser uma queixa importante em pelo menos 1/3 dos pacientes de AR da amostra. / Fatigue is a highly subjective symptom that is, difficult to characterize and define. Fatigue is extremely common among rheumatoid arthritis (RA) patients. The aim of this study was to assess fatigue in a cohort of Brazilian patients with RA and to analyze the relationship between fatigue and disease-specific variables. A common protocol of investigation was prospectively applied to 371 Brazilian patients diagnosed with RA according to the 1987 American College of Rheumatology (ACR) RA classification criteria. Clinical, demographic and laboratorial data were obtained. The laboratory data included the erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP). The number of painful joints was evaluated using the third item of the Disease Activity Index 28 (DAS 28). Age, gender, bone mass index (BMI), disease duration, quality of life (QoL) assessed by the physical and mental domains of the Medical Outcomes Study Short-Form 36-item Health Survey (SF-36P and SF-36M) and the functional capacity (FC) assessed by the Health Assessment Questionnaire - Disability Index (HAQ DI) were recorded. Anxiety and depression were assessed by the Hospital Anxiety and Depression Scale (HAD a/d). Fatigue was evaluated using the subscale of Fatigue Assessment of Chronic Illness Therapy who only scores fatigue complaints (FACIT-Fatigue). A confidence interval of 95% were applied as a measure of precision. The mean FACIT-Fatigue score was 39.88 8.64. The fatigue scores were correlated with FC as measured by the HAQ DI (-0.507; p < 0.0000), anxiety and depression as measured by the HAD a/d (-0.542 and -0.545; p < 0.0000 respectively) and with QoL as measured by the both domains of SF-36 correlated predominantly with physical domain (SF-36P: 0.584; p < 0.0000 and 0.405; p < 0,05 respectively).The scores were not associated with the ESR (-0.118; p < 0.05), CRP (-0.089), the disease activity measured by the DAS 28 (-0.250; p < 0.0000) or the number of painful joints (-0.135; p < 0.009). In this series of Brazilian patients with RA, we suggest a new significance for fatigue complaints as an independent parameter that is not related to inflammatory activity or the number of painful joints. Anxiety and functional impairment appears to be more related to fatigue, but additional studies and an inclusion of standard measures for monitoring and clinical management are required. Fatigue is an important complaint in at least 1/3 of this Brazilian patients.

Fadiga é um sintoma subjetivo de difícil definição. Extremamente comum em pacientes com Artrite Reumatoide. O objetivo deste estudo é estudar a fadiga numa amostra de pacientes brasileiros de dois hospitais de grande porte na cidade do Rio de Janeiro e analisar sua correlação com outras variáveis freqüentes da doença como a Qualidade de Vida, Capacidade Funcional, Ansiedade, Depressão e atividade inflamatória da doença.Um protocolo padrão foi prospectivamente aplicado a 371 pacientes como diagnóstico de AR de acordo com os critérios de classificação do American College of Rheumatology de 1987. Achados clínicos, demograficos e laboratoriais foram coletados.Os dados laboratoriais incluíram a velocidade de sedimentação das hemácias e dosagem da proteína C reativa. O número de juntas dolorosas foi obtido atraves do terceiro item do questionário de atividade inflamatória da doença DAS 28. Idade, gênero, índice de massa corporal, tempo de doença, qualidade de vida avaliada pelos domínios físico e mental do questionário Medical Outcomes Study Short-Form 36-item Health Survey (SF-36P e SF-36M), a capacidade funcional avaliada pelo Health Assessment Questionaire - Disability Index (HAQ DI). A ansiedade e a depressão foi mensurada pelo Hospital Anxiety and Depression Scale (HAD a/d). A fadiga foi avaliada pela utilização da subscalaprópria para mensuração das queixas de fadiga do questionário Fatigue Assessment of Chronic Illness Therapy (Facit FS). Foi aplicado o intervalo de confiança de 95% como medida de precisão. O valor médio de fadiga mensurado pelo Facit FS foi 39.88 8.64. O escore da fadiga correlacionou-se com capacidade funcional mensurada pelo HAQ DI (-0.507; p < 0.0000), a ansiedade e depressão mensurada pelo HAD a/d (-0.542 e -0.545; p < 0.0000 respectivamente) e com a qualidade de vida mensuradapor ambos domínios do SF-36, porém predominantemente com o seu domínio físico (SF-36P: 0.584; p < 0.0000 e 0.405; p < 0,05 respectivamente).Não encontramos associação com a velocidade de sedimentação das hemácias (-0.118; p < 0.05), da proteína C reativa (-0.089), da atividade de doença mensurada pelo DAS 28 (-0.250; p < 0.0000) ou com o número de juntas dolorosas (-0.135; p < 0.009). Nesta amostra de pacientes com Artrite reumatoide, sugerimos um novo significado para a fadiga, como um parâmetro independente, não relacionado a atividade inflamatória da doença ou ao número de juntas dolorosas. A fadiga mostrou-se associada principalmente a incapacidade funcional e a sintomas de ansiedade. Estudos adicionais e a adoção de métodos padronizados para seu monitoramento e manejo clínico são necessáriospara melhor compreensão da fadiga. A fadiga mostrou ser uma queixa importante em pelo menos 1/3 dos pacientes de AR da amostra. / Fatigue is a highly subjective symptom that is, difficult to characterize and define. Fatigue is extremely common among rheumatoid arthritis (RA) patients. The aim of this study was to assess fatigue in a cohort of Brazilian patients with RA and to analyze the relationship between fatigue and disease-specific variables. A common protocol of investigation was prospectively applied to 371 Brazilian patients diagnosed with RA according to the 1987 American College of Rheumatology (ACR) RA classification criteria. Clinical, demographic and laboratorial data were obtained. The laboratory data included the erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP). The number of painful joints was evaluated using the third item of the Disease Activity Index 28 (DAS 28). Age, gender, bone mass index (BMI), disease duration, quality of life (QoL) assessed by the physical and mental domains of the Medical Outcomes Study Short-Form 36-item Health Survey (SF-36P and SF-36M) and the functional capacity (FC) assessed by the Health Assessment Questionnaire - Disability Index (HAQ DI) were recorded. Anxiety and depression were assessed by the Hospital Anxiety and Depression Scale (HAD a/d). Fatigue was evaluated using the subscale of Fatigue Assessment of Chronic Illness Therapy who only scores fatigue complaints (FACIT-Fatigue). A confidence interval of 95% were applied as a measure of precision. The mean FACIT-Fatigue score was 39.88 8.64. The fatigue scores were correlated with FC as measured by the HAQ DI (-0.507; p < 0.0000), anxiety and depression as measured by the HAD a/d (-0.542 and -0.545; p < 0.0000 respectively) and with QoL as measured by the both domains of SF-36 correlated predominantly with physical domain (SF-36P: 0.584; p < 0.0000 and 0.405; p < 0,05 respectively).The scores were not associated with the ESR (-0.118; p < 0.05), CRP (-0.089), the disease activity measured by the DAS 28 (-0.250; p < 0.0000) or the number of painful joints (-0.135; p < 0.009). In this series of Brazilian patients with RA, we suggest a new significance for fatigue complaints as an independent parameter that is not related to inflammatory activity or the number of painful joints. Anxiety and functional impairment appears to be more related to fatigue, but additional studies and an inclusion of standard measures for monitoring and clinical management are required. Fatigue is an important complaint in at least 1/3 of this Brazilian patients.

Introdução: A artrite reumatoide (AR) é uma doença auto imune e crônica que provoca inflamação articular e sistêmica, afetando cerca de 0,5 a 1% da população adulta. A mesma está associada à alta morbidade e ao aumento da mortalidade principalmente devido à doença cardiovascular. Entende-se por Síndrome Metabólica (SM) um conjunto de distúrbios metabólicos, que se correlaciona com a obesidade e sedentarismo, porém ainda não há uma definição aceita universalmente. Sabe-se que a mesma tem como característica um grupo de aspectos clínicos e laboratoriais, onde estão incluídas a obesidade central, níveis reduzidos de HDL, níveis elevados de triglicerídeos, aumento da pressão arterial e hiperglicemia. Objetivos: Avaliar a prevalência da SM, numa coorte de pacientes com AR e sua relação com fatores específicos da doença. Métodos: Foi estudada uma coorte prospectiva com 283 pacientes portadores de AR, em acompanhamento no Ambulatório de Reumatologia do Hospital de Clínicas de Porto Alegre entre 2008 e 2016. Destes, 187 indivíduos, mantiveram acompanhamento neste mesmo ambulatório e concordaram em serem reavaliados no período entre janeiro e novembro de 2016. A SM foi definida de acordo com o National Cholesterol Education Program (NCEP). A atividade da doença foi avaliada através do Disease Activity Score (DAS28). Além disso, foram realizadas avaliação clínica, bioquímica e antropométrica dos pacientes. Para as análises estatísticas foi utilizado o Statistical Package for Social Sciences (SPSS) versão 21.0, o teste de Kolmogorov-Smirmov, para constatar a normalidade das variáveis quantitativas ,bem como para a definição dos teste paramétricos e não-paramétricos. Foram construídos os deltas das variáveis estudadas, utilizando-se a diferença entre as duas avaliações. A representação das variáveis quantitativas foram analisadas pela média e desvio padrão ou mediana e amplitude interquartílica. O teste de t de Studant foi utilizado para comparar os dois tempos de avaliação para as amostras pareadas. Ocorrendo assimetria o teste de Wilcoxon foi aplicado. As variáveis categóricas foram analisadas pelo teste de Mc Nemar. A Análise de Variância (ANOVA) em conjunto com o teste de Tukey foram utilizados para comparar a média entre os quatro grupos de Síndrome Metabólica. Os testes de Kruskal-Wallis e de Dunn foram usados, respectivamente, em caso de assimetria. Recorremos ao teste do qui-quadrado de Person para a comparação das variáveis categóricas . Para a verificação do grau de relação entre as variáveis aplicamos a Correlação de Pearson. A Regressão de Poisson multivariada foi utilizada para os fatores confundidores, neste estudo, consideramos a idade dos pacientes. Resultados: A prevalência de SM na primeira avaliação era de 43,9% e, e após 8 anos, passou a ser de 59,4%. Diminuição da circunferência da cintura, diminuição das PAs, triglicerídeos elevados e HDL baixo foram os componentes de SM mais freqüentemente.O DAS28 foi significativamente menor na reavaliação (p = 0,006). Conclusão: A prevalência de SM foi maior nos pacientes acompanhados no final de 8 anos, entretanto,a atividade da doença,e os níveis pressórios diminuíram neste período. O uso de corticóide foi menor ao final do acompanhamento e houve aumento do uso de terapia biológica nos pacientes reavaliados. / Background: Rheumatoid arthritis (RA) is a chronic, autoimmune, inflammatory disease that causes joint and systemic inflammation, affecting 0.5 to 1% of the world adult population. It is associated with high morbidity and increased mortality, mainly due to cardiovascular disease. Metabolic Syndrome (MS) is understood as a set of metabolic disorders that correlates with obesity and sedentary lifestyle; however, to this moment there is no definition that is universally accepted. It encompasses a group of clinical and laboratory, features that include central obesity, reduced HDL, high triglycerides, increased blood pressure, and hyperglycemia. Objectives: To evaluate the prevalence of MS in a cohort of patients with RA and its correlation to specific factors of the disease. Methods: A prospective cohort study was conducted with 283 patients with RA, followed at the Rheumatology Outpatient Clinic of the Hospital de Clínicas de Porto Alegre between 2008 and 2016. Of these, 187 continued to be followed in this same clinic and agreed to be reevaluated in the period between January and November 2016. MS was defined according to the National Cholesterol Education Program (NCEP). Disease activity was assessed using the Disease Activity Score (DAS28). Clinical, biochemical, and anthropometric evaluations were conducted. The Statistical Package for Social Sciences (SPSS) version 21.0 was used for the statistical analysis. The Kolmogorov-Smirmov test was used to verify the normality of the quantitative variables, as well as to define the parametric and non-parametric tests. The deltas of the studied variables were constructed using the difference between the two evaluations. The quantitative variables were analyzed by means and standard deviations or medians and interquartile ranges. The Student-t test was used to compare the two evaluation moments for the paired samples. When asymmetry occurred, the Wilcoxon test was applied. Categorical variables were analyzed using the Mc Nemar test. The Analysis of Variance (ANOVA) was used in conjunction with the Tukey test in order to compare the means between the four groups of Metabolic Syndrome. The Kruskal-Wallis and Dunn tests were used, respectively, in case of asymmetry. We used the Person chi-square test in order to compare the categorical variables. For the verification of the degree of relationship between the variables we applied Pearson's correlation. Multivariate Poisson Regression was used for the confounding factors, in this study, we considered the age of the patients. Results: The prevalence of MS in the first evaluation was 43.9% and, after 8 years, 59.4%. Decreased waist circumference, decreased BPs, elevated triglycerides and low HDL were the most frequent features of MS. The DAS28 was significantly lower in the reevaluation (p = 0.006). Conclusion: The prevalence of MS was higher in the patients followed, at the end of 8 years; disease activity, as well as pressure values (SBP and DBP) decreased during this period. Steroid use had decreased at the end of follow-up. There was more use of biological in the patients that were reassessed.

Introdução: A artrite reumatoide (AR) é uma doença auto imune e crônica que provoca inflamação articular e sistêmica, afetando cerca de 0,5 a 1% da população adulta. A mesma está associada à alta morbidade e ao aumento da mortalidade principalmente devido à doença cardiovascular. Entende-se por Síndrome Metabólica (SM) um conjunto de distúrbios metabólicos, que se correlaciona com a obesidade e sedentarismo, porém ainda não há uma definição aceita universalmente. Sabe-se que a mesma tem como característica um grupo de aspectos clínicos e laboratoriais, onde estão incluídas a obesidade central, níveis reduzidos de HDL, níveis elevados de triglicerídeos, aumento da pressão arterial e hiperglicemia. Objetivos: Avaliar a prevalência da SM, numa coorte de pacientes com AR e sua relação com fatores específicos da doença. Métodos: Foi estudada uma coorte prospectiva com 283 pacientes portadores de AR, em acompanhamento no Ambulatório de Reumatologia do Hospital de Clínicas de Porto Alegre entre 2008 e 2016. Destes, 187 indivíduos, mantiveram acompanhamento neste mesmo ambulatório e concordaram em serem reavaliados no período entre janeiro e novembro de 2016. A SM foi definida de acordo com o National Cholesterol Education Program (NCEP). A atividade da doença foi avaliada através do Disease Activity Score (DAS28). Além disso, foram realizadas avaliação clínica, bioquímica e antropométrica dos pacientes. Para as análises estatísticas foi utilizado o Statistical Package for Social Sciences (SPSS) versão 21.0, o teste de Kolmogorov-Smirmov, para constatar a normalidade das variáveis quantitativas ,bem como para a definição dos teste paramétricos e não-paramétricos. Foram construídos os deltas das variáveis estudadas, utilizando-se a diferença entre as duas avaliações. A representação das variáveis quantitativas foram analisadas pela média e desvio padrão ou mediana e amplitude interquartílica. O teste de t de Studant foi utilizado para comparar os dois tempos de avaliação para as amostras pareadas. Ocorrendo assimetria o teste de Wilcoxon foi aplicado. As variáveis categóricas foram analisadas pelo teste de Mc Nemar. A Análise de Variância (ANOVA) em conjunto com o teste de Tukey foram utilizados para comparar a média entre os quatro grupos de Síndrome Metabólica. Os testes de Kruskal-Wallis e de Dunn foram usados, respectivamente, em caso de assimetria. Recorremos ao teste do qui-quadrado de Person para a comparação das variáveis categóricas . Para a verificação do grau de relação entre as variáveis aplicamos a Correlação de Pearson. A Regressão de Poisson multivariada foi utilizada para os fatores confundidores, neste estudo, consideramos a idade dos pacientes. Resultados: A prevalência de SM na primeira avaliação era de 43,9% e, e após 8 anos, passou a ser de 59,4%. Diminuição da circunferência da cintura, diminuição das PAs, triglicerídeos elevados e HDL baixo foram os componentes de SM mais freqüentemente.O DAS28 foi significativamente menor na reavaliação (p = 0,006). Conclusão: A prevalência de SM foi maior nos pacientes acompanhados no final de 8 anos, entretanto,a atividade da doença,e os níveis pressórios diminuíram neste período. O uso de corticóide foi menor ao final do acompanhamento e houve aumento do uso de terapia biológica nos pacientes reavaliados. / Background: Rheumatoid arthritis (RA) is a chronic, autoimmune, inflammatory disease that causes joint and systemic inflammation, affecting 0.5 to 1% of the world adult population. It is associated with high morbidity and increased mortality, mainly due to cardiovascular disease. Metabolic Syndrome (MS) is understood as a set of metabolic disorders that correlates with obesity and sedentary lifestyle; however, to this moment there is no definition that is universally accepted. It encompasses a group of clinical and laboratory, features that include central obesity, reduced HDL, high triglycerides, increased blood pressure, and hyperglycemia. Objectives: To evaluate the prevalence of MS in a cohort of patients with RA and its correlation to specific factors of the disease. Methods: A prospective cohort study was conducted with 283 patients with RA, followed at the Rheumatology Outpatient Clinic of the Hospital de Clínicas de Porto Alegre between 2008 and 2016. Of these, 187 continued to be followed in this same clinic and agreed to be reevaluated in the period between January and November 2016. MS was defined according to the National Cholesterol Education Program (NCEP). Disease activity was assessed using the Disease Activity Score (DAS28). Clinical, biochemical, and anthropometric evaluations were conducted. The Statistical Package for Social Sciences (SPSS) version 21.0 was used for the statistical analysis. The Kolmogorov-Smirmov test was used to verify the normality of the quantitative variables, as well as to define the parametric and non-parametric tests. The deltas of the studied variables were constructed using the difference between the two evaluations. The quantitative variables were analyzed by means and standard deviations or medians and interquartile ranges. The Student-t test was used to compare the two evaluation moments for the paired samples. When asymmetry occurred, the Wilcoxon test was applied. Categorical variables were analyzed using the Mc Nemar test. The Analysis of Variance (ANOVA) was used in conjunction with the Tukey test in order to compare the means between the four groups of Metabolic Syndrome. The Kruskal-Wallis and Dunn tests were used, respectively, in case of asymmetry. We used the Person chi-square test in order to compare the categorical variables. For the verification of the degree of relationship between the variables we applied Pearson's correlation. Multivariate Poisson Regression was used for the confounding factors, in this study, we considered the age of the patients. Results: The prevalence of MS in the first evaluation was 43.9% and, after 8 years, 59.4%. Decreased waist circumference, decreased BPs, elevated triglycerides and low HDL were the most frequent features of MS. The DAS28 was significantly lower in the reevaluation (p = 0.006). Conclusion: The prevalence of MS was higher in the patients followed, at the end of 8 years; disease activity, as well as pressure values (SBP and DBP) decreased during this period. Steroid use had decreased at the end of follow-up. There was more use of biological in the patients that were reassessed.

Il existe un sur-risque de lymphome dans trois des principales maladies auto immunes (MAI) systémiques : la polyarthrite rhumatoïde (PR), le lupus érythémateux systémique (LES) et le syndrome de Sjögren (SSp) avec un risque relatif évalué respectivement à 2, 3 et 15 à 20. L’objectif de ce travail a été l’étude des mécanismes physiopathologiques impliqués dans la survenue de cette complication. Nous avons évalué le rôle de l’activité de la MAI. Nous avons pu montrer que l’ESSDAI, score d’activité du SSp, et la positivité du facteur rhumatoïde (FR) étaient 2 facteurs prédictifs de lymphome chez les patients atteints de SSp soulignant ainsi le rôle de l’activité de la maladie et de la stimulation chronique du lymphocyte B auto-réactif. L’étude de CXCL13 et CCL11 a mis en évidence l’association entre leur taux sérique et le risque de lymphomes dans le SSp. CXCL13 était aussi associé de manière indépendante avec l’activité de la maladie. Ce travail souligne l’existence d’un continuum entre activité de la maladie, activation chronique des LB et émergence d’un clone lymphomateux. Nous nous sommes intéressés aux susceptibilités génétiques favorisant les lymphomes des MAI. Nous avons étudié les anomalies de TNFAIP3 qui code pour la protéine A20, impliquée dans le contrôle de la voie NF-kB. Notre travail a démontré que plus des ¾ des patients SSp ayant développé un lymphome du MALT présentaient une anomalie de TNFAIP3 d’origine somatique ou germinale. Le concept novateur résultant de ce travail est qu’une mutation germinale entrainant un défaut de fonction minime dans toutes les cellules peut ne s’exprimer que dans un type cellulaire, le LB auto-immun soumis à une stimulation permanente dans le cadre d’une MAI. Dans un autre exemple de lymphome associé à la stimulation antigénique chronique, les lymphomes du VHC, nous avons démontré que le même polymorphisme exonique de TNFAIP3, le rs230926, était aussi associé au sous-groupe des lymphomes survenant chez les patients avec positivité du FR. Nous avons étudié l’impact des traitements anti-TNF sur la survenue de lymphome dans un contexte d’auto-immunité B. Dans une 1ere étude in vitro, nous avons démontré que les anti-TNF impactaient négativement l’activité anti-lymphomateuse des lymphocytes NK. Nous avons mené une étude sur un modèle de souris BAFF-Tg. Les résultats préliminaires sont en faveur d’une survie diminuée des souris traitées par anti-TNF. La cause (atteinte rénale ou lymphome) reste à déterminer. Ce travail démontre le rôle majeur de l’activité de la maladie et notamment de la stimulation antigénique chronique des lymphocytes B auto-immuns dans la lymphomagenèse des MAI. Dans ce contexte, un défaut de contrôle de l’activation du LB d’origine génétique ou une diminution de l’immunosurveillance par exemple par le biais de certains traitements immunosuppresseurs, est susceptible de précipiter la transformation lymphomateuse du LB auto-réactif et l’émergence de lymphome. / Three major systemic autoimmune diseases (AID), rheumatoid arthritis, lupus and primary Sjögren’s syndrome (pSS), have consistently been associated with the development of B‑cell non-Hodgkin lymphoma. The objective of this thesis was to study the mechanisms leading to lymphoma development in patients with AID. First, we have demonstrated that disease activity assessed by ESSDAI and positivity of rheumatoid factor (RF) were 2 independent predictors of lymphoma in pSS patients. Then, we have shown that CXCL13 and CCL11 serum levels were associated with lymphoma complicating pSS. CXCL13 was independently associated with disease activity. Second, we have assessed the role of genetic abnormalities of TNFAIP3 which encoded A20, a central gatekeeper of NF-kB. We have found that ¾ of pSS patients with MALT lymphomas had functional abnormalities of TNFAIP3 of somatic or germline origin. It demonstrates the major consequences of subtle germline abnormalities in gene involved in the control of NF-kB pathway in the context of chronic antigenic stimulation. Again, in lymphoma complicating hepatitis C, another situation of chronic antigenic stimulation, we found that a missense variant of TNFAIP3 was associated with the presence of RF in patients with lymphoma. Last, we have studied the impact of anti-TNF on development of AID associated lymphomas. In vitro, we found that chronic exposure to anti-TNF negatively impact anti-lymphoma activity of NK cells. In vivo, in mice transgenic for BAFF, we have found that mice treated with anti-TNF had a decreased survival. Studies are ongoing to determine the cause of this increased mortality. To sum up, this work demonstrates the key role of diseases activity and notably of chronic antigenic stimulation of auto-reactive B cell in lymphomas complicating AID. In this context, genetic impairment of check-point controlling B cell activation or decreased immunosurveillance induced by some immunosuppressive drugs may promote lymphomatous escape of auto-reactive B cell.

Systemic lupus erythematous (SLE) is an autoimmune and inflammatory disease that can affect all organs of the body. The purpose of this quantitative cross-sectional study was to examine SLE-related issues associated with depression and work-productivity impairment, and to assess if depression mediated the relationship between SLE disease activity and damage and work-productivity impairment. Participants were 257 residents of the state of Georgia in the United States with SLE and were recruited from the Georgians Organized Against Lupus study. Bandura'€™s social cognitive theory was the guiding theoretical framework of the study. Findings showed that the majority of participants worked full time (78.2%), identified as Black (72.8%), female (94.2%), above poverty level (77.4%), and had private health insurance (70.0%). Mean and median score results indicated that participants missed, on average, slightly less than half a day of work every 7 days, and had mild-to-moderate levels of work productivity impairment. Mean and median scores showed that participants reported mild-to-moderate levels of SLE disease activity and damage and depression. Linear regression results revealed significant relationships between SLE activity and damage and work productivity impairment. Hierarchical linear regression for mediation findings indicated that depression partially mediated the relationship between SLE disease activity and damage and work productivity impairment. The findings from this study might help to increase stakeholder awareness of SLE disease activity and damage and SLE effects on depression and work functioning.