Depression is a common comorbidity in rheumatoid arthritis (RA), yet it may not be adequately recognized during routine clinical care. RA symptoms may confer a risk for depression, and vice versa; depression may affect RA disease activity and response to treatment. The study aims were to compare patient- and physician-reported depression measures, evaluate the temporal bi-directional association between RA disease activity and depressive symptomology, and assess depression as a moderator of RA treatment. Patients were identified using a national RA registry sample (Consortium of Rheumatology Researchers of North America; CORRONA). Depression prevalence and incidence rates were estimated, and concordance and disagreement using measures reported separately by patients and physicians, as well as baseline cross-sectional associations between RA disease and a history of depression. A survival analysis was conducted to temporally predict the incident onset of self-reported depressive symptoms using the different metrics of RA disease activity. Also, mixed effects models were used to assess prospective changes in RA disease activity by prevalent and incident depressive symptom status. Lastly, logistic regression models compared the likelihood of clinical response to RA treatment during follow-up in those with and without depression when starting biologic disease modifying anti-rheumatic drug (DMARD) therapy. Patient-reported depression rates were much higher and significantly different from physician based comorbidity estimates. Patient and physician RA disease activity measures were associated with an increased risk for depression onset, but not laboratory-reported serum biomarkers. Similarly, depression was temporally associated with significantly slower rates of decline regarding every patient-reported disease activity measure, some physician-reported metrics, but not acute phase reactants. Moreover, there was a significantly lower probability of achieving clinical remission among those with depression on a biologic DMARD after 6 months and an analogous effect at 12-months that was slightly lower in magnitude, which did not reach statistical significance. Rheumatologists under-reported the occurrence of prevalent and incident depressive symptoms, and thus are likely unaware of its presence in their RA patients. Further, the results suggest the bi-directional effects between these conditions are related to the cognitive and behavioral aspects of depression and their interactions with disease activity, rather than shared immunological mechanisms in the context of cell-mediated immunity. When also considering the impact on clinical response to biologic DMARDS, the findings collectively imply that rheumatologists must address any challenges due to depression to provide the best care to their patients.

Introdução: Estudos epidemiológicos têm estabelecido que a artrite reumatoide está associada com um aumento de doença cardiovascular. A avaliação de anti-TNF sobre a redução do risco de infarto agudo do miocárdio e óbito por causa cardiovascular tem demonstrado resultados promissores. A avaliação econômica para esses desfechos ainda não está estabelecida. Objetivo: Realizar uma análise de custo efetividade de anti-TNF versus Dmards para evitar um caso novo de morbidade e óbito cardiovascular na artrite reumatoide. Método: Foi realizada uma análise de custo efetividade por meio do modelo de Markov, ciclo de transição de 6 meses e horizonte temporal de 30 anos sob perspectiva do sistema público de saúde do Brasil mensurado pela razão de custo efetividade incremental. Custo em Reais no ano de 2015 e efetividade em evitar um caso novo de doença coronariana isquêmica aguda e óbito cardiovascular. Resultados: O custo médio em 30 anos de Dmards e anti-TNF foi de R$ 14.291.105,28 e R$ 96.151.873,86, respectivamente. A efetividade incremental para doença arterial coronariana foi de 2,69 e consequente razão incremental de custo efetividade de R$ 30.527.502,27, enquanto para óbito cardiovascular a efetividade incremental foi de 1,33 casos evitados e uma razão incremental de custo efetividade de R$ 61.634.231,69. A análise univariada identificou que o parâmetro de maior impacto na razão incremental de custo efetividade de ambos os desfechos foi o medicamento anti-TNF. A análise de sensibilidade estabeleceu que, para atingir o valor de disposição a pagar por semestre para evitar um infarto agudo do miocárdio, o custo médio do anti-TNF deveria ser de R$ 1.337,47 ou diferença de incidência entre as estratégias de 0,032. Ainda, para evitar um óbito cardiovascular, o custo médio deveria ser de R$ 954,22 ou diferença de incidência de 0,071. Todas as análises realizadas estabeleceram uma relação desfavorável da estratégia do tratamento medicamentoso com anti-TNF. Conclusão: Os achados da análise de custo efetividade entre pacientes com artrite reumatoide para desfecho cardiovascular quando comparada a estratégia de tratamento medicamentoso de anti-TNF em relação à estratégia dominante com Dmards após os 6 primeiros meses de exposição aos medicamentos apontaram para uma relação desfavorável, ultrapassando o valor de disposição a pagar recomendado pelo Ministério da Saúde do Brasil no ano de 2015. Descritores: artrite reumatoide; doenças cardiovasculares; infarto do miocárdio; óbito; avaliação de custo-efetividade; anti fator de necrose tumoral; drogas anti-reumáticas modificadoras de doença. / Introduction: Epidemiological studies have established that rheumatoid arthritis is associated with an increase in cardiovascular disease. The evaluation of anti-TNF on the reduction of the risk of acute myocardial infarction and death due to cardiovascular causes has shown promising results. The economic evaluation for these outcomes is not yet established. Objective: To perform a cost-effectiveness analysis of anti-TNF versus Dmards to avoid a new case of cardiovascular morbidity and death in rheumatoid arthritis. Method: A cost effectiveness analysis was performed using the Markov model, a 6-month transition cycle and a 30-year time horizon under the perspective of the Brazilian public health system measured by the incremental cost-effectiveness ratio. Cost in Reais in the year 2015 and effectiveness in avoiding a new case of acute ischemic coronary disease and cardiovascular death. Results: The average cost in 30 years of Dmards and anti-TNF was R$ 14,291,105.28 and R$ 96,151,873.86, respectively. The incremental effectiveness for coronary artery disease was 2.69 and a consequent incremental cost-effectiveness ratio of R$ 30,527,502.27, while for cardiovascular death, incremental effectiveness was 1.33 cases avoided and an incremental cost-effectiveness ratio of R$ 61,634,231.69. The univariate analysis identified that the parameter of greatest impact in the incremental cost-effectiveness ratio of both outcomes was the anti-TNF drug. The sensitivity analysis established that the average cost of anti-TNF should be R$ 1,337.47 or incidence difference between strategies of 0.032 in order to reach the amount of willingness to pay per semester to avoid an acute myocardial infarction. Also, to avoid a cardiovascular death, the average cost should be R$ 954.22 or incidence difference of 0.071. All the analyzes carried out established an unfavorable relationship of the drug treatment strategy with anti-TNF. Conclusions: The findings of the cost-effectiveness economic analysis among individuals with rheumatoid arthritis for cardiovascular outcome when compared to the strategy of anti-TNF drug treatment compared to the dominant strategy with Dmards after the first 6 months of drug exposure pointed to an unfavorable relationship, surpassing the amount of willingness to pay recommended by the Ministry of Health of Brazil in the year 2015.

OBJETIVOS: Avaliar as alterações clínicas da superfície ocular, citologia de impressão (CI) e sintomas de olho seco (OS) dos pacientes com Espondilite Anquilosante (EA) e Artrite Reumatoide (AR). Classificar a intensidade de OS. Avaliar prospectivamente os parâmetros clínicos, laboratoriais e da superfície ocular dos pacientes com EA e AR submetidos a tratamento com drogas anti-TNF. MÉTODOS: Estudo prospectivo envolvendo inicialmente (pré-tratamento) 36 pacientes com EA e 20 pacientes com AR comparados com grupo controle de 39 voluntários saudáveis para o grupo de EA e 24 voluntários saudáveis para o grupo de AR. Do total inicial, 14 pacientes consecutivos com EA e 20 pacientes consecutivos com AR foram submetidos a terapia anti-TNF. Foram realizados os seguintes exames: teste de Schirmer I, tempo de rompimento do filme lacrimal, tingimento com corantes vitais e questionário dos sintomas de OS (Ocular Surface Disease Index-OSDI), citologia de impressão (CI) conjuntival, avaliação laboratorial inflamatória: velocidade de hemossedimentação e proteína C reativa (VHS e PCR) e atividade da doença pelas medidas de Bath Ankylosing Spondylitis Activity Index e Bath Ankylosing Spondylitis Functional Index (BASDAI e BASFI respectivamente) na EA e Disease Activity Score 28 (DAS 28) para AR. Além disso, avaliou-se a qualidade de vida pelo Health Assessment Questionnaire (HAQ) para ambas as doenças. As avaliações foram realizadas pré-tratamento e repetidas aos 3 meses (3M) e 12 meses (12M) após o início da terapia. RESULTADOS: Na avaliação pré-tratamento com drogas anti-TNF, os pacientes com EA apresentaram OS de intensidade leve a moderada (80,5% versus 43,6%, p=0,01) e maior escore de alteração da CI (55% versus 12,8%, p=0,007) associados a provas de atividade inflamatórias elevadas (p < 0,001) quando comparados com controles saudáveis. A avaliação longitudinal do tratamento com terapia anti-TNF demonstrou melhora da produção aquosa lacrimal (pré-tratamento: 13,7 ? 11,3 mm, aos 3M: 18,3 +- 11,1 mm e aos 12M: 19,3 +- 9,0 mm, p=0,04) assim como da CI conjuntival (pré-tratamento: 78,6% alterada, aos 3M: 57,1%, e aos 12M: 35,7%, p=0,03). Houve, paralelamente, melhora dos parâmetros inflamatórios e da atividade da doença (p < 0,05). No grupo de pacientes com AR, no momento pré-tratamento com drogas anti-TNF, foram observados maior frequência (75% versus 4%, p < 0,001) e intensidade leve de OS (65% versus 4%, p < 0,001) associados a sintomas moderados (escore OSDI 24,0 +- 17,6 versus 7,5 +- 14,3, p=0,001) quando comparados com controles saudáveis. Esses pacientes também apresentaram maior frequência de disfunção das glândulas de meibômio (55,0% versus 8,3%, p=0,001), maior escore de alteração da CI conjuntival (1,0 +- 0,6 versus 0.0 +- 0,2, p=0,001) e menor densidade de células caliciformes (431,3 +- 209,5 células/mm2 versus 804,8 +- 383,2 células/mm2, p < 0,001) quando comparados com o grupo controle. A análise prospectiva dos pacientes com AR tratados com drogas anti-TNF mostrou um aumento dos valores do teste de Schirmer (prétratamento: 11,8 +- 6,7 mm, aos 3M: 21,0 +- 10,4 mm, e aos 12M: 23,0 +- 9,7mm, p < 0,001), melhora da CI conjuntival (pré-tratamento: 1,0 +- 0,6, aos 3M: 0,8 +- 0,6, e aos 12M: 0,5 +- 0,5, p=0,005) e da densidade de células caliciformes (pré-tratamento: 429 +- 211,7 células/mm2, aos 3M: 908 +- 291,4 células/mm2, e aos 12M: 1265,4 +- 430,6 células/mm2, p=0,001). Os marcadores de atividade inflamatória sistêmicos (VHS e PCR) também melhoraram ao longo do tratamento (p=0,005 e p=0,006, respectivamente). CONCLUSÃO: Os pacientes com EA e AR avaliados nesse estudo apresentaram prevalência elevada de OS de intensidade leve a moderada associada à alteração da citologia conjuntival. A recuperação precoce e manutenção de longo prazo na produção aquosa da lágrima e na CI conjuntival, em especial, das células caliciformes, nos pacientes submetidos a terapia anti-TNF, pode refletir a melhora da condição inflamatória. Esse resultado histológico pode ter influência como biomarcador da inflamação na superfície ocular / OBJECTIVES: Evaluate ocular surface parameters, impression cytology (IC) and dry eye (DE) symptoms of patients with Ankylosing Spondylitis (AS) and Rheumatoid Arthritis (RA). Classify DE severity grade. Analyse prospectively clinical and laboratory, as well as ocular surface parameters of AS and RA patients, submitted to anti-TNF therapy. METHODS: This prospective study initially (baseline) enrolled 36 AS patients and 20 RA patients who were compared to a control group of 39 and 24 healthy volunteers for the AS group and RA group, respectively. From the initial group, 14 consecutive AS and 20 consecutive RA patients received anti-TNF therapy. They underwent the following exams: Schirmer I test, tear break-up time, vital dyes staining of the ocular surface, a questionnaire for dry eye symptoms- Ocular Surface Disease Index (OSDI), and conjunctival IC. Laboratory tests for inflammatory activity were assessed by erythrocyte sedimentation rate and C- reactive protein (ESR and CRP). The Bath Ankylosing Spondylitis Activity Index and Bath Ankylosing Spondylitis Functional Index (BASDAI and BASFI, respectively) in AS and Disease Activity Score 28 (DAS 28) in RA analyzed disease activity parameters. Besides, the Health Assessment Questionnaire evaluated the quality of life in both group of diseases. These measurements were taken at baseline (BL) and repeated at 3 months and 12 months (3M and 12M, respectively) after the beginning of anti-TNF therapy. RESULTS: At the baseline moment, AS patients presented mild to moderate DE (80.5% vs 43.6%, p=0.01) and a higher score of altered IC (55% vs 12.8%, p=0.007) associated with the systemic inflammatory activity (ESR and CRP, p < 0.001) when compared to healthy volunteers. The longitudinal evaluation of anti- TNF treatment showed an improvement of aqueous tear production (BL: 13.7 +- 11.3 mm, 3M: 18.3 +- 11.1 mm and 12M: 19.3 +- 9,0 mm, p=0.04). The IC also improved (BL: 78.6% altered IC, 3M: 57.1% and 12M: 35.7%, p=0.03). There was a parallel amelioration of systemic inflammatory markers and disease activity (p < 0.05). Concerning the RA group of patients, at the baseline moment, there was a higher frequency of DE (75% vs 4%, p < 0.001) as well as mild DE severity grade (65% vs 4%, p < 0,001) associated with moderate symptoms of DE (OSDI score: 24.0 +- 17.6 vs 7.5 +- 14.3, p=0.001) when compared to healthy volunteers. This group of patients also presented higher frequency of meibomian gland dysfunction (55% vs 8.3%, p=0.001), a worse score of IC (1.0 +- 0.6 vs 0.0 ? 0.2, p=0.001) and lower goblet cells count (431.3 +- 209.5 cells/mm2 vs 804.8 +- 383.2 cells/mm2, p< 0.001) when compared to the control group. The prospective analysis of RA patients treated with anti-TNF drugs demonstrated an increase of Schirmer\'s test (BL: 11.8 +- 6.7, 3M: 21.0 +- 10.4, 12M: 23.0 +- 9.7, p < 0.001) and an improvement of cytological grade (BL: 1.0 +- 0.6, 3M: 0.8 +- 0.6, 12M: 0.5 +- 0.5, p=0.005) and goblet cells density (BL: 429,0 +- 211.7 cells/mm2, 3M: 908,0 +- 291.4 cells/mm2, 12M: 1265.4 +- 430.6 cells/mm2, p=0.001). The systemic inflammatory markers (ESR and CRP) also improved throughout the treatment period (p=0.005 and p=0.006, respectively). CONCLUSION: Patients with AS and RA enrolled in this study presented a higher prevalence of mild to moderate DE associated with altered IC. The prompt and maintained aqueous tear and conjunctival cytology recovery, especially the goblet cells, in patients submitted to anti-TNF therapy seem to represent the improvement of inflammatory condition. This histological outcome may have an influence as a biomarker of ocular surface inflammation

INTRODUÇÃO: A Artrite Reumatóide (AR) é caracterizada pelo aspecto inflamatório crônico articular e é a doença autoimune mais comum em todo o mundo. A categoria de medicamentos modificadores do curso da doença (MMCD) é dividido em dois grupos, sintéticos e biológicos. Há controversos estudos em relação a comparação entre estas alternativas, principalmente, devido ao elevado custo dos biológicos. O objetivo deste estudo foi realizar uma avaliação econômica do tratamento da AR, comparando a terapia combinada de MMCD sintéticos versus MMCD biológicos, utilizando de dados da literatura e de custo na perspectiva do SUS. MÉTODOS: Foi realizado uma revisão sistemática com metanálise das bases Medline e Embase os ensaios clínicos randomizados(ECR) que fizeram comparação direta entre o uso de MMCD sintéticos versus os MMCD biológicos. A remissão foi considerada para DAS28 < 2,6. Os itens que compõe o custo seguiram a diretrizes do Ministério da Saúde do Brasil e os valores foram recuperados da tabela do Sistema de Informação Ambulatorial do SUS, e do Sistema de Gerenciamento da Tabela de Procedimentos, Medicamentos e OPM do SUS, dados do ano 2016/2017. RESULTADOS: Foram incluídos 6 ECR. No seguimento de até 6 meses o RR=0,70 (IC95% 0,57 a 0,85) a favor dos biológicos. No seguimento entre 12 a 24 meses não houve diferença estatisticamente significante, RR=0,91 (IC95% 0,80 a 1,05). Um ano do tratamento com MMCDs combinado custa R$2445,60 e os Anti-TNF custa R$ 52.821,57. CONCLUSÃO: A remissão da atividade clínica da AR pode ser obtida pelo uso de DMARD sintéticos ou por Agentes Biológicos. Análise de custo-minimização mostrou que uma economia substancial a cada mês evitado de uso dos MMCD biológicos / INTRODUCTION: Rheumatoid arthritis (RA) is the most common autoimmune disease in the world, which leads to a chronic joint inflammation. There are two types of disease-modifying anti-rheumatic drugs (DMARD): synthetical and biological. The comparison between both drugs is controversial, mostly because of the high cost of the biological ones. The aim of this study was to develop an economic evaluation of RA treatments, comparing combined therapy with synthetic DMARD versus biological DMARD, based on literature review and cost analysis on SUS data. METHODS: Systematic review with meta-analysis of randomized clinical trials (RCT) was conducted on Medline and Embase database about direct comparisons of synthetic DMARD and biological DMARD. Remission was set for DAS28 < 2.6. Cost analysis was based on the guidelines of the Brazilian Ministry of Health and cost values were extracted from the SUS\'s Ambulatory Information System table, Management System of Procedures Table, and Medicine and OPM table, for 2016/2017. RESULTS: Six RCT were included. For six months follow-up, RR=0.70 (IC95% 0.57 to 0.85) in favour of biologicals. For 12-24 months follow-up, both DMARD were similar, RR=0.91 (IC95% 0.80 to 1.05). One-year treatment with DMARD costs R$2445,60 e Anti-TNF costs R$ 52.821,57. CONCLUSION: Remission of clinical activity of RA can be reached with synthetic or biologic DMARD. Minimizing-cost analysis showed a monthly expressive saving avoinding the biologic DMARD

Para analisar e investigar as variáveis clínicas e radiográficas da articulação temporomandibular e do aparelho mastigatório de um grupo portadores de artrite reumatóide (AR) e de um grupo controle portadores de disfunção temporomandibular (DTM) foram avaliados 102 pacientes com artrite reumatóide e 70 pacientes com disfunção temporomandibular sem artrite reumatoide. Este estudo analisou a prevalência de DTM, o estado psicológico e gera as alterações radiográficas e a presença e características da dor articular e/ou muscular no segmento facial de ambos os grupos. Verificou-se que os paciente com AR apresentaram acomentimento da ATM e dores nos músculos da mastigação mas com menos freqüência que nos pacientes com DTM. Por outro lado, a presença de osteoartrite e osteoartrose na ATM foi mais evidente nos pacientes com AR que no grupo controle. Estas características foram compatíveis com o comprometimento da ATM pela própria doença. A dor no paciente com DTM foi difusa e com intensidade moderada a forte realçado por apresentarem maior croncidade / To evaluate and investigate clinical and radiological variables of the temporomandibular joint (TMJ) and masticatory system in 102 patients with rheumatoid arthritis (RA) and in control group consisted of 70 patients with temporomandibular disorders (TMD) without rheumatoid arthritis. This study analysed in both groups the prevalence of temporomandibular dysfunction, character of concerning self-rated mental well-being, radiographic alterations and presenting and character of temporomandibular joint pain and/or masticatory muscle pain in the face segment. In spite of the patients with RA showed masticatory pain dysfunction, the frequency was lower than in the patients with TMD. The RA group was reported development of TMJ symptoms like osteoarthrosis and osteoarthritis. This development is associated with functional impairment in the other joints of the body and severity of the RA systemic disease. In the control group the pain in the face segment and masticatory system was general with moderate to high intensity

INTRODUÇÃO: Artrite reumatoide (AR) é uma doença inflamatória autoimune comum, de predomínio feminino e presente em 1% da população brasileira. O acometimento do sistema respiratório é frequente e ocorre em aproximadamente 50% desta população, principalmente as doenças de vias aéreas e as doenças pulmonares intersticiais. Pacientes tabagistas têm maior chance de desenvolver AR em relação aos não tabagistas, mas o papel do tabaco na doença pulmonar da AR ainda está indefinido. Este trabalho foi dividido em 2 partes. Na primeira avaliamos as características epidemiológicas, clínicas, radiográficas e espirométricas dos pacientes com AR, e comparamos o grupo de pacientes com alterações em qualquer dos exames realizados com grupo onde os exames foram normais. Na segunda parte, fizemos uma avaliação mais aprofundada do sistema respiratório dos pacientes com alteração à espirometria e os comparamos de acordo com a exposição ao tabagismo: elevada (carga tabágica > 10 anos.maço) contra baixa ou ausente. MÉTODOS: Pacientes acompanhados no ambulatório de Artrite Reumatoide do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo foram submetidos a um estudo de corte transversal com avaliação clínica, oximetria de pulso em repouso, radiografia de tórax e espirometria. Aqueles que apresentavam espirometria alterada foram submetidos a tomografia de alta resolução do tórax (TCAR) e função pulmonar com espirometria, pletismografia, difusão de monóxido de carbono (DLCO) e teste de washout de nitrogênio por respiração única. RESULTADOS: Um total de 246 pacientes foram analisados. História de tabagismo prévio ou atual foi visto em metade da amostra. Houve baixa prevalência de nódulos reumatoides e Síndrome de Sjögren. Alterações à espirometria foram vistas em 30% dos pacientes, radiografia de tórax em 45% e oximetria de pulso em 13%. Exames normais estavam simultaneamente presentes em apenas 41% dos casos. Houve fraca correlação negativa entre carga tabágica e diferentes parâmetros da espirometria. No grupo de pacientes com elevada exposição ao tabaco, observamos uma maior frequência de enfisema à TCAR de tórax e menor DLCO, enquanto que no grupo com exposição baixa ou ausente houve maior prevalência de bronquiolite. CONCLUSÕES: Alteração combinada em radiografia de tórax, espirometria e oximetria de pulso foi mais frequentemente observada em pacientes com mais idade, história de tabagismo e uso prévio de metotrexate e biológicos. Apesar de frequentes, a maioria das alterações à radiografia de tórax e espirometria foram leves. A exposição ao tabagismo consegue explicar apenas uma pequena parte das alterações espirométricas da doença pulmonar da AR. A maioria dos pacientes com alteração à espirometria apresentou TCAR de tórax e função pulmonar sugestivas de doença pulmonar obstrutiva, principalmente bronquiolite. A presença de enfisema à TCAR é um marcador altamente específico de exposição ao tabaco / INTRODUCTION: Rheumatoid Arthritis (RA) is a frequent connective tissue disorder, occurring mainly in women, with a 1% prevalence in Brazil. Pulmonary disease, which is present in up to 50% of patients, manifests most commonly as interstitial lung disease (ILD) and airways disease. A high frequency of smoking is observed among RA patients, but its role on pulmonary involvement is unknown. This work was divided in 2 parts. At the first part, we analyzed epidemiological, clinical, radiographic and spirometric RA patients´ characteristics, and compared the group of patients with any abnormality on complementary medical tests against the group with normal tests. At the second part, patients with abnormal spirometry were submitted to a more complex respiratory evaluation, and we compared RA patients with high tobacco exposure ( > 10 pack-years) versus absent or low tobacco exposure. METHODS: RA patients undergoing regular follow-ups at the rheumatoid arthritis clinic of the Rheumatology Division, University of Sao Paulo Medical School, Brazil, were submitted to a cross-sectional clinical pulmonary evaluation, rest pulse oximetry, chest radiograph and spirometry. Those with abnormal spirometry were submitted to chest high-resolution computed tomography (HRCT) and pulmonary function tests with spirometry, plethysmography, carbon monoxide diffusion capacity (DLCO) and single breath nitrogen washout. RESULTS: A total of 246 RA patients underwent complete assessments. Half of the population reported tobacco exposure. Rheumatoid nodules and Sjögren Syndrome were uncommon. Spirometry was abnormal in 30% of the patients; CXR was abnormal in 45%, and pulse oximetry was abnormal in 13%. Normal CXR, spirometry and oximetry were observed simultaneously in only 41% of the RA patients. A weak negative correlation was found between tobacco exposure and spirometric parameters. Thorax HRCT emphysema and lower DLCO were more frequent in patients with high tobacco exposure, while patients with absent or low tobacco exposure had a higher frequency of bronchiolitis. CONCLUSIONS: A significant difference was observed in age, smoking status, and ever methotrexate or biologic treatments when comparing patients with normal and abnormal complementary medical tests. Even though radiographic and spirometric abnormalities were frequent, most of them were mild. Tobacco exposure was slightly responsible for RA patients´ spirometric abnormalities. HRCT and pulmonary function tests compatible with obstructive lung disease, mainly bronchiolitis, were the most frequent patterns among RA patients with abnormal spirometry. HRCT emphysema was a highly specific marker of tobacco exposure

INTRODUÇÃO: Artrite reumatoide (AR) é uma doença inflamatória autoimune comum, de predomínio feminino e presente em 1% da população brasileira. O acometimento do sistema respiratório é frequente e ocorre em aproximadamente 50% desta população, principalmente as doenças de vias aéreas e as doenças pulmonares intersticiais. Pacientes tabagistas têm maior chance de desenvolver AR em relação aos não tabagistas, mas o papel do tabaco na doença pulmonar da AR ainda está indefinido. Este trabalho foi dividido em 2 partes. Na primeira avaliamos as características epidemiológicas, clínicas, radiográficas e espirométricas dos pacientes com AR, e comparamos o grupo de pacientes com alterações em qualquer dos exames realizados com grupo onde os exames foram normais. Na segunda parte, fizemos uma avaliação mais aprofundada do sistema respiratório dos pacientes com alteração à espirometria e os comparamos de acordo com a exposição ao tabagismo: elevada (carga tabágica > 10 anos.maço) contra baixa ou ausente. MÉTODOS: Pacientes acompanhados no ambulatório de Artrite Reumatoide do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo foram submetidos a um estudo de corte transversal com avaliação clínica, oximetria de pulso em repouso, radiografia de tórax e espirometria. Aqueles que apresentavam espirometria alterada foram submetidos a tomografia de alta resolução do tórax (TCAR) e função pulmonar com espirometria, pletismografia, difusão de monóxido de carbono (DLCO) e teste de washout de nitrogênio por respiração única. RESULTADOS: Um total de 246 pacientes foram analisados. História de tabagismo prévio ou atual foi visto em metade da amostra. Houve baixa prevalência de nódulos reumatoides e Síndrome de Sjögren. Alterações à espirometria foram vistas em 30% dos pacientes, radiografia de tórax em 45% e oximetria de pulso em 13%. Exames normais estavam simultaneamente presentes em apenas 41% dos casos. Houve fraca correlação negativa entre carga tabágica e diferentes parâmetros da espirometria. No grupo de pacientes com elevada exposição ao tabaco, observamos uma maior frequência de enfisema à TCAR de tórax e menor DLCO, enquanto que no grupo com exposição baixa ou ausente houve maior prevalência de bronquiolite. CONCLUSÕES: Alteração combinada em radiografia de tórax, espirometria e oximetria de pulso foi mais frequentemente observada em pacientes com mais idade, história de tabagismo e uso prévio de metotrexate e biológicos. Apesar de frequentes, a maioria das alterações à radiografia de tórax e espirometria foram leves. A exposição ao tabagismo consegue explicar apenas uma pequena parte das alterações espirométricas da doença pulmonar da AR. A maioria dos pacientes com alteração à espirometria apresentou TCAR de tórax e função pulmonar sugestivas de doença pulmonar obstrutiva, principalmente bronquiolite. A presença de enfisema à TCAR é um marcador altamente específico de exposição ao tabaco / INTRODUCTION: Rheumatoid Arthritis (RA) is a frequent connective tissue disorder, occurring mainly in women, with a 1% prevalence in Brazil. Pulmonary disease, which is present in up to 50% of patients, manifests most commonly as interstitial lung disease (ILD) and airways disease. A high frequency of smoking is observed among RA patients, but its role on pulmonary involvement is unknown. This work was divided in 2 parts. At the first part, we analyzed epidemiological, clinical, radiographic and spirometric RA patients´ characteristics, and compared the group of patients with any abnormality on complementary medical tests against the group with normal tests. At the second part, patients with abnormal spirometry were submitted to a more complex respiratory evaluation, and we compared RA patients with high tobacco exposure ( > 10 pack-years) versus absent or low tobacco exposure. METHODS: RA patients undergoing regular follow-ups at the rheumatoid arthritis clinic of the Rheumatology Division, University of Sao Paulo Medical School, Brazil, were submitted to a cross-sectional clinical pulmonary evaluation, rest pulse oximetry, chest radiograph and spirometry. Those with abnormal spirometry were submitted to chest high-resolution computed tomography (HRCT) and pulmonary function tests with spirometry, plethysmography, carbon monoxide diffusion capacity (DLCO) and single breath nitrogen washout. RESULTS: A total of 246 RA patients underwent complete assessments. Half of the population reported tobacco exposure. Rheumatoid nodules and Sjögren Syndrome were uncommon. Spirometry was abnormal in 30% of the patients; CXR was abnormal in 45%, and pulse oximetry was abnormal in 13%. Normal CXR, spirometry and oximetry were observed simultaneously in only 41% of the RA patients. A weak negative correlation was found between tobacco exposure and spirometric parameters. Thorax HRCT emphysema and lower DLCO were more frequent in patients with high tobacco exposure, while patients with absent or low tobacco exposure had a higher frequency of bronchiolitis. CONCLUSIONS: A significant difference was observed in age, smoking status, and ever methotrexate or biologic treatments when comparing patients with normal and abnormal complementary medical tests. Even though radiographic and spirometric abnormalities were frequent, most of them were mild. Tobacco exposure was slightly responsible for RA patients´ spirometric abnormalities. HRCT and pulmonary function tests compatible with obstructive lung disease, mainly bronchiolitis, were the most frequent patterns among RA patients with abnormal spirometry. HRCT emphysema was a highly specific marker of tobacco exposure

Eighty-two patients with breast cancer, twenty-seven patients with nasopharyngeal carcinoma and sixty-five patients with rheumatoid arthritis in this study were selected based on voluntary, randomization and double blind grouping criteria. / In nasopharyngeal carcinoma patients, the decrease in percentage and the absolute count of T lymphocytes in the TCM group was significantly lower than those in the placebo group. Besides, the decrease of the absolute count of T helper and T suppressor in the TCM group was significantly lower than that in the placebo group (all p &lt; 0.05). The decrease may be due to radiotherapy. However, there was no significant difference in plasma sIL-2R and soluble tumor necrosis factor receptor 2 (sTNFR2) between the TCM group and the placebo group. / In rheumatoid arthritis patients, there was no significant difference in plasma. C-reactive protein (CRP), in the percentage, absolute count, and the ratio of CD4+/CD8+/NK/B lymphocytes between the TCM group and the placebo group. / Results showed that the absolute count of T helper lymphocytes (CD4+), the ratio of T helper lymphocytes (CD4+)/T suppressor and cytotoxic lymphocytes (CD8+), and the percentage and the absolute count of B lymphocytes were significantly elevated in the patients with breast cancer after taking Yunzhi-Danshen capsules, while plasma soluble interleukin-2 receptor (sIL-2R) concentration was significantly decreased (all p &lt; 0.05). / This study shows that the selected traditional Chinese medicine have determinable immunomodulatory effects in patients with cancer and rheumatoid arthritis. (Abstract shortened by UMI.) / Traditional Chinese medicine (TCM) has been used to treat chronic diseases and tumor allegedly by immunomodulatory mechanisms. Breast cancer and nasopharyngeal cancer are prevalent carcinoma diseases in Hong Kong. The immune system of such patients could be adversely affected during the course of conventional chemotherapy or radiotherapy. Rheumatoid arthritis is an inflammatory autoimmune disease of the joints. The aim of this study was to assess the immunomodulatory effects of TCM Yunzhi-Danshen in auxiliary treatment of both kinds of cancer patients, and Lingzhi (Ganoderma Lucidum)-San Miao San ( Atractylodes lancea, Phellodendron amurense and Achyranthes bidentata B1) in supplementation treatment of patients with rheumatoid arthritis. / by Bao Yixi. / "July 2005." / Adviser: Wai-Kei Lam. / Source: Dissertation Abstracts International, Volume: 67-01, Section: B, page: 0166. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2005. / Includes bibliographical references (p. 150-167). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. [Ann Arbor, MI] : ProQuest Information and Learning, [200-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstracts in English and Chinese. / School code: 1307.

<p>Uvod: Reumatoidni artritis (RA) je bolest koja dovodi do ireverzibilnog o&scaron;tećenja zglobova usled čega je neophodno pri postavljanju dijagnoze započeti lečenje. TNF-alfa inhibitori predstavljaju revolucionarno otkriće u lečenju RA, pri čemu su najče&scaron;će kori&scaron;ćeni Etanercept i Adalimumab. Oni nisu efikasni kod svih pacijenata kod kojih se primene, a mehanizmi gubitka odgovora nisu jasni. Cilj rada je odrediti uticaj Etanercepta i Adalimumaba na aktivnost bolesti (merenjem DAS28 SE i DAS28 CRP skora) i funkcionalni status pacijenata (merenjem HAQ-DI upitnika), broj bolnih i otečnih zglobova pre i tokom godinu dana primene ovih lekova, kao i utvrditi povezanost koncentracije Etanercepta i Adalimumaba u krvi sa vrednostima DAS28 SE u momentu odreĎivanja koncentracije leka. Praćena je i učestalost neželjenih efekata kod pacijenata lečenih sa ova dva leka. Ispitan je i uticaj primene Metotreksata na nivoe lekova u krvi, kao i doza Metotreksata pre i 6 meseci nakon uvoĎenja Etanercepta ili Adalimumaba. Metode: Studija je sprovedena u Specijalnoj bolnici za reumatske bolesti i Klinici za nefrologiju i kliničku imunologiju, Kliničkog centra Vojvodine u Novom Sadu i obuhvatila je 88 pacijenata kod kojih je postavljena dijagnoza RA, od kojih je 49 bilo lečeno Etanerceptom, a 39 Adalimumabom. Analizirana je medicinska dokumentacija, a nakon početka primene TNF-alfa inhibitora svim ispitanicima je u toku godinu dana svaka tri meseca raĎena kontrola koja je podrazumevala anamnezu i fizički pregled, analizu biohemijskih nalaza krvi, merena je aktivnost bolesti merenjem indeksa aktivnosti bolesti DAS28 SE i DAS28 CRP i raĎena procena funkcionalnog statusa tako &scaron;to je pacijent popunjavao HAQ-DI upitnik. Rezultati: Aktivnost RA merena DAS28 SE i DAS28 CRP indeksima, funkcionalni status meren HAQ-DI upitnikom, broj bolnih i otečenih zglobova i vrednosti reaktanata akutne faze značajno su veći pre početka terapije Etanerceptom i Adalimumabom i smanjuje se tokom prvih 6 meseci lečenja ovim lekovima i potom se taj efekat terapije održava do kraja perioda praćenja. Nema statistički značajne razlike u poreĎenju Etanercepta i Adalimumaba u odnosu na učestalost neželjenih dejstava. Doza Metotreksata je statistički značajno manja 6 meseci nakon upotrebe biolo&scaron;kog leka Etanercept i Adalimumab. Pacijenti lečeni Metotreksatom uz Adalimumab imali su statistički značajno veće nivoe leka, nego oni koji ga nisu koristili. Zaključak: TNF-alfa inhibitori ne dovode do zaustavljanja bolesti kod svih pacijenata kod kojih se primene. Mehanizam gubitka odgovora na terapiju TNF-alfa inhibitorima nije jasan. Kako bi se donela najbolja odluka za pacijenta, neophodno je odrediti nivo leka u krvi, kao i nivo antitela na lek prilikom svake promene stanja pacijenta. Za sada nema dovoljno studija koje ukazuju da li postoji veza izmeĎu ekspresije TNF-alfa gena i nivoa TNF-alfa u krvi, te da li bi se merenjem TNF-alfa u krvi mogla korigovati terapija i doza TNF-alfa inhibitora &scaron;to će verovatno biti predmet budućih istraživanja.</p> / <p>Rheumatoid Arthritis (RA) is a disease that leads to irreversible joint damage, which makes necessary to start treatment when the diagnosis is set. TNF-alpha inhibitors represent a revolutionary discovery in the treatment of RA, and the most commonly used are Etanercept and Adalimumab. They are not effective in all patients, and the mechanisms of loss of response are not clear. The aim of this study is to determine the effect of Etanercept and Adalimumab on disease activity (by measuring DAS28 SE and DAS28 CRP score) and the functional status of patients (by measuring the HAQ-DI questionnaire), the number of painful and swollen joints before and during the first year of administration of these drugs. Also, it was determined a correlation between the concentration of Etanercept and Adalimumab in blood and the values of DAS28 SE at the moment of drug concentration measurement. The incidence of adverse effects in patients treated with these two drugs was also observed. It was examined the effect of Methotrexate on drug levels in the blood as well as the dose of Methotrexate before and 6 months after the introduction of Etanercept or Adalimumab. Methods: The study was conducted at the Special Hospital for Rheumatic Diseases and the Clinic of Nephrology and Clinical Immunology, Clinical Center of Vojvodina in Novi Sad. It included 88 patients with RA, 49 were treated with Etanercept and 39 with Adalimumab. Medical documentation was analyzed, and during the first year of TNF-alpha inhibitor administration, every three months were done anamnesis and physical examination, analysis of blood biochemical findings, measurements of the disease activity with DAS28 SE and DAS28 CRP score and a functional status assessment with the HAQ-DI questionnaire. Results: Disease activity measured by DAS28 SE and DAS28 CRP scores, functional status measured with HAQ-DI questionnaire, number of painful and swollen joints and acute phase reactant values are significantly higher before Etanercept and Adalimumab therapy and decreased during the first 6 months of treatment with these drugs and then this effect of therapy is maintained until the end of the monitoring period. There is no statistically significant difference in the comparison of Etanercept and Adalimumab with respect to the frequency of adverse events. The dose of Methotrexate was statistically significantly lower for 6 months after the use of Etanercept and Adalimumab. Patients treated with Methotrexate and Adalimumab had statistically significantly higher drug levels than those who did not use it. Conclusion: TNF-alpha inhibitors are not effective in all patients who used them. The mechanism of loss of response to TNF-alpha inhibitors is not clear. In order to make the best decision for the patient, it is necessary to determine the drug level in the blood as well as the level of antibodies to the drug in each change in the patient&#39;s condition. For now, there are not enough studies to indicate whether there is a link between expression of the TNF-alpha gene and the level of TNF-alpha in the blood, and whether the measurement of the TNF-alpha in blood could be used for therapy correction and change of dose of TNF-alpha inhibitor, which is likely to be the subject of the future research.</p>

The societal burden of autoimmune diseases and donor organ transplant rejection in developed countries reflects the lack of effective immune suppressive drugs. The main objective of my thesis was to develop novel fusion proteins targeting receptors linked to autoimmunity; strategies that will allow the suppression of autoreactive cells while sparing resting lymphocytes. Interleukin (IL) 15 has been demonstrated to exert its effects mainly on activated T-cells triggered via their T-cell receptor (TCR). Since we found that the fusion of granulocyte-macrophage colony stimulating factor (GMCSF) to IL15 - aka GIFT15 - paradoxically leads to aberrant signalling downstream of the IL15R and blocks interferon (IFN)-gamma secretion in a mixed lymphocyte reaction (MLR), we hypothesized to use this fusokine in proof-of-principle cell transplantation models and shown that GIFT15 can indeed block the rejection of allogeneic and xenogeneic cells in immunocompetent mice. Additionally, we found that ex vivo GIFT15 treatment of mouse splenocytes lead to the generation of regulatory B-cells (Bregs). These Bregs express high levels of MHCII, IL10 and are capable to block antigen (Ag)-presentation in vitro as third party bystander cells. Moreover, a single injection of these GIFT15-generated Bregs in mice with pre-developed experimental autoimmune encephalomyelitis (EAE) leads to long lasting remission of disease. / Along those lines, we also found that mesenchymal stromal cells (MSCs) lead to the paracrine conversion of CCL2 to an antagonist form capable of specifically inhibiting plasma cells and activated Th17 cells. This mechanistic insight informed the design of a second class of suppression fusokine. Namely, the fusing of antagonist CCL2 to GMCSF - aka GMME1. We tested its potential use in autoimmune diseases such as EAE and rheumatoid arthritis (RA). We demonstrated that GMME1 leads to asymmetrical signalling and inhibition of plasma cells as well as Th17 EAE/RA-reactive CD4 T-cells. The net outcome of these pharmacological effects is the selective depletion of CCR2-reactive T-cells as demonstrated both in vitro and in vivo. / Overall, our data support the use of our fusion proteins as part of a powerful and specific immunosuppressive strategy either as directly injectable protein biopharmaceuticals or through the ex vivo generation of autologous Bregs in the case of GIFT15.