Base Teórica: A artrite reumatoide (AR) é uma doença crônica e inflamatória que além de sintomas articulares pode levar à perda de massa muscular com peso estável ou aumentado, condição denominada caquexia reumatoide (CR). A CR está associada com pior prognóstico, mas ainda é negligenciada na prática clínica. Objetivo: Avaliar a prevalência de CR em um hospital público terciário de Porto Alegre e determinar sua correlação com características da AR, com níveis de atividade física e com as medicações em uso. Métodos: Estudo transversal com 91 pacientes com AR que foram submetidos à densitometria corporal total (DEXA) para medida total e regional de índice de massa gorda (IMG; Kg/m2), índice de massa magra (IMM; Kg/m2), conteúdo mineral ósseo (CMO) e índice de massa livre de gordura (IMLG; Kg/m2) para avaliar a prevalência de CR pelas duas definições mais recentemene utilizadas na literatura: IMLG < percentil 10 com IMG > percentil 25 e IMLG < percentil 25 com IMG > percentil 50. Foram exploradas as medidas de associação dos parâmetros de composição corporal com características da AR – idade, duração da doença, atividade de doença (através do DAS 28), capacidade funcional (através do HAQ), atividade inflamatória (através da proteína C reativa – PCR – e velocidade de hemossedimentação – VHS), nível de atividade física (através do questionário IPAQ) e medicações em uso. Resultados: A idade média dos participantes foi 56,8 ± 7,3, a duração de doença foi 9 anos (3-18), o DAS 28 3,65 ± 1,32, o HAQ 1,12 (0,25 – 1,87) e o tempo de uso entre os que usaram biológico foi de 25 meses (17,8 – 52,5). A CR foi evidenciada em 17,6% dos pacientes com AR de acordo com a definição mais rigorosa e em 33% de acordo com a classificação mais abrangente. O IMLG teve correlação negativa com idade (r= -0,219; p=0,037) e duração da doença (rs= -0,214; p=0,042). O IMG teve correlação positiva com PCR (rs=0,229; p=0,029), VHS (rs=0,235; p=0,025), DAS 28 (rs=0,273; p=0,009) e HAQ (rs=0,297; p=0,004). Na comparação de pacientes com e sem CR, de acordo com a definição mais rigorosa, dos 26 pacientes usando biológico apenas 1 tinha CR (3,8%), enquanto dos que não usavam, 15 (23%) tinham CR (p=0,033). Conclusão: A prevalência de CR foi considerável e, portanto, merece estudos adicionais. A composição corporal neste estudo, especialmente o IMLG, teve associação inversa com idade e tempo de diagnóstico. Além disso, pacientes em uso de biológico tiveram diferença significativa na prevalência de CR, sugerindo papel protetor do uso de biológico na CR. / Background: Rheumatoid arthritis (RA) is a chronic and inflammatory disease that besides articular symptoms leads to loss of muscle mass in presence of stable or increased fat mass (FM), condition defined as rheumatoid cachexia (RC). RC is associated with a worse prognosis, but it is still overlooked in clinical practice. Objective: To evaluate the prevalence of rheumatoid cachexia (RC) in patients with rheumatoid arthritis (RA) and determine its correlation with the features of RA, the level of physical activity and with the current therapy. Methods: Ninety one RA patients in a cross-sectional study underwent total body dual-energy x-ray absorptiometry (DXA) for measurement of total and regional fat mass index (FMI; Kg/m2), lean mass index (LMI; Kg/m2), bone mineral content (BMC; Kg/m2) and fat free mass index (FFMI; Kg/m2) to assess the prevalence of RC. The associations of measures of body composition with RA features - age, diagnosis time, Health Assessment Questionnaire (HAQ), Disease Activity Score in 28 joints (DAS 28), C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) -, level of physical activity (measured by International Physical Activity Questionnaire – IPAQ) and current therapy were explored. Results: Mean age was 56,8 ± 7,3 , disease duration 9 years (3 – 18), DAS28 3,65 ± 1,32, HAQ 1,12 (0,25 – 1,87) and use duration of biological agents was 25 months (17,8 – 52,5). Seventeen per cent of the patients had FFMI below the 10th percentile and FMI above the 25th percentile of a reference population and 33% of the patients had FFMI below the 25th percentile and FMI above the 50th percentile, condition known as RC, according to the more recently used definitions. FFMI correlated negatively only with age (r=-0,219; p=0,037) and disease duration (rs=-0,214; p=0,042). FMI correlated positively with CRP (rs=0,229; p=0,029), ESR (rs=0,235; p=0,025), DAS 28 (rs=0,273; p=0,009) and HAQ (rs=0,297; p=0,004). Of the 26 patients using biological therapy, 25 were non cachetic (p=0,033) according to the stricter definition of RC. In another words, 3,8% (n=1) and 23% (n=15) of the patients receiving and not receiving biological agents had RC, respectively (p=0,033). Conclusion: The prevalence of RC was considerable and deserves additional research. Body composition, in this study, particularly FFMI is inversely associated with age and disease duration. Besides that, patients under biological therapy had lower prevalence of RC, suggesting a protective effect of biological agents.

Introdução: A estratégia de tratamento baseado em metas tem sido extensamente estudada em pacientes com AR inicial. No entanto, estudos sobre os benefícios de longo prazo do controle de atividade de doença em pacientes com AR estabelecida ainda são escassos. Objetivo: Avaliar a efetividade de longo prazo da estratégia de tratamento baseado em metas em pacientes com artrite reumatoide estabelecida na prática diária. Métodos: Pacientes com AR, previamente tratados de forma convencional, iniciaram estratégia de tratamento baseado em metas, sendo incluídos de março de 2005 a fevereiro de 2007 e acompanhados até dezembro de 2014. Os pacientes eram avaliados a cada 3 meses até remissão ou baixa atividade de doença serem alcançadas, e após a cada 6 meses. O tratamento seguiu um escalonamento de acordo com as recomendações vigentes. A atividade de doença foi mensurada através do DAS28 e do CDAI e a capacidade funcional, através do HAQ-DI. As informações foram extraídas pela revisão de formulários e de tabelas padronizadas. Variações na atividade de doença e na capacidade funcional foram comparadas pelo teste de Wilcoxon e Equações de Estimativas Generalizadas (GEE) A mortalidade foi avaliada através da curva de Kaplan-Meier. Resultados: Duzentos e vinte e nove pacientes foram incluídos, com duração média de doença 10,6±7,4 anos. Dentre os pacientes em moderada e alta atividade de doença no início da coorte, houve significativa redução do DAS28 (4,6±0,1 vs. 3,1±0,1; p<0,001) e do CDAI (21,2±1,0 vs. 7,9±0,7; p<0,001). Também houve redução do HAQ-DI (1,3±0,05 vs 1,0±0,1; p<0,001). A proporção de pacientes em remissão ou em baixa atividade de doença aumentou de 20% para 62% pelo DAS28. Com a estratégia de tratamento baseado em metas, houve um aumento na proporção de pacientes em uso de biológico para 30%. A taxa de mortalidade foi de 24,2 por 1000 pacientes-ano, discretamente superior à descrita na literatura. Conclusão: A estratégia de tratamento baseado em metas com objetivo de remissão e de baixa atividade de doença é efetivo em pacientes com AR estabelecida. / Introduction: Treating RA to a target has become a landmark strategy to be pursued in every patient. Nonetheless, few studies have addressed the true long-term impact of a T2T strategy in a real-world setting with established RA patients. Objective. To examine the long-term effectiveness of a treat-to-target (T2T) strategy in patients with established rheumatoid arthritis (RA) in daily practice. Methods. Patients with RA who were previously given the standard of care were started on a T2T strategy between March 2005 and February 2007 and followed through December 2014. Participants were seen every 3 months until remission/low disease activity was achieved and every 6 months thereafter. Treatment escalation followed a step-up strategy, according to national recommendations. Disease activity was measured by the DAS28 score and Clinical Disease Activity Index (CDAI), and physical function by the Health Assessment Questionnaire (HAQ). Data were extracted with standardized forms and a chart review. Changes in disease activity and physical function were compared using Wilcoxon’s test and generalized estimating equations. Mortality was analyzed using a Kaplan–Meier survival curve. Results. Two hundred and twenty-nine patients were included, with a mean (S.D.) disease duration of 10.6 (7.4) years. Significant reductions were observed in DAS28 (4.6±0.1 vs. 3.1±0.1; p<0.001), CDAI (21.2±1.0 vs. 7.9±0.7; p<0.001), and HAQ (1.3±0.05 vs 1.0±0.1; p<0.001) scores. The proportion of participants in remission/with low disease activity according to DAS28 increased from 20% to 62%. During implementation of the T2T strategy, a gradual increase in the proportion of participants using biologics was observed, to nearly 30%. The mortality rate was 24.2 per 1000 patient-years, slightly higher than that reported in other cohorts. Conclusion. A treat-to-target strategy aiming for remission or low disease activity is effective in patients with established RA.

Orientadores: Manoel Barros Bértolo, Lilian Tereza Lavras Costallat / Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas / Made available in DSpace on 2018-08-26T07:51:21Z (GMT). No. of bitstreams: 1 Yazbek_MichelAlexandre_D.pdf: 3193834 bytes, checksum: 4155cea9577385c29405700add4864ef (MD5) Previous issue date: 2014 / Resumo: A etiopatogenia da Artrite Reumatoide (AR) envolve fatores genéticos, imunológicos e ambientais que interagem entre si. Os principais fatores de risco estudados são a presença dos alelos do epítopo compartilhado (shared epitope- SE), dos anticorpos anti-peptídeos cíclicos citrulinados (anti-CCP) e do tabagismo. Há evidências que o Epstein-Barr vírus (EBV), ao interagir com esses fatores de risco, possa causar uma resposta imune anômala em indivíduos susceptíveis. Essas interações também podem contribuir para o desenvolvimento da AR. O objetivo principal desse estudo é estabelecer se há uma associação entre o EBV com os alelos do SE, os anticorpos anti-CCP e o tabagismo em pacientes brasileiros com AR. Os objetivos secundários são: avaliar a correlação entre os alelos do SE, os anticorpos anti-CCP e o tabagismo; detectar a exposição ao EBV e quantificar sua carga viral e estimar o risco de cada fator estudado para o desenvolvimento da AR nessa casuística. Nesse estudo caso-controle, incluímos 140 pacientes brasileiros com AR e 143 controles saudáveis; pareados por idade, sexo e etnia. Foi feita uma caracterização clínico-laboratorial da casuística. Foram realizadas a genotipagem para identificar os alelos do SE, a determinação dos anticorpos anti-CCP pelo método de ELISA e coletada a história de tabagismo de todos os sujeitos da pesquisa. Para avaliar a exposição ao EBV, realizamos a dosagem dos anticorpos anti-Epstein-Barr Nuclear Antigen 1 (anti-EBNA1). Para quantificar a carga viral do EBV, realizamos o método quantitativo da reação em cadeia polimerase em tempo real ou real-time PCR. A análise comparativa entre os grupos mostrou uma positividade significativamente maior para os alelos do SE, anticorpos anti-CCP e tabagismo no grupo de pacientes. A análise dos anticorpos anti-EBNA1 mostrou uma positividade alta, tanto em pacientes como em controles, sem diferença significativa. Entretanto, a quantificação da carga viral pela PCR em tempo real mostrou-se muito maior em pacientes do que em controles (p<0.001). As análises associativas dos anticorpos anti-EBNA1 com os outros fatores estudados não se mostraram significativas; assim como as análises associativas da carga viral do EBV pela PCR em tempo real. A positividade do anti-CCP foi maior em pacientes com os alelos do SE que são tabagistas ou ex-tabagistas (p=0.038). Nas análises de regressão logística, a variável com maior risco para o desenvolvimento da AR foi a positividade dos anticorpos anti-CCP. Apesar dos pacientes com AR apresentarem uma carga viral do EBV aumentada, esse estudo não conseguiu associá-la aos demais fatores de risco estudados. Sugerimos que esses achados possam ocorrer devido a um controle deficitário do EBV em pacientes com AR, mas que não está relacionado aos fatores de risco mais conhecidos da doença. A imunidade celular defeituosa dos pacientes com AR dificulta o controle de uma infecção latente do vírus. Portanto, não é possível estabelecer uma relação causal direta entre o EBV e a AR / Abstract: The pathogenesis of rheumatoid arthritis (RA) involves genetic, immunological and environmental factors. The main risk factors are the presence of the shared epitope alleles (shared epitope- SE), anti-cyclic citrullinated peptide antibodies (Anti-CCP) and smoking. There is evidence that the Epstein-Barr virus (EBV), when interacts with these risk factors, may cause an abnormal immune response in susceptible individuals. These interactions may contribute to the development of RA. The main objective of this study is to establish whether there is an association between EBV and alleles of SE, anti-CCP antibodies and smoking in Brazilian patients with RA. Secondary objectives are the assessment of the correlation between alleles of SE, anti-CCP antibodies and smoking; the detection of EBV; the quantification of EBV viral load and the estimation of the likelihood of each analyzed factor for the development of RA in this sample. In this case-control study, we included 140 Brazilian patients with RA and 143 healthy controls; matched for age, sex and ethnicity. We performed a clinical and laboratory characterization of the sample. Genotyping was performed to identify SE alleles, anti-CCP antibodies were examined by ELISA and smoking information was collected from all subjects. To assess the exposure to EBV, we examined anti-Epstein-Barr Nuclear Antigen 1 (anti-EBNA1) antibodies. To quantify the viral load of EBV, we performed the quantitative method of polymerase chain reaction in real time or real-time PCR. The comparative analysis between groups showed a significantly higher positivity for the alleles of SE, anti-CCP antibodies and smoking in patients. The analysis of anti-EBNA1 antibodies showed a high positivity, both in patients and in controls, with no significant difference. However, the quantification of viral load by real-time PCR proved to be much higher in patients than in controls (p <0.001). Associative analysis of anti-EBNA1 antibodies with other factors studied were not significant; as well as the association analyzes of the EBV viral load by PCR in real time. The positivity of anti-CCP antibodies was higher in patients with SE alleles which are smoker or ex-smoker (p = 0.038). In logistic regression analyzes, the variable with higher risk for RA was the positivity of anti-CCP antibodies. Although patients with RA present an increased EBV viral load, this study did not link EBV to the other risk factors studied. We suggest that these findings may be due to a deficient control of EBV in RA patients, which is unrelated to the better-known disease risk factors. Defective cellular immunity of patients with RA complicates the control of latent virus infection. Therefore it is not possible to establish a direct causal relationship between EBV and RA / Doutorado / Clinica Medica / Doutor em Clínica Médica

The aim of this study was to establish whether a splint programme is effective in preventing the deterioration of already evident swan neck and boutonniere deformities in rheumatoid arthritis (RA). A randomised clinical trial was done on 34 RA patients with swan neck and 34 RA patients with boutonniere deformities. The literature revealed that several factors such as age, gender, socio-economic status, time after onset of the illness and lifestyle could influence results. Care was taken to allocate, as far as possible equal numbers of patients with these attributes to the experimental and control groups. It became clear from the literature that swan neck and boutonniere deformities could manifest themselves in different forms and stages or grades of deterioration. Various splints to halt the downward spiral of the deformity were recommended, without proper scientific verification, by the authors. No specifications as to which splint was recommended for which form or grade of deformity or instructions for wearing of the splints were included. For the study the PIP hyperextension splint and the three-point-PIP extension splint was chosen for the swan neck and boutonniere deformities respectively. Patients were followed up for one year. Results were marginally positive for the prevent ion of swan neck deformities by the hyperextension splint programme, but results for the three-point PIP extension splint programmes were negative for grade I boutonniere deformities. Loss of flexor muscle strength was evident in almost all the groups (experimental and control) but more so for grade I swan neck and grade I boutonniere deformities. The variability of measurements were found to be large. Many possible sources of variation were identified, which included biological differences between people, different courses the illness could take and a weak test-retest reliability of some goniometer measurements. This fact and the relatively small sample subgroups caused some results to be not significant on the 5% level. From the significant findings, and other not significant tendencies that were too persistent to ignore, linked to the different manifestations and grades of swan neck and boutonniere deformities, recommendations were made. These suggestions will have to be tested by experimentation.

Autoimmune diseases such as rheumatoid arthritis (RA) are associated with debilitating chronic inflammation, autoantibody production, articular bone erosions and systemic bone loss. The underlying mechanisms and cell types that initiate these diseases are not fully understood, and current therapies mainly address downstream mechanisms and do not fully halt disease progression in all patients. Moreover, previous studies have largely focused on the role of adaptive immunity in driving these diseases, and less attention has been given to the contribution of innate immune pathways such as DNA sensor signaling pathways in initiating and/or perpetuating autoimmunity and erosive inflammatory arthritis. Detection of microbial nucleic acids by DNA sensors such as endosomal toll-like receptors (TLRs) and cytosolic sensors is an early form of antiviral defense. Upon detection of nucleic acid, TLRs dependent on Unc93B and cytosolic sensors dependent on the adaptor stimulator of interferon genes (STING) orchestrate production of type 1 interferons and pro-inflammatory cytokines to resolve infection. Additionally, the cytosolic DNA sensor absent in melanoma 2 (AIM2), which is not dependent on STING, also recognizes microbial DNA and coordinates the cleavage of pro-IL-1β. Previous studies have largely focused on the role of these DNA sensors in macrophages and dendritic cells in the context of antiviral immunity. In recent years, however, the inappropriate recognition of host nucleic acids by these sensors has been associated with several autoimmune diseases including RA. This dissertation aims to delineate the mechanisms by which DNA sensors contribute to inflammatory arthritis and bone remodeling in the context of a murine model of autoimmunity. In DNase II deficient mice, excessive accrual of undegraded, endogenous DNA leads to robust production of type 1 interferons (IFNs) and proinflammatory cytokines. The high levels of type 1 IFNs result in anemia and embryonic lethality; therefore, the gene for the type 1 IFN receptor (IFNaR) has also been deleted so that the mice survive. DNase II-/- IFNaR-/- double knockout (DKO) mice develop erosive inflammatory arthritis, anti-nuclear antibodies, and splenomegaly not seen in the DNase II+/- IFNaR-/- (Het) control group. To evaluate whether cytosolic or endosomal DNA sensors contribute to the clinical manifestations of DKO mice, genes involved in TLR or cytosolic sensor signaling were deleted on the DKO background. Genetically altered mice include STING/DNaseII/IFNaR TKO (STING TKO), AIM2/DNase II/IFNaR TKO (AIM2 TKO), and Unc93b/DNase II/IFNaR TKO (Unc93 TKO) mice. Our hypothesis was that the STING, AIM2, and/or Unc93 pathways would contribute to the autoimmune manifestations in DNase II deficient mice. Rigorous examination of inflammation in these lines revealed important roles for both the STING and AIM2 pathways in arthritis. Despite the substantial effects of the STING and AIM2 pathways on arthritis, STING TKO and AIM2 TKO mice still exhibited prominent autoantibody production. Interestingly, inflammation persisted in Unc93 TKO mice while autoantibody production to nucleic acids was abrogated. Collectively, these data indicate that innate immune pathways contribute to the initiation/perpetuation of inflammatory arthritis and demonstrate that cytosolic and endosomal pathways play distinct roles in the manifestations of autoimmunity. Moreover, they reveal a previously undescribed role for AIM2 as a sensor of endogenous nucleic acids in inflammatory arthritis. Thus, therapeutics that target the STING and AIM2 pathways may be beneficial for the treatment of inflammatory joint diseases. While the role of hematopoietic cells in driving autoimmunity has been well established, the contribution of stromal elements to disease pathogenesis is less well understood. Therefore, we generated bone marrow chimeras to delineate the contribution of hematopoietic and non-hematopoietic cells to the various autoimmune manifestations in DKO mice. These studies revealed that both donor hematopoietic and host radioresistant cells are required for inflammation in the joint as well as for other features of autoimmunity in DKO mice, including splenomegaly, extramedullary hematopoiesis, and autoantibody production. This data demonstrates that stromal host cells play a major role in DNA-driven autoimmunity. Moreover, these results suggest that targeting not only hematopoietic but also stromal elements may be advantageous in the setting of inflammatory arthritis. In the final chapter of this thesis, a role for innate immune sensor pathways in bone is described. The majority of inflammatory arthritides have been shown to lead to systemic loss of bone. Surprisingly, however, we found that DKO mice accumulate trabecular bone in the long bones over time as well as ectopic bone in the spleens, both sites of robust DNA accrual. Moreover, deficiency of the STING pathway abrogated this bone accumulation. Collectively, these data demonstrate that DNA accrual promotes dysregulated bone remodeling through innate immune sensing pathways. These findings are the first to reveal a role for the STING pathway in bone and may unveil novel targets for the treatment of diseases associated with bone disorders.

A psychological intervention involving relaxation training and biofeedback training for the control of peripheral skin temperature was investigated in this study with 27 female rheumatoid arthritics as participants. Based on analysis of the temperature data, it was concluded that the biofeedback response was not learned. From electromyographic data, it was concluded that participants did learn to relax. The hypothesis that the two treatment components would have beneficial effects on the physical, functional, and psychological aspects of rheumatoid arthritis was answered partially. No differential effects as a function of biofeedback training were found as the data for the temperature increase and temperature decrease groups were statistically combined in multiple analyses of variance for repeated measures. Although no differential effects were obtained, numerous positive changes were found. Correlated with the relaxation training were decreases in reported subjective units of discomfort, percentage of time hurting, percentage of body hurting, and general severity of pain. Improved sleep patterns were reported as was increased performance of activities of daily living. Reductions were also found in psychological tension, and in the amount of time mood was influenced by the disease. Shifts were not found in imagery, locus of control, and other psychological dimensions. Constitutional improvements were also absent.

京都大学 / 新制・課程博士 / 博士(医学) / 甲第24991号 / 医博第5025号 / 新制||医||1069(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 生田 宏一, 教授 椛島 健治, 教授 上野 英樹 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

Diss. (sammanfattning) Linköping : Univ., 2003. / Härtill 5 uppsatser.

published_or_final_version / Psychiatry / Master / Master of Philosophy

I investigated the humoral immune response to streptococcal cell walls (SCW) in arthritis susceptible Lewis and resistant Fisher rats. All rats were given a single intraperitoneal injection of either SCW or saline (controls). Rats were sacrificed, three rats per time point, over an eleven week period and serum was collected for ELISA. SCW injected Lewis rats produced anti-SCW antibody, whereas control rats did not. Anti-SCW antibody was significantly elevated over controls between days 14-28 (post injection). Both saline and SCW injected Fisher rats produced anti-SCW antibody, but with different kinetics. Anti-SCW antibody increased by day 7 and remained elevated over controls till day 21, after which there was no difference. ELISA were designed to determine the SCW epitope(s) recognized by anti-SCW antibody. Formamide extracts of SCW, peptidoglycan and polysaccharide, were investigated along with the terminal epitope of polysaccharide, N-acetyl-D-glucosamine, and the peptidoglycan precursor peptide. The data revealed that anti-SCW antibody was directed against a combined SCW epitope, given the lack of significant binding to any of the SCW epitopes tested. Isotype analysis of anti-SCW antibody revealed that the Lewis response was composed primarily of IgG2a whereas the Fisher response was composed primarily of IgM. Binding of rat IgG isotypes to whole streptococcus, SCW, peptidoglycan, and polysaccharide was investigated, given the possibility of background binding by the streptococcal Fc-receptor. Streptococcal binding of rat IgG was specific for IgG2c and the polysaccharide portion of SCW was necessary for binding. Passive immunization of naive Lewis rats with antibody from rats with active arthritis was ineffective at transferring the disease. However, subcutaneous injection of affinity purified anti-SCW antibody or IgG into Lewis rats, followed twenty-four hours later by a single intraperitoneal injection of SCW, suppressed the acute phase and inhibited the chronic disease. IgM rheumatoid factor (RF) was present in the serum of both saline and SCW injected Lewis and Fisher rats. However, SCW injection only induced a significant increase in IgM RF (between days 3-7) in Lewis rats. Passive immunization of Fisher rats with affinity purified IgM RF (from Lewis serum), three days post SCW injection, was ineffective at inducing arthritis.