Recomendações para rastreamento de Tuberculoses Latente (TBL) em pacientes que receberão tratamento com antagonistas do TNF-alfa (anti- TNF) permanecem controversas para regiões endêmicas Objetivo: Esse estudo buscou demonstrar a eficácia em longo prazo do rastreamento e tratamento da TBL em pacientes portadores de Artrite Reumatoide (AR) recebendo anti-TNF. Métodos: 202 pacientes com AR, antes do início do anti-TNF, foram rastreados para TBL por meio do teste tuberculínico (TT), Radiografia de tórax (RX) e história de prévia de exposição à tuberculose (EXP). Todos os pacientes foram seguidos com intervalos de um a três meses. Resultados: 85 pacientes (42%) foram tratados com um único agente anti-TNF e 117 pacientes (58%) mudaram de anti-TNF uma ou duas vezes. O rastreamento para TBL foi positivo em 66 pacientes, 44 apresentaram TT positivo, 23 apresentavam história de exposição (EXP), e 14, alterações radiográficas (RX). EXP isoladamente foi responsável por 14 diagnósticos em pacientes TT negativos. Pacientes portadores de TBL receberam tratamento com Isoniazida (300 mg/dia por seis meses) e nenhum deles desenvolveu TB. Durante os seguimentos, o TT foi repetido em 51 pacientes. A conversão foi observada em cinco: três foram diagnosticados com TBL e dois com TB ativa (14 e 36 meses após receber terapia anti-TNF), sugerindo nova exposição a TB. Conclusão: O rastreamento e tratamento da TBL antes do início da terapia com anti-TNF é efetiva em regiões endêmicas, e reforça a relevância da história de contato com TB para o diagnóstico da TBL em pacientes com AR / Recommendations for screening of latent tuberculosis infection (LTBI) in patients eligible for anti-TNF agents remain unclear in endemic regions. Objective: This study aimed to evaluate the long-term efficacy of LTBI screening/treatment in patients with rheumatoid arthritis (RA) receiving TNF blockers. Design: 202 RA patients were screened for LTBI prior to receiving anti-TNF treatment, by means of tuberculin skin test (TST), chest radiography (X-Ray), and history of tuberculosis exposure (EXP). All subjects were regularly followed at 1- to 3-month intervals. Results: Eighty-five patients (42%) were treated with a single anti-TNF agent, and 117 patients (58%) switched anti-TNF agents once or twice. LTBI screening was positive in 66 patients, 44 presented positive TST, 23 had a history of EXP, and 14, abnormal X-Ray. Exposure alone accounted for LTBI diagnosis in 14 patients with negative TSTs. LTBI patients were treated with Isoniazid (300 mg/day during six months) and none developed TB. During follow up, TST was repeated in 51 patients. Conversion was observed in five: three were diagnosed with LTBI and two with active TB (14 and 36 months after receiving anti-TNF therapy, suggesting new TB exposure). Conclusion: LTBI screening and treatment prior to anti-TNF treatment is effective in endemic areas and reinforces the relevance of contact history for diagnosing LTBI in RA patients

Introdução: A vacinação contra a influenza pandêmica A/H1N1 resultou em soroproteção em mais de 85% dos indivíduos saudáveis. Entretanto, dados em pacientes com artrite reumatoide (AR) são escassos. Objetivos: O objetivo deste estudo é avaliar a imunogenicidade e a segurança em curto prazo da vacina contra influenza pandêmica A/H1N1 em pacientes com AR e a influência da atividade da doença e da medicação nesta resposta. Métodos: Trezentos e quarenta pacientes adultos com AR em seguimento e tratamento regular e 234 controles saudáveis foram examinados antes e 21 dias após receber uma dose da vacina sem adjuvante contra influenza A/California/7/2009. A atividade da doença (DAS28), o tratamento em uso e os títulos de anticorpos também foram avaliados. As taxas de soroproteção (títulos de anticorpos >= 1:40) e soroconversão (percentagem de pacientes com aumento de título de anticorpos maior ou igual a 4, se o título pré- vacinal fosse maior ou igual a 1:10; ou título pós-vacinal de pelo menos 1:40, se o título pré-vacinal era menor que 1:10), as médias geométricas dos títulos (MGT) e o fator de incremento das médias geométricas (FI-MGT) foram calculados. Os eventos adversos foram também registrados. Resultados: Os pacientes com AR e os controles tinham taxas pré-vacinais de soroproteção (10,8% vs. 11,5%) e MGT (8,0 vs. 9,3) comparáveis (p>0,05). Após a vacinação, foi observada redução significativa na resposta dos pacientes com AR versus controles (p<0,001) em todos os desfechos sorológicos: taxas de soroproteção (60,0 vs. 82,9%) e soroconversão (53,2% vs. 76,9%), MGT (57,5 vs. 122,9) e FI-MGT (7,2 vs. 13,2). A atividade de doença não prejudicou a soroproteção ou a soroconversão e se manteve estável em 97,4% dos pacientes. O metotrexato e o abatacepte foram associados à redução da resposta vacinal. A vacinação foi bem tolerada, com poucos efeitos adversos. Conclusão: Os dados confirmaram tanto a segurança em curto prazo como, diferente da maioria dos trabalhos com influenza sazonal, a redução da soroproteção em pacientes com AR, não relacionada à atividade de doença e à maioria das medicações em uso (com exceção do metotrexato e do abatacepte). A extrapolação da resposta imunológica de uma vacina para outra pode não ser possível e estratégias específicas de imunização (possivelmente em duas doses) podem ser necessárias / Background: Pandemic influenza A/H1N1 vaccination yielded seroprotection in more than 85% of healthy individuals. However, similar data are scarce in rheumatoid arthritis (RA) patients. Objectives: The objective of this study is to evaluate the immunogenicity and the short-term safety of anti- pandemic influenza A/H1N1 vaccine in RA patients, and the influence of disease activity and medication to the response. Methods: Three hundred and forty adult RA patients in regular follow-up and treatment, and 234 healthy controls were assessed before and 21 days after adjuvant-free influenza A/California/7/2009 vaccine. Disease activity (DAS28), current treatment and anti-pandemic influenza A/H1N1 antibody titres were also evaluated. Seroprotection (antibody titre >=1:40) and seroconversion (the percentage of patients with a fourfold or greater increase in antibody titre, if prevaccination titre was 1:10 or greater, or a postvaccination titre of 1:40 or greater, if prevaccination titre was less than 1:10) rates, geometric mean titres (GMT) and factor increase in geometric mean titre (FI-GMT) were calculated and adverse events registered. Results: RA patients and controls showed similar (p>0.05) prevaccination seroprotection (10.8% vs. 11.5%) and GMT (8.0 vs. 9.3). After vaccination a significant reduction (p<0.001) was observed in all endpoints in RA patients versus controls: seroprotection (60.0 vs. 82.9%; p<0.0001) and seroconversion (53.2% vs. 76.9%) rates, GMT (57.5 vs. 122.9) and FI-GMT (7.2 vs. 13.2). Disease activity did not preclude seroprotection or seroconversion and remained unchanged in 97.4% of patients. Methotrexate and abatacept were associated with reduced responses. Vaccination was well tolerated with minimal adverse events. Conclusions: The data confirmed both short-term anti-pandemic A/H1N1 vaccine safety and, different from most studies with seasonal influenza, reduced seroprotection in RA patients, unrelated to disease activity and to most medications (except methotrexate and abatacept). Extrapolation of xii immune responses from one vaccine to another may therefore not be possible and specific immunization strategies (possibly booster) may be needed

Introdução: A artrite reumatoide (AR) é a doença inflamatória autoimune mais comum entre a população adulta, caracterizada por poliartrite aditiva e simétrica em pequenas e grandes articulações, com consequente envolvimento sinovial e gradual degeneração articular. Pacientes com AR possuem diminuição de força e massa muscular com perda funcional progressiva e péssima qualidade de vida. Treinamento de força (TF) é efetivo e seguro em reverter a atrofia muscular, porém alguns pacientes são incapazes de realizar TF de alta intensidade, devido a limitações inerentes a doença. O TF associado à restrição parcial do fluxo sanguíneo (TF-RFS) emerge como alternativa ao treinamento convencional, em função das baixas cargas utilizadas e menor estresse articular. Objetivo: Avaliar os efeitos do treinamento de força associado à restrição parcial do fluxo sobre a força, massa muscular, capacidade funcional e qualidade de vida em pacientes com AR. Métodos: 48 mulheres com AR foram randomizadas em tres grupos: treinamento de força de alta intensidade sem restrição do fluxo sanguíneo (TFA: 70% de uma repetição máxima [1-RM]), treinamento de força de baixa intensidade associado à restrição parcial do fluxo sanguíneo (TF-RFS: 30% de 1-RM) e um grupo controle sem treinamento (GC). Os grupos TFA e TF-RFS receberam treinamento de força supervisionado duas vezes por semana, durante doze semanas consecutivas. Antes e após a intervenção, avaliou-se a capacidade de produção de força nos membros inferiores (teste de 1-RM), a área de secção transversa (AST) do quadríceps, a capacidade funcional (timed stand test [TST], timed-up-and-go test [TUG] e Health Assessment Questionnaire [HAQ]) e a qualidade de vida (Short Form Health Survey [SF- 36]). Resultados: Os grupos TF-RFS e TFA foram similares em aumentar a força dinâmica máxima, tanto no leg-press (+22,8% e +24,2%, p < 0,0001) quanto na cadeira extensora (+19,7%% e +23,8%, p<0,0001), respectivamente. A AST do quadríceps também aumentou significantemente após a intervenção em ambos TF-RFS e TFA (+9,5%% e +10,8%, p < 0,0001), respectivamente. Os grupos TF-RFS e TFA obtiveram aumentos similares no TST (+11,2% e +14,7%, p < 0,0001) e no TUG (-6,8%, p < 0.0053 e -8,7%, p < 0,0001), respectivamente. Todos estes resultados foram significantemente maiores (p < 0,05) quando comparados ao GC. Os domínios limitação física e dor do questionário SF-36, assim como, o escore do HAQ melhoraram de forma significativa apenas no TF-RFS (+45,7%, +22,5% e -55,9%, respectivamente, p < 0.05). Apenas um paciente foi excluído, porém oito pacientes (50%) relataram dor nos joelhos relacionadas ao treino de alta intensidade, fato que não aconteceu no grupo treinado com restrição do fluxo sanguíneo. Conclusão: O TF-RFS foi efetivo em melhorar a força e massa muscular nos membros inferiores, bem como, a funcionalidade e a qualidade de vida nos pacientes com AR, surgindo como uma modalidade terapêutica eficaz e segura para o tratamento destes pacientes / Introduction: Rheumatoid arthritis (RA) is the most common autoimmune inflammatory disease among the adult population and is marked by additive and symmetrical polyarthritis in small and large joints, with consequent synovial involvement and gradual joint degradation. Patients with RA have decreased muscle strength and mass with progressive functional loss and poor quality of life. Resistance training is effective and safe to reverse muscle atrophy, but some patients are unable to perform a conventional high-intensity exercise program due to disease-related limitations. Blood flow restriction training arises as an alternative to conventional training, due to lower loads and lesser joint stress imposed to the patient. Objective: To evaluate the effects of a low- intensity resistance training program associated with partial blood flow restriction in patients with RA. Methods: Forty-eight women with RA were randomized into one of the three groups: high-intensity resistance training (HI- RT: 70% one repetition maximum [1-RM]); low-intensity resistance training with partial blood flow restriction (BFRT: 30% 1-RM); and control group. Patients completed a 12-week supervised training program and were assessed for lower-limb 1-RM, quadriceps cross-sectional area (CSA), physical function (timed-stands test [TST], timed-up-and-go test [TUG], Health Assessment Questionnaire [HAQ]), and quality of life (Short Form Health Survey [SF-36]) at baseline and after the intervention. Results: BFRT and HI-RT were similarly effective in increasing maximal dynamic strength in both leg-press (+22.8% and +24.2%, all p < 0.0001) and knee extension (+19.7% and+23.8%; all p < 0.0001). Quadriceps CSA was also significantly increased in both BFRT and HI-RT (+9.5% and +10.8%; all p < 0.0001, respectively). Comparable improvements in TST (+11.2% and +14.7%; all p < 0.0001) and TUG (-6.8%, p < 0.0053 and -8.7%, p < 0.0001), were also observed in BFRT and HI-RT, respectively. Improvements in both groups were significantly greater than those of CG (all p < 0.05). SF-36 role physical, bodily pain and HAQ scores were improved only in BFRT (+45.7%, +22.5% and -55.9%, respectively; all p < 0.05). HI-RT resulted in one case of withdrawal and several cases of exercise-induced pain, which did not happen in BFRT. Conclusion: BFRT was effective in improving muscle strength, mass, function, and health-related quality-of-life in patients with RA, emerging as a viable therapeutic modality in RA management

The development of essential medicines is being slowed by a lack of efficiency in drug development as ninety per cent of drugs fail at some stage during clinical evaluation. This attrition in drug development is seen not because of a reduction in pharmaceutical research expenditure nor is it caused by a declining understanding of biology, if anything, these are both increasing. Instead, drugs are failing because we are unable to effectively predict how they will work before they are given to patients. This is due to limitations of the current methods used to evaluate a drug's toxicity and efficacy prior to its development. Quite simply, these methods do not account for the full complexity of biology in humans. Systems pharmacology models are a likely candidate for increasing the efficiency of drug discovery as they seek to comprehensively model the fundamental biology of disease mechanisms in a quantit- ative manner. They are computational models, designed and hailed as a strategy for making well-informed and cost effective decisions on drug viability and target druggability and therefore attempt to reduce this time-consuming and costly attrition. Using text mining and text classification I present a growing landscape of systems pharmacology models in literature growing from humble roots because of step-wise increases in our understanding of biology. Furthermore, I develop a case for the capability of systems pharmacology models in making predictions by constructing a model of interleukin-6 signalling for rheumatoid arthritis. This model shows that druggable target selection is not necessarily an intuitive task as it results in an emergent but unanswered hypothesis for safety concerns in a monoclonal antibody. Finally, I show that predictive classification models can also be used to explore gene expression data in a novel work flow by attempting to predict patient response classes to an influenza vaccine.

Introdução: A hanseníase é uma doença infecciosa crônica causada pelo Mycobacterium leprae. É considerada um dos maiores problemas de saúde pública nos países em desenvolvimento. Os principais sinais clínicos são manchas de pele com perda de sensibilidade e envolvimento de nervos periféricos. Manifestações musculoesqueléticas são descritas em adultos, mas este envolvimento é raramente descrito na população pediátrica. Objetivo: Avaliar envolvimento musculoesquelético e auto-anticorpos em pacientes pediátricos com hanseníase. Métodos: Foram avaliados 50 pacientes com hanseníase e 47 crianças e adolescentes saudáveis de acordo com manifestações musculoesqueléticas (artralgia, artrite e mialgia), síndromes dolorosas musculoesqueléticas (fibromialgia juvenil, síndrome de hipermobilidade articular benigna, síndrome miofascial e tendinite) e painel de auto-anticorpos e crioglobulinas. Escores de avaliação de saúde e tratamento foram realizados nos pacientes com hanseníase. Resultados: A frequência de manifestações musculoesqueléticas foi maior em pacientes com hanseníase comparada aos controles (14% vs. 0%, p=0,0012). Cinco pacientes com hanseníase tinham poliartrite assimétrica das pequenas articulações das mãos (10% vs. 0%, p=0,057). Comprometimentos da função do nervo, reação tipo I hansênica, e neuropatia silenciosa foram observados nos pacientes com hanseníase (p=0,0006; p=0,003; p=0,0059; respectivamente). Nenhum dos pacientes e controles apresentou síndromes de dor musculoesquelética e as frequências dos anticorpos e crioglobulinas foram semelhantes nos dois grupos (p > 0,05). Comprometimentos da função nervosa, reação hansênica tipo I e neuropatia silenciosa foram observados em pacientes com versus sem manifestações musculoesqueléticas (p=0,0036; p=0,0001; p=0,309; respectivamente), bem como subtipos de hanseníase multibacilar (86% vs. 42%, p=0,045). A escala visual analógica do médico (VAS), dos pacientes (VAS), de dor (VAS) e CHAQ foram maiores em pacientes com manifestações musculoesqueléticas (p=0,0001; p=0,002; p=0002; p=0,001, respectivamente). Conclusão: Este foi o primeiro estudo a identificar manifestações musculoesqueléticas associadas com disfunção de nervos periféricos em pacientes pediátricos. A hanseníase deve ser incluída no diagnóstico diferencial de artrite assimétrica, principalmente em regiões endêmicas / Introduction: Leprosy is a chronic infectious disease caused by Mycobacterium leprae. It is considered one of major public health issue in developing countries. The important clinical signs of leprosy are hypopigmented or reddish localized skin lesions with loss of sensation and peripheral nerves involvement. Musculoskeletal manifestations were described in leprosy adult patients and these involvements were rarely described in pediatric leprosy population. Objective: To evaluate musculoskeletal involvement and autoantibodies in pediatric leprosy patients. Methods: 50 leprosy patients and 47 healthy children and adolescents were assessed according to musculoskeletal manifestations (arthralgia, arthritis and myalgia), musculoskeletal pain syndromes (juvenile fibromyalgia, benign joint hypermobility syndrome, myofascial syndrome and tendinitis) and a panel of autoantibodies and cryoglobulins. Health assessment scores and treatment were performed in leprosy patients. Results: The frequency of at least one musculoskeletal manifestation was significantly higher in leprosy patients compared to controls (14% vs. 0%, p=0.0012) and five leprosy patients had asymmetric polyarthritis of small hands joints (10% vs. 0%, p=0.057), Nerve function impairment, type I leprosy reaction and silent neuropathy were significantly observed in leprosy patients (p=0.0006; p=0.003; p=0.0059; respectively). None of the patients and controls presented musculoskeletal pain syndromes and the frequencies of all antibodies and cyoglobulins were similar in both groups (p>0.05). Further analysis of leprosy patients showed that the frequencies of nerve function impairment, type I leprosy reaction and silent neuropathy were significantly observed in patients with versus without musculoskeletal manifestations (p=0.0036; p=0.0001; p=0.309; respectively), as well as multibacillary subtypes in leprosy (86% vs. 42%, p=0.045). The median of physician visual analogue scale (VAS), patients VAS, pain VAS and CHAQ were significantly higher in leprosy patients with musculoskeletal manifestations (p=0.0001; p=0.002; p=0002; p=0.001; respectively). Conclusions: This was the first study to identify musculoskeletal manifestations associated with nerve dysfunction in pediatric leprosy patients. Hansen´s disease should be included in the differential diagnosis of asymmetric arthritis, especially in endemic regions

La polyarthrite rhumatoïde (PR) est le rhumatisme inflammatoire chronique le plus fréquent. Cette maladie est caractérisée par une auto-immunité et une synovite hypertrophique, responsables d'une destruction des articulations périphériques. Les macrophages contribuent aux phénomènes inflammatoires de la PR. Ces cellules peuvent présenter différents états d'activation ou " polarisation ", réversibles, dépendant de leur environnement, notamment cytokinique. Les biothérapies (bDMARDs) ont représenté une avancée majeure dans la prise en charge des manifestations inflammatoires des formes sévères de PR. Toutefois, peu d'études ont évalué si ce bénéfice était lié à une action spécifique sur le macrophage. L'objectif de ce travail de transversal était : (i) d'évaluer in vitro l'effet des principales biothérapies de la PR (anti-TNF : etanercept, adalimumab, certolizumab ; anti-IL- 6R : tocilizumab ; CTLA4-Ig : abatacept) sur la différenciation et l'activation de macrophages dérivés de monocytes issus de patients atteints de PR et de sujets sains, (ii) d'identifier des marqueurs de polarisation du macrophage, corrélés à l'activité de la maladie (DAS28). Parmi les bDMARDs évalués, seuls les anti-TNF ont montré une action sur la polarisation des macrophages. En contexte de différenciation avec M-CSF, les bDMARDs anti-TNF ont induit un biais vers une polarisation non inflammatoire dite alternative. En contexte d'activation inflammatoire, les bDMARDs anti-TNF ont induit une préservation sélective des marqueurs de polarisation liés à l'IL-10 (CD16, CD163, MerTK) et une inhibition des marqueurs inflammatoires (CD40, CD80). Nous avons montré que ce changement phénotypique s'accompagnait : (i) d'un changement fonctionnel concordant avec une polarisation induite par l'IL-10, (ii) d'une inhibition de la production des cytokines de l'inflammation (TNF, IL-6, IL-12), (iii) et d'une majoration de la phagocytose. Nous avons montré que ce mécanisme était dû à une production précoce d'IL-10 et dépendant de STAT3. De plus, nous avons pu montrer que le certolizumab, un anti-TNF, induisait une réponse anti-inflammatoire, impliquant le facteur de transcription NRF2 (nuclear factor erythroid-2-related factor 2), un régulateur central dans la réponse au stress oxydatif. Enfin, nous avons observé que l'expression de CD16, à la surface des macrophages non activés, était corrélée négativement à l'activité de la PR. Ces travaux concourent à montrer l'intérêt du ciblage du macrophage dans la PR et nous ont d'identifier de potentielles cibles théranostiques dans le traitement de la PR par anti-TNF. / Rheumatoid arthritis (RA) is the most frequent chronic inflammatory rheumatism. This disease is characterized by an auto-immunity and a hyperplasic synovitis, both responsible for peripheral joints destruction. Macrophages contribute to inflammatory aspects of RA. This cell type can present various states of activation or "polarization", reversible and dependent on its environment, notably cytokines. Biologics (bDMARDs) represented a revolution in severe RA treatment. However, data regarding their specific action on macrophage are scarce. The aim of our translational work was: (i) to assess the in vitro effect of RA bDMARDs (anti-TNF: etanercept, adalimumab, certolizumab; anti-IL-6R: tocilizumab; CTLA4-Ig: abatacept) on the phenotype of monocytes-derived-macrophages from RA patients and healthy volunteers, during differentiation and activation phases, (ii) to identify polarization markers correlated with disease activity (DAS28). Among bDMARDs, only anti-TNF modulated macrophage polarization. During differentiation, anti-TNF bDMARDs induced a bias toward the so-called alternative non-inflammatory polarization. In inflammatory context, anti-TNF bDMARDs induced a selective preservation of markers associated with IL-10 (CD16, CD163, MerTK) and an inhibition of inflammatory markers (CD40, CD80). We showed that these changes in phenotype were associated with changes in functions consistent with: (i) a polarization induced by IL10, (ii) a decrease in inflammatory cytokines production (TNF, IL-6, IL-12), (iii) and an increase in phagocytosis. We showed that this mechanism was dependant on early IL-10 production and STAT3 signaling. Moreover, we have showed that certolizumab, an anti-TNF agent, induced an anti-inflammatory response, implicating the transcription factor NRF2 (nuclear factor erythroid-2- related factor 2), a central regulator of the response to oxidative stress. We observed that CD16 expression on non-activated macrophages was negatively correlated with RA activity. This work contributes to demonstrate the relevance of macrophage targeting in RA, and enabled us to identify theranostic targets for RA treatment with anti-TNF bDMARDs.

Submitted by Mariana De Almeida Lourenço (maalmeida1@terra.com.br) on 2019-01-29T12:04:26Z No. of bitstreams: 1 TESE_Mariana_Almeida_FINAL.pdf: 3376155 bytes, checksum: 3ab5bd7934378b17e0fc5c3b3bdc4cb9 (MD5) / Rejected by Adriana Aparecida Puerta null (dripuerta@rc.unesp.br), reason: Prezada Mariana, O documento enviado para a coleção Campus Unesp Rio Claro foi recusado pelo(s) seguinte(s) motivo(s): - Ficha catalográfica: Note que abaixo do quadrado conta o Instituto errado. Está Biblioteca da Faculdade de Ciências Farmacêuticas, Araraquara. Necessário refazer no site e corrigir o campus. Agradecemos a compreensão e aguardamos o envio do novo arquivo. Atenciosamente, Biblioteca Campus Rio Claro Repositório Institucional UNESP https://repositorio.unesp.br on 2019-01-29T18:30:27Z (GMT) / Submitted by Mariana De Almeida Lourenço (maalmeida1@terra.com.br) on 2019-01-30T11:47:23Z No. of bitstreams: 1 TESE_Mariana_Almeida_Lourenco.pdf: 3376137 bytes, checksum: b295dd19c611a8e8c01700329ec22a7f (MD5) / Approved for entry into archive by Adriana Aparecida Puerta null (dripuerta@rc.unesp.br) on 2019-01-30T12:50:36Z (GMT) No. of bitstreams: 1 lourenço_ma_dr_rcla.pdf: 3179228 bytes, checksum: 9affa4b46e866d3534005db21feb3961 (MD5) / Made available in DSpace on 2019-01-30T12:50:36Z (GMT). No. of bitstreams: 1 lourenço_ma_dr_rcla.pdf: 3179228 bytes, checksum: 9affa4b46e866d3534005db21feb3961 (MD5) Previous issue date: 2018-12-17 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) / A articulação do joelho é frequentemente acometida por sinovite em pacientes com artrite reumatoide (AR). Esse processo inflamatório provoca um reflexo de inibição muscular artrogênica e consequente diminuição de força nos extensores de joelho, além de dor, edema e prejuízos funcionais. A infiltração intra-articular (IIA) com hexacetonide de triancinolona (HT) tem se mostrado eficaz no controle do acometimento articular em pacientes com AR. O objetivo geral do presente estudo foi analisar os efeitos da infiltração intra-articular em mulheres com AR de HT ou solução salina em parâmetros como força muscular de extensores de joelho, dor, edema, funcionalidade e amplitude de movimento. Vinte e uma mulheres com AR foram randomizadas aleatoriamente para receber 3ml de HT (GI) ou de solução salina (GC) no joelho, com avaliações feitas em 4 momentos: imediatamente antes a IIA, após 2, 6 e 12 semanas. Foram aplicados questionários para funcionalidade (WOMAC, Lequesne, HAQ), escala visual analógica para dor ao repouso e ao movimento, circumetria, teste de força de extensores de joelho, biofotogrametria para amplitude de movimento e os testes físicos Timed Up And Go (TUG) e Teste de Sentar e Levantar. Na análise estatística foi realizado teste de normalidade de Shapiro-Wilk, Teste de Levene para homogeneidade dos grupos, análise de variância (ANOVA) mista com medidas repetidas para comparação intra e inter grupos, correlação de Pearson e regressão linear com significância de P< 0,05. Foi observado diminuição da dor ao repouso e ao movimento, redução do edema e melhora da funcionalidade no grupo que recebeu o medicamento, porém não houve diferença significativa entre os grupos com relação à força muscular e amplitude de movimento. O presente estudo mostrou que, embora não haja diferença na força muscular e amplitude de movimento, a eficácia da IIA com HT em joelho parece ser superior na melhora da dor, edema e funcionalidade quando comparada a solução salina em mulheres com AR. / The knee joint is often affected by synovitis in rheumatoid arthritis (RA) patients. This inflammatory process causes a reflex of arthrogenic muscle inhibition and consequent decrease of strength in the knee extensors, pain, swelling and functional impairment. Intra-articular infiltration (IIA) with triamcinolone hexacetonide (HT) has been shown to be effective in controlling joint involvement in RA patients. The general objective of the present study was to analyze the effects of intraarticular infiltration in RA women´s knee with HT or saline solution in parameters such as knee extensors muscle strength, pain, swelling, functionality and range of motion. Twenty-one RA women were randomly assigned to receive 3ml of TH (GI) or saline solution (GC) in the knee, with assessments made in 4 moments: immediately before the IIA, after 2, 6 and 12 weeks. Functional questionnaires (WOMAC, Lequesne, HAQ), visual analogue scale for pain, circummetry, knee extensor strength test, biophotogrammetry for range of motion and the physical test Timed Up And Go (TUG). Statistical analysis was performed using the Shapiro-Wilk normality test, Levene test for homogeneity of groups, mixed analysis of variance (ANOVA) with repeated measures for intra and inter group comparison, Pearson's correlation and linear regression with significance of P <0,05. Decreased pain at rest and movement, reduction of swelling and improvement of functionality in the group receiving the medication were observed, but there was no significant difference between the groups in relation to muscle strength and range of motion. The present study showed that, although there is no difference in muscle strength and range of motion, the effectiveness of IIA with HT in knee appears to be superior in improving joint inflammation and functionality when compared to saline solution in RA women.

Wong Hei Lui. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2001. / Includes bibliographical references (leaves 192-226). / Abstracts in English and Chinese. / Publications Based On The Work In This Thesis --- p.i / Abstract --- p.ii / Acknowledgements --- p.vii / Abbreviations --- p.viii / Chapter Chapter 1 --- Introduction --- p.1 / Chapter 1.1 --- Normal joint --- p.1 / Chapter 1.11 --- Biology of joint --- p.1 / Chapter 1.12 --- Structure of synovial joint --- p.1 / Chapter 1.13 --- Components of the mature synovial joint --- p.3 / Chapter 1.131 --- Articular cartilage --- p.3 / Chapter 1.1311 --- Water --- p.4 / Chapter 1.1312 --- Cartilage matrix --- p.4 / Chapter 1.1313 --- Chondrocyte --- p.5 / Chapter 1.132 --- Synovium --- p.5 / Chapter 1.1321 --- Synovium vasculature --- p.6 / Chapter 1.1322 --- Synovial blood flow --- p.7 / Chapter 1.133 --- Synovial fluid --- p.8 / Chapter 1.134 --- Bone --- p.9 / Chapter 1.2 --- Pathological processes of arthritis --- p.11 / Chapter 1.21 --- Activation of immune cells in arthritis --- p.11 / Chapter 1.22 --- Synovial proliferation --- p.13 / Chapter 1.221 --- Synovial lining cell activation --- p.13 / Chapter 1.222 --- Pannus invasion --- p.14 / Chapter 1.23 --- Cartilage and bone degradation --- p.14 / Chapter 1.231 --- Depletion of proteoglycan (GAG) --- p.15 / Chapter 1.232 --- Collagen denature --- p.15 / Chapter 1.3 --- Tachykinins (TKs) --- p.17 / Chapter 1.31 --- History --- p.17 / Chapter 1.32 --- "Synthesis, storage and release of TKs" --- p.17 / Chapter 1.33 --- Tachykinin receptors --- p.18 / Chapter 1.331 --- Characterization of NK1 receptor --- p.19 / Chapter 1.332 --- Characterization of NK2 receptor --- p.19 / Chapter 1.333 --- Characterization of NK3 receptor --- p.20 / Chapter 1.34 --- Effector systems of TKs --- p.21 / Chapter 1.35 --- Termination of TK signals --- p.21 / Chapter 1.351 --- Enzymatic breakdown --- p.21 / Chapter 1.352 --- Receptor desensitization --- p.22 / Chapter 1.353 --- Receptor endocytosis --- p.22 / Chapter 1.36 --- TK receptor antagonists --- p.23 / Chapter 1.361 --- Selective NK1 receptor antagonists --- p.23 / Chapter 1.362 --- Selective NK2 receptor antagonists --- p.24 / Chapter 1.363 --- Selective NK3 receptor antagonists --- p.25 / Chapter 1.4 --- Roles of tachykinins in arthritis --- p.28 / Chapter 1.41 --- Correlation between tachykinins and joint inflammation --- p.28 / Chapter 1.42 --- Roles of tachykinins in immune cell activation --- p.30 / Chapter 1.43 --- Roles of tachykinins in synovial proliferation --- p.31 / Chapter 1.44 --- Roles of tachykinins in cartilage degradation --- p.32 / Chapter 1.5 --- Animal model of arthritis --- p.33 / Chapter 1.51 --- Instability model --- p.33 / Chapter 1.52 --- Immobilization model --- p.34 / Chapter 1.53 --- Noxious agent-induced model --- p.34 / Chapter 1.531 --- Collagen-induced erosive arthritis --- p.34 / Chapter 1.532 --- Cartilage oligometric matrix protein-induced arthritis --- p.35 / Chapter 1.533 --- Oil-induced arthritis --- p.35 / Chapter 1.534 --- Streptococcal cell wall-induced arthritis --- p.35 / Chapter 1.535 --- Adjuvant-induced arthritis --- p.36 / Chapter 1.536 --- Pristane-induced arthritis --- p.36 / Chapter 1.6 --- Current anti-arthritic therapies --- p.39 / Chapter 1.61 --- Non steroid anti-inflammatory drugs --- p.39 / Chapter 1.62 --- Glucocorticoid --- p.44 / Chapter 1.63 --- Second-line treatment --- p.46 / Chapter 1.631 --- Sulfasalazine --- p.46 / Chapter 1.632 --- Gold salts --- p.47 / Chapter 1 633 --- D-penicillamine --- p.48 / Chapter 1.634 --- Antimalarial --- p.49 / Chapter 1 .635 --- Methotrexate --- p.51 / Chapter 1.64 --- New trends for treatment of arthritis --- p.53 / Chapter 1.641 --- Anti-cytokine therapy --- p.53 / Chapter 1.642 --- Anti-angiogenesis therapy --- p.54 / Chapter 1.7 --- Aims of study --- p.57 / Chapter Chapter 2 --- Material and drugs --- p.62 / Chapter Chapter 3 --- Methodology --- p.62 / Chapter 3.1 --- Animals used and anaesthetization --- p.62 / Chapter 3.2 --- Measurement of plasma protein extravasation --- p.63 / Chapter 3.3 --- Measurement of knee joint sizes --- p.64 / Chapter 3.4 --- Measurement of knee joint blood flow --- p.65 / Chapter 3.5 --- Measurement of histological changes --- p.65 / Chapter 3.51 --- Dissection and fixation --- p.65 / Chapter 3.52 --- Decalcification --- p.66 / Chapter 3.53 --- Processing --- p.66 / Chapter 3.54 --- Embedding --- p.67 / Chapter 3.55 --- Sectioning --- p.67 / Chapter 3.56 --- Staining --- p.69 / Chapter 3.6 --- Data analysis --- p.69 / Chapter 3.61 --- Scoring systems --- p.72 / Chapter Chapter 4 --- A model of monoarthritis in rats --- p.72 / Chapter 4.1 --- Introduction --- p.72 / Chapter 4.2 --- Method --- p.73 / Chapter 4.3 --- Results --- p.73 / Chapter 4.31 --- Lewis rats --- p.73 / Chapter 4.32 --- Sprague-Dawley (SD) rats --- p.74 / Chapter 4.33 --- Comparison of FCA-induced changes in Lewis and SD rats --- p.74 / Chapter 4.34 --- Histological studies on arthritic SD rats --- p.75 / Chapter 4.4 --- Discussion --- p.93 / Chapter 4.5 --- Conclusions --- p.95 / Chapter Chapter 5 --- Effect of Substance P on adjuvant-induced arthritis --- p.96 / Chapter 5.1 --- Introduction --- p.96 / Chapter 5.2 --- Method --- p.98 / Chapter 5.3 --- Results --- p.99 / Chapter 5.31 --- Evans blue extravasation --- p.99 / Chapter 5.32 --- Joint size --- p.100 / Chapter 5.33 --- Knee joint blood flow --- p.101 / Chapter 5.34 --- Histology results --- p.102 / Chapter 5.341 --- Infiltration of immune cells in synovial tissue --- p.102 / Chapter 5.342 --- Synovial tissue proliferation --- p.102 / Chapter 5.343 --- Cartilage degradation --- p.103 / Chapter 5.344 --- Bone degradation --- p.103 / Chapter 5.4 --- Discussion --- p.120 / Chapter 5.5 --- Conclusions --- p.125 / Chapter Chapter 6 --- Effects of tachykinin receptor antagonists on FCA-induced arthritis / Chapter 6.1 --- Introduction --- p.126 / Chapter 6.2 --- Method --- p.128 / Chapter 6. 21 --- Intravenous NK1 receptor antagonists on FCA-induced arthritis --- p.128 / Chapter 6. 22 --- Intraperitoneal TK receptor antagonists on FCA-induced arthritis --- p.128 / Chapter 6.3 --- Results --- p.129 / Chapter 6.31 --- Intravenous NK1 227}0اreceptor antagonists on FCA-induced arthritis Evans blue extravasation and joint swelling --- p.129 / Chapter 6.32 --- Intraperitoneal tachykinin receptor antagonists on FCA- induced arthritis Evans blue extravasation and joint swelling --- p.129 / Chapter 6.33 --- Intraperitoneal tachykinin receptor antagonists on FCA- induced immune cell accumulation --- p.130 / Chapter 6.34 --- Intraperitoneal tachykinin receptor antagonists on FCA- induced synovial tissue proliferation --- p.131 / Chapter 6.35 --- Intraperitoneal tachykinin receptor antagonists on FCA- induced cartilage degration and bone erosion --- p.131 / Chapter 6.4 --- Discussion --- p.159 / Chapter 6.5 --- Conclusions --- p.162 / Chapter Chapter 7 --- Individual and combined effects of dexamethasone and TK receptor antagonists on FCA-induced arthritis --- p.163 / Chapter 7.1 --- Introduction --- p.163 / Chapter 7.2 --- Method --- p.166 / Chapter 7.3 --- Results --- p.167 / Chapter 7.31 --- Evans blue extravasation --- p.167 / Chapter 7.32 --- Knee joint size --- p.167 / Chapter 7.33 --- Body weight --- p.168 / Chapter 7.34 --- Cellular infiltration --- p.168 / Chapter 7.35 --- Synovial tissue proliferation --- p.168 / Chapter 7.36 --- Cartilage degradation --- p.169 / Chapter 7.4 --- Discussion --- p.184 / Chapter 7.5 --- Conclusions --- p.187 / Chapter Chapter 8 --- General discussions and conclusions --- p.188 / References --- p.192

Le lymphocyte B (LB) joue un rôle important dans la polyarthrite rhumatoïde (PR), en produisant des auto-anticorps qui ont un rôle pathogène, en activant les lymphocytes T, en sécrétant des cytokines pro-inflammatoires et en permettant la formation de centres germinatifs. Plus récemment, il a été montré que le LB pouvait également produire de l'interleukine (IL) 10, une cytokine anti-inflammatoire qui lui procure des fonctions régulatrices. Ces B régulateurs ont notamment la capacité de différencier les lymphocytes T en T régulateurs. De nombreux traitements sont actuellement disponibles dans la PR, notamment les anti-TNF alpha et les inhibiteurs du récepteur de l'IL-6 (tocilizumab). Dans la première partie de cette thèse, nous avons comparé les LB circulants de patients atteints de PR et de contrôles. Nous avons étudié l'influence de l'activité de la maladie et des traitements sur les LB. Nous avons montré qu'il existait une lymphopénie B globale chez les patients atteints de PR avec une répartition des différents sous-types de LB superposable à celle des contrôles. Les patients ayant une maladie active avaient significativement plus de LB mémoires totaux, pré- et post-switch, CD24hiCD27+ et double négatifs que les patients ayant une maladie peu active. Les traitements anti-TNF et le tocilizumab ne modifiaient pas la répartition des sous-types de LB. Nous avons également montré qu'un taux de plus de 26% de LB mémoires CD27+ avant l'instauration d'un traitement par anti-TNF était associé à la réponse clinique à 3 mois. Les LB mémoires semblent produire plus de TNF que les LB naïfs et par ce biais pourraient induire une réponse Th1. Dans la seconde partie de cette thèse, nous avons tout d'abord cherché à mieux définir les LB régulateurs. Nous avons ensuite étudié leur présence et leur rôle dans la PR. Chez les sujets sains, les LB CD24hiCD27+ et CD24hiCD38hi semblent produire plus d'IL-10 que les autres LB, qui peuvent néanmoins en sécréter. Il semble donc plus adapter de définir les B régulateurs comme B producteurs d'IL-10 ou B10. Les patients atteints de PR avaient significativement moins de B10 que les contrôles en pourcentage et en valeur absolue. Chez les patients ayant un facteur rhumatoïde (FR) positif, il y avait une corrélation inverse entre le pourcentage de B10 et le taux de FR. Il y avait une corrélation inverse entre l'activité de la maladie (DAS28) et le pourcentage de B10, qui était particulièrement marquée pour les PR évoluant depuis moins de 5 ans. Chez ces patients, il y avait également une corrélation inverse entre les B10 et l'inflammation biologique (protéine C réactive). L'instauration d'anti-TNF ou de tocilizumab ne modifiait pas le taux de B10. Les CD24hiCD27+ et CD24hiCD38hi induisaient plus de lymphocytes T régulateurs chez les contrôles que les autres LB (CD24lo/-) alors que ça n'était plus le cas chez les patients atteints de PR, montrant que ces sous-types ont perdu cette fonction régulatrice dans la PR. En conclusion, bien qu'il existe une lymphopénie B, la répartition des sous-types de LB ne semble pas différente entre les patients atteints de PR et les contrôles. Néanmoins, il existe des anomalies fonctionnelles avec notamment une perte de la capacité à produire de l'IL-10 et à induire des T régulateurs chez les patients atteints de PR. / B cells play an important role in rheumatoid arthritis (RA), producing autoantibodies which have a pathogenic role, activating T cells, secreting pro-inflammatory cytokines and allowing the formation of germinal centers. More recently, it was shown that the B cells could also produce interleukin (IL)-10, an anti-inflammatory cytokine which provides their regulatory functions. Those regulatory B cells have the ability to differentiate T cell into regulatory T cells. Many treatments are currently available in RA, including TNF-alpha inhibitors and IL-6 receptor inhibitor (tocilizumab). In the first part, we compared circulating B cells in RA patients and in controls, and we studied the influence of disease activity and treatment on B cells. We have shown that there is a global B cell lymphopenia in RA patients with a similar B cell subtype distribution as controls. Patients with active disease had significantly more pre- and post-switch, CD24hiCD27+ and double negative memory B cells than patients with low disease activity. Anti -TNF treatment and tocilizumab did not change the distribution of B cell subsets. We also showed than patient with more than 26% of CD27+ memory B cells prior TNF inhibitor initiation was associated with clinical response at 3 months. Memory B cells produced more TNF alpha than naive B cells and can potentially induce a Th1 response. B cell subtypes were not associated with response to tocilizumab. In the second part, we first sought to better define regulatory B cells. We then studied their presence and role in RA. In healthy subjects, CD24hiCD27+ and CD24hiCD38hi B cells seem to produce more IL-10 than the other B cells that can nevertheless rarely produce some. It seemed more acurate to define regulatory B cells as IL-10 producing B cells also called B10 cells. Patients with RA had significantly less B10 cells than controls in percentage and absolute values. In rheumatoid factor (RF) positive patients, there was an inverse correlation between the percentage of B10 and the rate of RF. There was an inverse correlation between disease activity (DAS28) and the percentage of B10, which was particularly significant for patients with a disease duration of less than 5 years. In these patients, there was also an inverse correlation between B10 and biological inflammation (C-Reactive Protein). TNF inhibitors or tocilizumab did not change B10 cell rate. The CD24hiCD27 + and CD24hiCD38hi induce more regulatory T cells in controls than other LB (CD24lo/-) while it was not the case in patients with RA, indicating that these subtypes have lost this regulatory function in RA. In conclusion, although there are B cell lymphopenia, the distribution of B cell subsets does not seem to differ between RA patients and controls. Nevertheless, there are functional abnormalities including a loss of the ability to produce IL -10 and induce regulatory T in patients with RA.

INTRODUÇÃO: Doenças reumáticas, como a artrite idiopática juvenil (AIJ) podem afetar significativamente a vida sexual do indivíduo. A inflamação e a fadiga associadas com artrite crônica podem levar à disfunção articular, contraturas musculares, diminuição da força muscular e uma variedade de deformidades que podem comprometer a sexualidade. Desta forma, o objetivo deste estudo foi elaborar, desenvolver e aplicar um questionário auto-aplicativo com o intuito de avaliar a vida sexual de uma população homogênea de pacientes do sexo masculinos com AIJ poliarticular e fator reumatóide negativo. PACIENTES E MÉTODOS: Um questionário autoaplicativo de avaliação sexual masculina (QASM) foi desenvolvido por um painel de experts e aplicado a todos os pacientes e controles, relativo a aspectos funcionais e comportamentais da sexualidade e satisfação sexual masculina. Foram avaliados pacientes do sexo masculino com AIJ poliarticular com fator reumatóide negativo conforme os critérios do ILAR de 2004 e doença inativa. A inatividade da doença foi definida como inflamação em pelo menos uma articulação e velocidade de hemossedimentação elevado nos últimos três meses. Como grupo controle foram avaliados 120 adolescentes e jovens do sexo masculino pareados por idade e classe sócioeconômica. O HAQ foi aplicado em todos os pacientes. Teste t-student, quiquadrado, exato de Fisher e não paramétrico de Mann-Whitney foram utilizados e P<0,05 foi considerado significante. RESULTADOS: Trinta e dois pacientes com AIJ poliarticular, FR-, com média de idade de 20,8 ± 3,8 anos e tempo médio de duração da doença igual a 15,4 ± 3,6 anos foram avaliados. A prática de masturbação foi similar nos pacientes e controles (87,5% vs. 91%, p>0,999) e dor articular foi observada em apenas 2 pacientes com AIJ (7%). Relação sexual regular (no mínimo 1x/semana) foi mencionada por 78% dos pacientes com AIJ e por 62% dos controles (p=86). Dor articular durante a relação sexual foi significativamente mais freqüente nos 48% dos pacientes vs. 3% dos controles (p<0,001), sendo nos pacientes em quadris (n=3), joelhos (n=5) e ambos quadris e joelhos (n=4) e nos punhos de 2 controles. Reforçando este achado, a média de pontuação do HAQ foi maior nos pacientes com dor articular durante a relação sexual (1,82 ± 0,27 vs. 1,43 ± 0,32; p=0,007) e durante a masturbação (2 + 0,17 vs. 1,58 + 0,3; p=0,019). Notavelmente, desejo e satisfação sexuais estavam preservados em todos os pacientes e controles. CONCLUSÃO: Nos nossos pacientes com AIJ poliarticular FR -, o QASM foi aplicável e mostrou que a sexualidade está preservada, apesar do longo tempo de doença, morbidade, disfunção e dor articular / INTRODUCTION: Rheumatic diseases such as juvenile idiopathic arthritis (JIA) may significantly affect a person´s sexual life. Both inflammation and fatigue associated with persistent arthritis may lead to joint impairment, muscular contractures, reduced muscular strength and a variety deformities which may affect the sexuality. Therefore, the aim of this study was to elaborate, develop and apply a self-admisnistered questionnarie in order to evaluate sexual life of a homogeneous population of male patients with rheumatoid factor (RF) negative polyarticular JIA. PATIENTS AND METHODS: A self applied questionnarie of male sexual evaluation (MSEQ) was developed by a group of experts and was applied to all the patients and control group, relating to functional and behavior aspects of male sexuality and sexual satisfaction. A cohort of male patients with RF negative polyarticular JIA according to 2004 ILAR revised criteria and inactive disease was studied. The inactive disease was considered as absence of any synovitis associated to low ESR for at least three months. As control group 120 male adolescents and youths subjects age-matched with same socioeconomic status were evaluated. HAQ was applied to all patients.Tstudent, chi-square, Fishers exact and non-parametric Mann-Whitney tests were perfomed and p<0.05 was significant. RESULTS: Thirty two (32) patients with polyarticular JIA, FR-, mean age 20.8 + 3.8 yrs (16-26 yrs), mean disease duration = 15.4 ± 3.6 yrs (13-20 yrs) were assessed. Masturbation practice was similar among patients and controls (87,5% vs. 91%, p>0,999) although joint pain was solely observed in 2 JIA individuals (7%). Regular sexual intercourse (at least 1x/week) was mentioned by 78% JIA patients and 62% controls (p=0.86). Joint pain during intercourse was more frequent in 48% patients vs. 3% controls (P<0.001), in patients on hips (n=3), knees (n=5), both hips and knees (n=4), and in the controls on wrist (n=2) . Reforcing this findings, the mean HAQ score was higher on 12 patients with joint pain during intercourse and during masturbation comparing to 13 without joint pain (1.77 ± 0.31 vs. 1.2 ± 0.14; p<0.05). Notabily desire and sexual satisfaction were preserved in all the patients and control group. CONCLUSION:In this cohort of male patients with RF- polyarticular JIA, MSEQ was applicable and showed that sexual life is preserved, despite long term disease, morbidity, dysfunction and joint pain