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AimThe broad aim of this thesis was to explore the risk of malignancy in people with rheumatoid arthritis (RA), treated with anti-tumour necrosis factor (TNF) drugs.MethodsThis thesis used data from patients with RA registered with the British Society of Rheumatology Biologics Register-RA. The risk of cancer in biologic-naive patients treated with traditional disease modifying drugs (nbDMARD) was compared to that in the general population by calculating standardised incidence ratios (SIR). The influence of anti-TNF on cancer risk was then explored by comparing the risk in the anti-TNF cohort to that in the nbDMARD cohort using Cox proportional hazard models.ResultsThe risk of cancer was increased in the nbDMARD cohort by 28% compared to the general population (SIR 1.28, 95% confidence interval (CI) 1.10, 1.48). Risks of lung cancer (SIR 2.39, 95% CI 1.75, 3.19), Hodgkin lymphoma (SIR 12.82, 95% CI 4.16, 29.92) and Non-Hodgkin Lymphoma (SIR 3.12, 95% CI 1.79, 5.07) were increased compared to the general population and both prostate cancer and cancers of the female genital organs reduced; SIRs 0.35 (95% CI 0.11, 0.82) and 0.35 (95% CI 0.10, 0.90) respectively. There was no difference in the risk of cancer in patients treated with anti-TNF compared to nbDMARD, after adjusting for differences in baseline characteristics; Hazard ratio for lymphoma: 1.00 (95% CI 0.49, 2.05); cancers of the solid organs: 0.83 (95% CI 0.64, 1.07); and keratinocyte skin cancer: basal cell carcinoma 1.06 (95% CI 0.64, 1.75), squamous cell carcinoma 1.62 (95% CI 0.44, 5.90). ConclusionsSubjects with RA, treated with nbDMARD were at increased risk of cancer compared to the general population. In particular, lung cancer, lymphoma and KSC were increased. Treatment with the TNF inhibitors ETA, INF or ADA was not associated with a difference in relative risk of lymphoma, solid cancer or skin cancers when compared to nbDMARD.

Ankylosing spondylitis (AS) is a chronic, inflammatory rheumatic disease that has a highly variable disease course. Three biologic agents, adalimumab, etanercept, and infliximab, have been developed for the treatment of AS. We conducted three studies: 1) an exploratory analysis of a year-long longitudinal dataset to gain insight into the variability of disease activity, physical function, and well-being and to explore the relationship between these outcome measures; 2) a systematic review of the available evidence for the efficacy of biologic treatment; 3) a systematic review of potential adverse effects of this treatment. We found that repeated measures of disease activity, function and well-being fluctuate considerably between patients, with complex patterns occurring over time within patients. There was mostly high quality evidence that these biologics are efficacious against placebo. We did not find evidence of an increase in serious adverse events or serious infections from short-term randomized controlled trials.

<p>Det har skett en utveckling av flera nya biologiska läkemedel sedan slutet av 1990-talet för patienter med en reumatisk sjukdom. Några av dessa läkemedel administreras som intravenösa infusioner, vilket innebär att patienterna är tvungna att komma till en poliklinik för att erhålla sitt läkemedel. Detta kan påverka det dagliga livet samt patienternas oberoende och att undersöka hur patienterna uppfattar denna situation är av betydelse. Inom reumatologin är det ingen studie gjord som undersökt detta. </p><p>Syftet med studien var att beskriva hur patienter med reumatiska sjukdomar uppfattar beroendet vid intravenös anti TNF-alfa behandling administrerad av en sjuksköterska.</p><p>Studien genomfördes med en deskriptiv kvalitativ design och fenomenografisk ansats. Tjugo patienter som får intravenös anti TNF-alfa behandling har intervjuats.</p><p>I resultatet framkom tre beskrivningskategorier: det trygga beroendet (möta kontinuitet, möta kompetens, erhålla tillgänglighet och få information), det delaktiga beroendet (kunna påverka och få frihet), det energigivande beroendet (få avkoppling, bli bemött, bli omhändertagen och möta miljön). Patienterna uppfattade en trygghet och delaktighet i sin behandling och uppgav att det var energigivande att regelbundet träffa en sjuksköterska. Vid utformning av sjuksköterskans roll i polikliniskt omvårdnadsarbetet vid intravenös anti TNF-alfa behandling bör patienternas uppfattning utgöra grunden. Vidare skulle det vara intressant att undersöka hur patienter som sköter sin anti TNF-alfa behandling själva genom subkutana injektioner och som aldrig haft en regelbunden kontakt med en sjuksköterska beskriver sin situation.</p>

Det har skett en utveckling av flera nya biologiska läkemedel sedan slutet av 1990-talet för patienter med en reumatisk sjukdom. Några av dessa läkemedel administreras som intravenösa infusioner, vilket innebär att patienterna är tvungna att komma till en poliklinik för att erhålla sitt läkemedel. Detta kan påverka det dagliga livet samt patienternas oberoende och att undersöka hur patienterna uppfattar denna situation är av betydelse. Inom reumatologin är det ingen studie gjord som undersökt detta. Syftet med studien var att beskriva hur patienter med reumatiska sjukdomar uppfattar beroendet vid intravenös anti TNF-alfa behandling administrerad av en sjuksköterska. Studien genomfördes med en deskriptiv kvalitativ design och fenomenografisk ansats. Tjugo patienter som får intravenös anti TNF-alfa behandling har intervjuats. I resultatet framkom tre beskrivningskategorier: det trygga beroendet (möta kontinuitet, möta kompetens, erhålla tillgänglighet och få information), det delaktiga beroendet (kunna påverka och få frihet), det energigivande beroendet (få avkoppling, bli bemött, bli omhändertagen och möta miljön). Patienterna uppfattade en trygghet och delaktighet i sin behandling och uppgav att det var energigivande att regelbundet träffa en sjuksköterska. Vid utformning av sjuksköterskans roll i polikliniskt omvårdnadsarbetet vid intravenös anti TNF-alfa behandling bör patienternas uppfattning utgöra grunden. Vidare skulle det vara intressant att undersöka hur patienter som sköter sin anti TNF-alfa behandling själva genom subkutana injektioner och som aldrig haft en regelbunden kontakt med en sjuksköterska beskriver sin situation.

Ankylosing spondylitis (AS) is a chronic, inflammatory rheumatic disease that has a highly variable disease course. Three biologic agents, adalimumab, etanercept, and infliximab, have been developed for the treatment of AS. We conducted three studies: 1) an exploratory analysis of a year-long longitudinal dataset to gain insight into the variability of disease activity, physical function, and well-being and to explore the relationship between these outcome measures; 2) a systematic review of the available evidence for the efficacy of biologic treatment; 3) a systematic review of potential adverse effects of this treatment. We found that repeated measures of disease activity, function and well-being fluctuate considerably between patients, with complex patterns occurring over time within patients. There was mostly high quality evidence that these biologics are efficacious against placebo. We did not find evidence of an increase in serious adverse events or serious infections from short-term randomized controlled trials.

Ankylosing spondylitis (AS) is a chronic, inflammatory rheumatic disease that has a highly variable disease course. Three biologic agents, adalimumab, etanercept, and infliximab, have been developed for the treatment of AS. We conducted three studies: 1) an exploratory analysis of a year-long longitudinal dataset to gain insight into the variability of disease activity, physical function, and well-being and to explore the relationship between these outcome measures; 2) a systematic review of the available evidence for the efficacy of biologic treatment; 3) a systematic review of potential adverse effects of this treatment. We found that repeated measures of disease activity, function and well-being fluctuate considerably between patients, with complex patterns occurring over time within patients. There was mostly high quality evidence that these biologics are efficacious against placebo. We did not find evidence of an increase in serious adverse events or serious infections from short-term randomized controlled trials.

English Abstract Crohn's disease together with ulcerative colitis, is a type of inflammatory bowel disease (IBD) with increasing incidence and prevalence in developed countries. IBD is an immunologically mediated multifactorial disease and it's mechanism of action is still unknown. Current well- established treatment targets the inflammation with corticosteroids and immunosuppressive drugs. Apart from the intestinal inflammation, which is the primary target of the treatment, patients are characteristically afflicted with intestinal dysbiosis. Therefore, possible interventions might be an adjuvant or biological therapy. Adjuvant therapy directly aims the microbiota with probiotics, whereas the target of biological therapy is TNF-α, a pro- inflammatory cytokine excessively secreted by macrophages. The aim of this thesis is to evaluate intestinal microbiota composition changes in IBD patients with regard to courses of adjuvant and biological therapy. Bacterial diversity was analyzed using three different DNA extraction techniques. Rapid beat beating + column (RBB+C) was chosen for analyzing patient samples, as it showed the highest DNA yield and the highest DNA purity. Primarily the bacterial diversity was analyzed using degradation gradient gel electrophoresis (DGGE) with subsequent sequencing of bands of...

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.

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No. of bitstreams: 1 Tese - Antonio Luiz Ribeiro Boechat Lopes.pdf: 13031715 bytes, checksum: d88fbd133c649844648684a05e01cc76 (MD5) Previous issue date: 2010-12-15 / Não Informada / Rheumatoid Arthritis (RA) is a autoimmune disease that affects 1% of worldwide population and promotes polyarthritis and joint destruction with work disability. About 60% of the risk factors of RA are related to genetic characteristics of individuals. The functional polymorphisms of the TNF gene -308 G/A andPTPN22 1858 C/T were associated with RA in several studies.The aim of this study was to investigate the influence of the TNF 308 G/A polymorphism in the promoter region of the tumor necrosis factor- gene and PTPN22 1858 C/T on rheumatoid arthritisand tuberculosis patients from the Brazilian Amazon. A total of 545 individuals 205 healthy controls without arthritis and 132 individuals suffering from rheumatoid arthritis and 208 tuberculosis patients  were genotyped for these polymorphisms using a methodology based on PCR-RFLP. Rheumatoid factor, age more than 60 years old and more than 10 disease years, was found to be risk factors for systemic disease (p=0,0001). The frequency of the A allele (TNF2) in rheumatoid arthritis sufferers was not found to be significantly higher than in the controls (p=0.671; OR=1.16; confidence interval=0.59 – 2.25). However, using a logistic regression model when the patients were stratified according to whether the manifestations were preponderantly articular or systemic, there was a strong association between the TNF2 allele and the systemic disease (p=0.001; OR=4.75; confidence interval=1.82 – 12.40) as well as the use of anti-TNF immunotherapy (p=0.021; OR 2.93; confidence interval=1.15 –7.46). On the other hand, PTPN22 1858T allele was not associated with systemicdisease (p=0,071; OR=3,17; confidence interval=0.83 – 11.73), but we found association between this allele and biologic anti-TNF immunotherapy (p=0,021; OR=4.39; confidence interval=1.08 – 17.86). Moreover, there was found no association between PTPN22 15858 C/T and rheumatoid arthritis nor tuberculosis. These results suggest that the TNF2 allele is associated with the more serious forms of the disease in individuals from the Brazilian Amazon but not with a risk for developing RA. / A Artrite Reumatoide (AR) é uma doença autoimune que afeta 1% da população geral, promovendo poliartrite e destruição articular com variados graus de incapacidade. Cerca de 60% dos fatores de risco da AR são relacionados a caracteres genéticos do indivíduo. Os polimorfismos funcionais dos genes TNF -308 G/A e PTPN22 1858 C/T foram associados à AR e à Tuberculose em diversos estudos. O objetivo deste estudo foi analisar a influência do polimorfismo da região promotora do gene do Fator de Necrose Tumoral-α, TNF -308 G/A e do gene PTPN22 1858 C/T na Artrite Reumatoide (AR) e na Tuberculose pulmonar em indivíduos procedentes do Amazonas. Para isso, foram genotipados, pela técnica baseada em PCR-RFLP para o polimorfismo TNF 308 G/A (TNF2) e PTPN22 1858T, 545 indivíduos sendo 205 controles sem Artrite, 208 pacientes com Tuberculose e 132 portadores de AR. Não foi observado aumento da frequência dos alelosTNF2ouPTPN22 1858T em portadores de Artrite Reumatoide e Tuberculose em comparação aos controles (p=0,218; p=0,376, respectivamente). Foram identificados como fatores preditivos para manifestações sistêmicas da Artrite Reumatoide: o Fator Reumatoide positivo, a idade maior que 60 anos e o tempo de doença (p=0001).Quando os dados foram estratificados segundo as formas predominantemente articulares ou sistêmicas, o alelo TNF2 esteve fortemente associado às formas sistêmicas (p=0,001; OR=4,75; Intervalo de confiança = 1,82 – 12,40), além de estar associado ao uso de imunobiológicos Anti-TNF (p=0,021; OR=2,93; Intervalo de confiança=1,15 – 7,49). O alelo PTPN22 1858T também está associado ao uso de imunobiológicos (p=0,021; OR= 4,39; Intervalo de Confiança=1,08 – 17,86), mas não está relacionado às formas sistêmicas (p=0,071; OR = 3,17; Intervalo de Confiança = 0,83 – 11,73). Entretanto, o polimorfismo de PTPN22 1858 C/T não foi associado à Artrite Reumatoide ou à Tuberculose Pulmonar. Estes resultados sugerem que o alelo TNF2 está associado às formas mais graves da AR em indivíduos do Amazonas, mas não ao risco de desenvolver Artrite Reumatoide.