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.

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.

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Les stratégies de traitement biologiques ciblant le TNF-α se sont avérées efficaces pour réduire l'inflammation et les symptômes cliniques dans plusieurs maladies inflammatoires chroniques et sont maintenant couramment utilisées pour les patients qui ne répondent pas aux AINS au cours de la spondyloarthrite (SpA). Cependant, 30 à 40% des patients ne répondent pas aux anti-TNF, et il est actuellement impossible de prédire la réponse des patients à ces biomédicaments. Pour améliorer les résultats cliniques, nous avons besoin d’une part d’une meilleure compréhension des mécanismes d’action des anti-TNF sur le système immunitaire, et d’autre part de biomarqueurs permettant de prédire la réponse à ces biomédicaments afin de guider la décision thérapeutique. Mon projet de doctorat a porté sur deux objectifs complémentaires: (i) l'objectif principal était de progresser dans notre compréhension des mécanismes pathogéniques impliqués dans la SpA axiale et de définir de quelle façon les anti-TNF-α affectent les réponses immunitaires des patients, (ii) de développer des biomarqueurs pour prédire la réponse thérapeutique aux inhibiteurs du TNF. En collaboration avec l'équipe du Pr. Dougados à l'Hôpital Cochin, nous avons recruté deux cohortes indépendantes de patients SpA ayant une maladie active et pour lesquels nous avons collecté des échantillons de sang avant l'initiation du traitement par anti-TNF puis 1 semaine et 3 mois après le début du traitement. Les réponses immunitaires de ces patients ont été analysées à l'aide de tests hautement standardisés réalisés ex-vivo sur sang circulant. Ces tests "TruCulture" se présentent sous forme de seringues, dans lesquelles 1 ml de sang total est mis à incuber avec un stimulus spécifique ; 20 stimuli différents ont été testé et validé avant et après traitement dans les deux cohortes de patients. Nous avons observé une réduction très significative de la sécrétion de IL-1ra, IL-1β, IL-8, and MIP-1β en réponse à des stimuli microbiens et à des agonistes des TLR dans les échantillons de sang prélevés 7 jours et/ou 3 mois après le début du traitement. Pour identifier les bases moléculaires de l’action des inhibiteurs du TNF nous avons analysé l'expression des gènes dans ces différentes conditions de stimulation. L'analyse bioinformatique quantitative de l'expression des gènes (QuSAGE) a révélé que les gènes les plus modulés par le traitement anti-TNF étaient NF-KB et les gènes cibles de NF-kB, y compris le TNF lui-même et l’IL1B. Nos données suggèrent que les inhibiteurs du TNF agissent principalement en perturbant une boucle autorégulatrice pilotée par NF-kB. Afin d'identifier les signatures immunologiques de réponse aux anti-TNF avant le début du traitement, nous avons corrélé les réponses immunitaires chez les patients analysés au temps 0 à la réponse thérapeutique aux anti-TNF mesurée à 3 mois. Nos résultats suggèrent que les patients atteints de SpA et exprimant des niveaux inférieurs de PAX5 et des niveaux supérieurs de SPP1 en réponse à la stimulation avec SEB avant l'initiation de la thérapie anti-TNF ont les meilleures réponses thérapeutiques. Notre recherche montre que les tests TruCulture sont un outil efficace pour étudier les fonctions immunitaires chez les patients atteints de SpA et que les effets du traitement anti-TNF peuvent être mesurés lorsque les cellules immunitaires sont stimulées. En terme de recherche translationnelle, nous avons identifié des molécules qui pourront être utilisés comme biomarqueurs pour aider les cliniciens à prédire les réponses thérapeutiques aux traitements anti TNF / The introduction of anti-TNF therapy has proven effective to reduce inflammation and clinical symptoms in several chronic inflammatory diseases. However, 30-40% of patients do not respond to TNF blockers and it is currently not possible to predict responsiveness of patients to anti-TNF therapy. Furthermore, their impact on the immune system is incompletely understood. The goals of my PhD project were (i) to define the impact of anti-TNF therapy on immune responses to microbial challenges and stimuli targeting specific immune pathways in spondyloarthritis (SpA) patients, and (ii) to identify immunological correlates associated with therapeutic responses to TNF-blockers.Using a set of whole-blood, syringe-based assays to perform ex vivo stimulation while preserving physiological cellular interactions (TruCulture assays), we have performed a pilot study in SpA patients and investigated immune responses to 20 different stimuli before and 3 months after initiation of anti-TNF therapy. These findings were validated in a replication cohort, also assessing the effects of anti-TNF agents after only one week of treatment. We observed a highly significant reduction of the secretion of IL-1ra, IL-1β, IL-8 and MIP-1β in response to selected stimuli after 3 months of treatment compared to the baseline. Interestingly, these changes were already detectable after a single injection of an anti-TNF agent. To gain insight into the molecular mechanism of TNF blockers, we profiled gene expression in the stimulation cultures from all patients. Quantitative set analysis for gene expression (QuSAGE) revealed that the gene modules most affected by anti-TNF therapy are NF-kB transcription factors and inhibitors and NF-kB target genes, including TNF itself and IL1B. Our data suggest that TNF-blockers primarily act by disrupting an autoregulatory loop driven by NF-kB. We also tested whether there is a correlation between the responses of immune cells to specific stimuli and the clinical response to TNF-blockers. The decision tree model that we trained and validated suggests that SpA patients who expressed lower levels of PAX5 and higher levels of SPP1 in response to SEB stimulation before initiation of anti-TNF therapy had the best therapeutic responses. Our study shows that TruCulture assays are an efficient and robust tool to monitor immune functions in SpA patients and that the effects of anti-TNF therapy can be measured when immune cells are challenged, but not at steady state. Our data also indicate that analyzing immune responses in patients before therapy is a promising strategy to develop biomarkers for prediction of therapeutic responses to TNF-blockers

B-lymphocytes are lymphoid cells, which are a part of the adaptive/innate immune system and generate antibodies. Recently, many studies have supported hypothesis that different rather minor B-lymphocyte subpopulations may play a direct and indirect role in immunopathogenesis in human pathologies such as Crohn's disease (CD). The aim of current study was therefore to investigate distribution of frequencies of B lymphocyte subpopulations (from transient to mature effector B cell stages) in peripheral blood of healthy subjects (CO), patients with Crohn's disease (CD) and ulcerative colitis (UC). Thus, using 11-colour flow cytometry we have analysed 30 blood samples of individuals, including 14 healthy controls, 11 patients with Crohn's disease and 5 with UC. In 6 patients with CD we have had an opportunity to analyze blood samples collected 2 hours after an administration of anti-TNF therapy. Higher frequencies of memory B-lymphocytes (CD19+ CD27+ , CD19+ CD20+ CD27+ and CD19+ CD20+ CD27+ IgM+) were found in patients with CD as compared to COs. (20.06±13.58%; 17.61±13.48%; 88.60±20.56% vs. 11.75±26.47%; 11.25±26.50%; and 66.82±22.60%), in case of CD19+CD20-CD27-IgM+ B-lymphocytes the difference was statistically significant (57.15±17.21% in CD vs. 19.59±31.79% in CO; p=0.0341), which is in accordance...

Base teórica: A introdução de agentes biológicos, especialmente os bloqueadores do fator de necrose tumoral (anti-TNF), para o tratamento de doenças reumáticas aumentou o risco de desenvolver tuberculose (TB). O rastreio para infecção tuberculosa latente (ILTB) é fortemente recomendado antes de iniciar a terapia com agentes anti-TNF. Os objetivos deste estudo foram identificar a prevalência de ILTB e TB entre pacientes com doenças reumáticas em uso dos medicamentos anti-TNF. Métodos: Estudo transversal. Foram revisados os registros médicos eletrónicos de todos os doentes adultos (≥ 18 anos) em uso da terapia anti-TNF. Todos os pacientes foram submetidos ao teste tuberculínico (TT) antes de iniciar o tratamento com os medicamentos anti-TNF. Resultados: No total, 176 pacientes foram incluídos no estudo. A idade média de todos os pacientes foi de 51,9 ± 12,4 anos, 34,7% eram do sexo masculino e 90,9% eram brancos. As doenças subjacentes mais comuns foram: Artite Reumatóide (AR) em 89 pacientes (50,6%), Espondilite Anquilosante (EA) em 49 (27,8%) e Artrite Psoriática (AP) em 31 (17,6%). A prevalência de TT positivo foi de 29,5%. O contato domiciliar com TB foi significativamente associado com TT positivo (p = 0,020). Os pacientes com AR apresentaram reações TT menores do que os pacientes com EA (p = 0,022). Houve seis casos de TB (3,4%) diagnosticados durante a terapia anti-TNF. Conclusões: Demonstrou-se alta prevalência de TT positivo (29,5%) em pacientes com doenças reumáticas em uma região com alta prevalência de TB. Nossos dados corroboram a recomendação do Colégio Americano de Reumatologia (ACR) de que os pacientes que vivem em configurações de alta incidência de TB devem ser testados anualmente para ILTB. / Background: The introduction of biological agents, especially the blockers of tumor necrosis factor (anti-TNF), for the treatment of rheumatic diseases increased the risk of developing tuberculosis (TB). Screening for latent TB infection (LTBI|) is strongly recommended before starting therapy with anti-TNF agents. The objectives of this study were to identify the prevalence of LTBI and TB among patients with rheumatic diseases on anti-TNF drugs. Methods: Cross-sectional study. The electronic medical records of all adult patients (≥ 18 years old) undergoing anti-TNF treatment were reviewed. Every patient underwent TST test before starting anti-TNF treatment. Results: In total, 176 patients were included in the study. The mean age of all patients was 51.9 ± 12.4 years, 34.7% were males, and 90.9% were white. The most common underlying diseases were: RA in 89 patients (50.6%), AS in 49 (27.8%), and PA in 31 (17.6%). The prevalence of positive TST was 29.5%. Household contact with TB was significantly associated with a positive TST (p=0.020). RA patients had lower TST reactions than AS patients (p=0.022). There were six cases of TB (3.4%) diagnosed during anti-TNF therapy. Conclusions: We demonstrated a high prevalence of positive TST (29.5%) among patients with rheumatic diseases in a region with high TB prevalence. Our data corroborates the ACR’s recommendation that patients who live in high TB incidence settings should be tested annually for LTBI.

Base teórica: A introdução de agentes biológicos, especialmente os bloqueadores do fator de necrose tumoral (anti-TNF), para o tratamento de doenças reumáticas aumentou o risco de desenvolver tuberculose (TB). O rastreio para infecção tuberculosa latente (ILTB) é fortemente recomendado antes de iniciar a terapia com agentes anti-TNF. Os objetivos deste estudo foram identificar a prevalência de ILTB e TB entre pacientes com doenças reumáticas em uso dos medicamentos anti-TNF. Métodos: Estudo transversal. Foram revisados os registros médicos eletrónicos de todos os doentes adultos (≥ 18 anos) em uso da terapia anti-TNF. Todos os pacientes foram submetidos ao teste tuberculínico (TT) antes de iniciar o tratamento com os medicamentos anti-TNF. Resultados: No total, 176 pacientes foram incluídos no estudo. A idade média de todos os pacientes foi de 51,9 ± 12,4 anos, 34,7% eram do sexo masculino e 90,9% eram brancos. As doenças subjacentes mais comuns foram: Artite Reumatóide (AR) em 89 pacientes (50,6%), Espondilite Anquilosante (EA) em 49 (27,8%) e Artrite Psoriática (AP) em 31 (17,6%). A prevalência de TT positivo foi de 29,5%. O contato domiciliar com TB foi significativamente associado com TT positivo (p = 0,020). Os pacientes com AR apresentaram reações TT menores do que os pacientes com EA (p = 0,022). Houve seis casos de TB (3,4%) diagnosticados durante a terapia anti-TNF. Conclusões: Demonstrou-se alta prevalência de TT positivo (29,5%) em pacientes com doenças reumáticas em uma região com alta prevalência de TB. Nossos dados corroboram a recomendação do Colégio Americano de Reumatologia (ACR) de que os pacientes que vivem em configurações de alta incidência de TB devem ser testados anualmente para ILTB. / Background: The introduction of biological agents, especially the blockers of tumor necrosis factor (anti-TNF), for the treatment of rheumatic diseases increased the risk of developing tuberculosis (TB). Screening for latent TB infection (LTBI|) is strongly recommended before starting therapy with anti-TNF agents. The objectives of this study were to identify the prevalence of LTBI and TB among patients with rheumatic diseases on anti-TNF drugs. Methods: Cross-sectional study. The electronic medical records of all adult patients (≥ 18 years old) undergoing anti-TNF treatment were reviewed. Every patient underwent TST test before starting anti-TNF treatment. Results: In total, 176 patients were included in the study. The mean age of all patients was 51.9 ± 12.4 years, 34.7% were males, and 90.9% were white. The most common underlying diseases were: RA in 89 patients (50.6%), AS in 49 (27.8%), and PA in 31 (17.6%). The prevalence of positive TST was 29.5%. Household contact with TB was significantly associated with a positive TST (p=0.020). RA patients had lower TST reactions than AS patients (p=0.022). There were six cases of TB (3.4%) diagnosed during anti-TNF therapy. Conclusions: We demonstrated a high prevalence of positive TST (29.5%) among patients with rheumatic diseases in a region with high TB prevalence. Our data corroborates the ACR’s recommendation that patients who live in high TB incidence settings should be tested annually for LTBI.

Base teórica: A introdução de agentes biológicos, especialmente os bloqueadores do fator de necrose tumoral (anti-TNF), para o tratamento de doenças reumáticas aumentou o risco de desenvolver tuberculose (TB). O rastreio para infecção tuberculosa latente (ILTB) é fortemente recomendado antes de iniciar a terapia com agentes anti-TNF. Os objetivos deste estudo foram identificar a prevalência de ILTB e TB entre pacientes com doenças reumáticas em uso dos medicamentos anti-TNF. Métodos: Estudo transversal. Foram revisados os registros médicos eletrónicos de todos os doentes adultos (≥ 18 anos) em uso da terapia anti-TNF. Todos os pacientes foram submetidos ao teste tuberculínico (TT) antes de iniciar o tratamento com os medicamentos anti-TNF. Resultados: No total, 176 pacientes foram incluídos no estudo. A idade média de todos os pacientes foi de 51,9 ± 12,4 anos, 34,7% eram do sexo masculino e 90,9% eram brancos. As doenças subjacentes mais comuns foram: Artite Reumatóide (AR) em 89 pacientes (50,6%), Espondilite Anquilosante (EA) em 49 (27,8%) e Artrite Psoriática (AP) em 31 (17,6%). A prevalência de TT positivo foi de 29,5%. O contato domiciliar com TB foi significativamente associado com TT positivo (p = 0,020). Os pacientes com AR apresentaram reações TT menores do que os pacientes com EA (p = 0,022). Houve seis casos de TB (3,4%) diagnosticados durante a terapia anti-TNF. Conclusões: Demonstrou-se alta prevalência de TT positivo (29,5%) em pacientes com doenças reumáticas em uma região com alta prevalência de TB. Nossos dados corroboram a recomendação do Colégio Americano de Reumatologia (ACR) de que os pacientes que vivem em configurações de alta incidência de TB devem ser testados anualmente para ILTB. / Background: The introduction of biological agents, especially the blockers of tumor necrosis factor (anti-TNF), for the treatment of rheumatic diseases increased the risk of developing tuberculosis (TB). Screening for latent TB infection (LTBI|) is strongly recommended before starting therapy with anti-TNF agents. The objectives of this study were to identify the prevalence of LTBI and TB among patients with rheumatic diseases on anti-TNF drugs. Methods: Cross-sectional study. The electronic medical records of all adult patients (≥ 18 years old) undergoing anti-TNF treatment were reviewed. Every patient underwent TST test before starting anti-TNF treatment. Results: In total, 176 patients were included in the study. The mean age of all patients was 51.9 ± 12.4 years, 34.7% were males, and 90.9% were white. The most common underlying diseases were: RA in 89 patients (50.6%), AS in 49 (27.8%), and PA in 31 (17.6%). The prevalence of positive TST was 29.5%. Household contact with TB was significantly associated with a positive TST (p=0.020). RA patients had lower TST reactions than AS patients (p=0.022). There were six cases of TB (3.4%) diagnosed during anti-TNF therapy. Conclusions: We demonstrated a high prevalence of positive TST (29.5%) among patients with rheumatic diseases in a region with high TB prevalence. Our data corroborates the ACR’s recommendation that patients who live in high TB incidence settings should be tested annually for LTBI.