Objetivo: Comparar os resultados obtidos com a sialoendoscopia na melhora do fluxo salivar aferido através cintilografia em pacientes com síndrome de Sjögren primária. Material e método: Pacientes provenientes do Ambulatório de Reumatologia do HCPA com diagnóstico de Síndrome de Sjögren Primária foram submetidos a cintilografia de parótidas previamente ao procedimento de sialoendoscopia. Durante o procedimento de sialoendoscopia, uma das glândulas parótida foi lavada com solução fisiológica e a outra com solução de corticóide, escolha esta predeterminado por randomização. Após completo um mês do procedimento, um novo exame de cintilografia de glândulas parótidas foi realizado visando observar o fluxo salivar para comparação. Resultados: Participaram e completaram a pesquisa 13 pacientes, todas do sexo feminino, com idade média de 53,38 anos (27 - 76 anos). Houve melhora dos resultados de excreção salivar com radiofármaco no exame de cintilografia, após a realização da sialoendoscopia, em 10 pacientes, perfazendo 76,92% da amostra. Analisando cada glândula tratada separadamente (26 glândulas), houve melhora após a sialoendoscopia em 18 glândulas (69,23%), 8 destas utilizaram dexametasona e 10 utilizaram solução fisiológica na lavagem. Não houve melhora em 8 glândulas (30,77%). Conclusão: Este estudo mostra a sialoendoscopia como importante ferramenta na melhora do fluxo salivar aferido por cintilografia em pacientes com Síndrome de Sjögren Primária, aumentando a excreção salivar através da dilatação e consequente desobstrução dos ductos. Sugere que não há diferença estatisticamente significativa entre as soluções de lavagem intraductal solução fisiológica e solução com dexametasona. / Objective: To compare the results utilizing sialendoscopy to improve salivary flow mensured by scintigraphy in Primary Sjögren’ Syndrome. Material and method: Patients from Rheumatology clinic of Porto Alegre’s Clinic Hospital with diagnose of Primary Sjögren' Syndrome were submitted to parotid’s scintigraphy previous to sialendoscopy of both parotid. During the perform of sialendoscopy, one of the parotid gland was wash down with saline solution and the other with dexamethasone solution. Previous determination of the sides was achieved by randomization. After one month of procedure, a new scintigraphy of parotid’s glands was performed to observe the salivary flow for further comparison. Results: Participated and completed the study 13 patients, all female, with average age of 53,38 years (17 - 76 years old). The improve of salivary excretion on scintigraphy was achieved in 10 patients, performing 76,92% of the sample. Analyzing each gland in separate (26 glands), the improve after sialendoscopy was achieved in 18 glands (69,23%), 8 of these used dexamethasone and 10 used saline solution in washing. There was no improve in 8 glands (30,77%). Conclusion: This study demonstrate the use of sialedoscopy as an important tool to improve salivary flow mensured by scintipraphy in Primary Sjögren’ Syndrome patients, increasing the salivary excretion due to the dilatation and consequently clearing of ducts. It suggests that is no statistically difference between the solutions saline versus dexamethasone.

Objetivo: Comparar os resultados obtidos com a sialoendoscopia na melhora do fluxo salivar aferido através cintilografia em pacientes com síndrome de Sjögren primária. Material e método: Pacientes provenientes do Ambulatório de Reumatologia do HCPA com diagnóstico de Síndrome de Sjögren Primária foram submetidos a cintilografia de parótidas previamente ao procedimento de sialoendoscopia. Durante o procedimento de sialoendoscopia, uma das glândulas parótida foi lavada com solução fisiológica e a outra com solução de corticóide, escolha esta predeterminado por randomização. Após completo um mês do procedimento, um novo exame de cintilografia de glândulas parótidas foi realizado visando observar o fluxo salivar para comparação. Resultados: Participaram e completaram a pesquisa 13 pacientes, todas do sexo feminino, com idade média de 53,38 anos (27 - 76 anos). Houve melhora dos resultados de excreção salivar com radiofármaco no exame de cintilografia, após a realização da sialoendoscopia, em 10 pacientes, perfazendo 76,92% da amostra. Analisando cada glândula tratada separadamente (26 glândulas), houve melhora após a sialoendoscopia em 18 glândulas (69,23%), 8 destas utilizaram dexametasona e 10 utilizaram solução fisiológica na lavagem. Não houve melhora em 8 glândulas (30,77%). Conclusão: Este estudo mostra a sialoendoscopia como importante ferramenta na melhora do fluxo salivar aferido por cintilografia em pacientes com Síndrome de Sjögren Primária, aumentando a excreção salivar através da dilatação e consequente desobstrução dos ductos. Sugere que não há diferença estatisticamente significativa entre as soluções de lavagem intraductal solução fisiológica e solução com dexametasona. / Objective: To compare the results utilizing sialendoscopy to improve salivary flow mensured by scintigraphy in Primary Sjögren’ Syndrome. Material and method: Patients from Rheumatology clinic of Porto Alegre’s Clinic Hospital with diagnose of Primary Sjögren' Syndrome were submitted to parotid’s scintigraphy previous to sialendoscopy of both parotid. During the perform of sialendoscopy, one of the parotid gland was wash down with saline solution and the other with dexamethasone solution. Previous determination of the sides was achieved by randomization. After one month of procedure, a new scintigraphy of parotid’s glands was performed to observe the salivary flow for further comparison. Results: Participated and completed the study 13 patients, all female, with average age of 53,38 years (17 - 76 years old). The improve of salivary excretion on scintigraphy was achieved in 10 patients, performing 76,92% of the sample. Analyzing each gland in separate (26 glands), the improve after sialendoscopy was achieved in 18 glands (69,23%), 8 of these used dexamethasone and 10 used saline solution in washing. There was no improve in 8 glands (30,77%). Conclusion: This study demonstrate the use of sialedoscopy as an important tool to improve salivary flow mensured by scintipraphy in Primary Sjögren’ Syndrome patients, increasing the salivary excretion due to the dilatation and consequently clearing of ducts. It suggests that is no statistically difference between the solutions saline versus dexamethasone.

Objetivo: Comparar os resultados obtidos com a sialoendoscopia na melhora do fluxo salivar aferido através cintilografia em pacientes com síndrome de Sjögren primária. Material e método: Pacientes provenientes do Ambulatório de Reumatologia do HCPA com diagnóstico de Síndrome de Sjögren Primária foram submetidos a cintilografia de parótidas previamente ao procedimento de sialoendoscopia. Durante o procedimento de sialoendoscopia, uma das glândulas parótida foi lavada com solução fisiológica e a outra com solução de corticóide, escolha esta predeterminado por randomização. Após completo um mês do procedimento, um novo exame de cintilografia de glândulas parótidas foi realizado visando observar o fluxo salivar para comparação. Resultados: Participaram e completaram a pesquisa 13 pacientes, todas do sexo feminino, com idade média de 53,38 anos (27 - 76 anos). Houve melhora dos resultados de excreção salivar com radiofármaco no exame de cintilografia, após a realização da sialoendoscopia, em 10 pacientes, perfazendo 76,92% da amostra. Analisando cada glândula tratada separadamente (26 glândulas), houve melhora após a sialoendoscopia em 18 glândulas (69,23%), 8 destas utilizaram dexametasona e 10 utilizaram solução fisiológica na lavagem. Não houve melhora em 8 glândulas (30,77%). Conclusão: Este estudo mostra a sialoendoscopia como importante ferramenta na melhora do fluxo salivar aferido por cintilografia em pacientes com Síndrome de Sjögren Primária, aumentando a excreção salivar através da dilatação e consequente desobstrução dos ductos. Sugere que não há diferença estatisticamente significativa entre as soluções de lavagem intraductal solução fisiológica e solução com dexametasona. / Objective: To compare the results utilizing sialendoscopy to improve salivary flow mensured by scintigraphy in Primary Sjögren’ Syndrome. Material and method: Patients from Rheumatology clinic of Porto Alegre’s Clinic Hospital with diagnose of Primary Sjögren' Syndrome were submitted to parotid’s scintigraphy previous to sialendoscopy of both parotid. During the perform of sialendoscopy, one of the parotid gland was wash down with saline solution and the other with dexamethasone solution. Previous determination of the sides was achieved by randomization. After one month of procedure, a new scintigraphy of parotid’s glands was performed to observe the salivary flow for further comparison. Results: Participated and completed the study 13 patients, all female, with average age of 53,38 years (17 - 76 years old). The improve of salivary excretion on scintigraphy was achieved in 10 patients, performing 76,92% of the sample. Analyzing each gland in separate (26 glands), the improve after sialendoscopy was achieved in 18 glands (69,23%), 8 of these used dexamethasone and 10 used saline solution in washing. There was no improve in 8 glands (30,77%). Conclusion: This study demonstrate the use of sialedoscopy as an important tool to improve salivary flow mensured by scintipraphy in Primary Sjögren’ Syndrome patients, increasing the salivary excretion due to the dilatation and consequently clearing of ducts. It suggests that is no statistically difference between the solutions saline versus dexamethasone.

Le syndrome sec de Gougerot Sjögren (SGS) est une maladie auto-immune chronique qui présente des dommages progressifs et irréversibles des glandes exocrines lacrymales et salivaires. Cette pathologie affecte entre 0.1 et 3 % de la population et est plus commune chez les femmes avec un ratio de 9 femmes pour 1 homme. Dans la glande salivaire, une infiltration lymphocytaire est observée et est associée avec la destruction de l'épithélium sécrétoire, qui joue un rôle central dans l'initiation et le développement du SGS. Le processus physiopathologique est loin d’être compris et semble dépendant de phénomènes épigénétiques. En effet, des perturbations importantes de la méthylation de l'ADN sont observées dans les cellules épithéliales en lien avec le niveau d’infiltration lymphocytaire des glandes salivaires.L'objectif de ce travail est de mieux comprendre les changements épigénétiques au cours du SGS et en particulier les défauts de méthylation/déméthylation de l’ADN observés dans les Cellules Epithéliales de Glandes Salivaires (SGEC) et leurs rôles dans le développement de la pathologie.Dans ce but, Une étude globale de la méthylation de l'ADN a été réalisée après culture cellulaire destinée à isoler les SGEC de patients SGS. La puce « human methylation 450k » d’Illumina utilisée couvre plus de 485 000 sites CpG du génome. Des analysesbioinformatiques nous ont permis d'obtenir un panel de gènes différentiellement méthylés. Nous avons ainsi mis en évidence l’importance de la voie calcique (déméthylée, connue pour avoir un impact sur la salivation) et de la voie WNT (hyperméthylée). De plus nous avons pu identifier une régulation interféron et montrer l’importance d’un changement du type d'interféron (I à II) lors de l’évolution vers un lymphome de type MALT. En outre, nous montrons qu’il existe une inter-relation forte entre les processus épigénétiques et les facteurs génétiques associés au SGS. Enfin la dernière partie de ce travail met en lumière l’implication d’un environnement inflammatoire dans le contrôle du processus de méthylation/déméthylation de l’ADN dans les cellules épithéliales.Ainsi, les altérations du méthylome des SGECs pourraient contribuer à la pathophysiologie du SGS et à son évolution en un lymphome du MALT, ceci en lien avec son environnement inflammatoire. / Sjögren Syndrome (SjS) is a chronic autoimmune disease characterized by a progressive and irreversible damage of exocrine glands, particularly salivary and lacrymal glands. This pathology affects between 0.1 and 3% of the population and is more common in women with a ratio of 9 women for 1 man. In salivary glands, a lymphocytic infiltration is observed and associated with the destruction of the secretory epithelium, which plays a central role in initiation and development of the SjS. The process remains incompletely clarified and contains a strong epigenetic component. Indeed, important disturbances of the process of DNA methylation are observed in epithelial cells and they are linked with the level of lymphocyte infiltration in salivary glands.The objective of this work is to better understand epigenetic changes during the SjS and in particular the DNA methylation/demethylation defects observed in Salivary Gland Epithelial Cells Epithelial (SGEC) and their roles in the pathology development.For that purpose, a global study of DNA methylation was done on 12 patients SGECs with the Infinium HumanMethylation450 BeadChip (Illumina). The 450k HM allows to cover more than 485,000 CpG sites on the whole genome. Bioinformatic analysis allowed us to obtain genes panels which are differentially methylated during this pathological phenomenon. In an interesting way, we identified the potential involvement of the calcic (hypomethylated, known to impact salivation) and WNT pathways (hypermethylated). Besides we were able to identify interferon regulation and the shift from interferon type I to type II with mucosa associated lymphoid tissue (MALT) lymphoma evolution. Furthermore, the simultaneous genomic–epigenomic analysis revealed significant associations between SjS-associated genetic risk factors and epigenetic modifications. Finally, the last part of this work highlights inflammatory environment involvement to control DNA methylation/demethylation in salivary gland epithelial cells.Altogether, alterations of DNA methylation in SGEC may contribute to SjS pathophysiology and evolution to MALT and this in link with the inflammatory environment.

Primary biliary cirrhosis (PBC) is a chronic cholestatic liver disease, which primarily affects middle-aged women. The liver histology is characterized by inflammation and destruction of the intrahepatic bile ducts as well as a high frequency of granuloma. Although the etiology is unknown, the occurrence of associated multiorganic abnormalities such as Sjogren's syndrome, scleroderma, rheumatic disorders and thyroid gland diseases have been cited as evidence favouring an autoimmune background. Addison and Gull in 1851 described the first patient with jaundice and xanthomatosis. PBC was first mentioned in 1876 as an entity by Hanot. PBC was considered to be a rare disease until in 1973 Sherlock and Scheuer described 100 patients. Since then a greater awareness of the disease combined with a wider use of laboratory screening methods has led to the discovery of an increasing number of patients with PBC. In an epidemiological investigation of PBC in the northern part of Sweden a point prevalence of 151 per 106 was found, which is the highest so far reported, and the mean annual incidence amounted to 13.3 per 106. Asymptomatic PBC was present in more than one third of the patients which is consistent with the finding in other epidemiological investigations and is supposed to explain the higher prevalence of PBC and the better prognosis. Nevertheless 25 patients died during the study period, 14 as a direct consequence of the liver disease. Chronic intrahepatic cholestasis has been reported in sarcoidosis and, moreover, a high frequency of liver granuloma is found. The implication of the present study is that a negative Kveim test in combination with positive mitochondrial antibodies is accurate in differentiating PBC from sarcoidosis. Multisystem involvement is frequently observed in PBC and the present study confirms this. In the prospective investigation of 26 PBC patients 50 % had arthropathy considered to be associated with PBC. Rheumatoid arthritis was found in 5 patients, who all had symptoms of liver disease in addition. Lung function impairment was present in 56% (1 asymptomatic PBC). Most commonly a reduced diffusion capacity was found (36%). Bronchial asthma was present in three patients, and severe lung emphysema in one. Features of Sjogren's syndrome was found in 73% (3 asymptomatic PBC). In 6 patients keratoconjunctivitis sicca (KCS) was evident with the rose bengal test demonstrating corneal staining and a Schirmer test of less than 5 mm. Radiological findings of sialectasia were demonstrated in 6 patients, of whom 5 had KCS as well. The ultimate treatment in PBC is liver transplantation and to calculate the need for that, good epidemiological surveys are needed, and also indicators of hepatocellular function. The present investigation indicates that determination of the von Willebrand factor could be used for this purpose. / <p>Härtill 6 uppsatser</p> / digitalisering@umu

Les maladies auto-immunes et systémiques sont des maladies sur lequel le champ de la recherche pose son œil de façon appuyée depuis 15 ans, du fait de l’émergence de thérapies biologiques ciblées. Ces pathologies sont volontiers hétérogènes, au mieux de fréquence ou caractéristiques particulières dans les populations d’origine Africaine. La connaissance de l’épidémiologie, et des caractéristiques de ces maladies est un préalable essentiel à la mise en place de recherche plus fondamentale pour aider à décomposer leurs physiopathologies souvent extrêmement complexes. En effet, la comparaison de différences marquées entre deux expressions dans des populations différentes d’une même maladie peut permettre d’aider à en dénouer le fil. Nous proposons dans ce travail une estimation des caractéristiques du lupus cutané et du lupus systémique en Guyane Française qui retrouve une faible fréquence de la maladie, la plus faible jamais retrouvée dans une population subsaharienne. Nous décrivons en Martinique sur le plan épidémiologique comme clinique une forme rare de myosite appelée syndrome des anti-synthétases semblant très particulière, l’épidémiologie et la description de la maladie de Kikuchi-Fujimoto pour la première fois dans la littérature, l’épidémiologie et les caractéristiques à base de population de la maladie de Behcet, des principales vascularites (périartérite noueuse, micropolyangéite, granulomatose éosinophile avec polyangéite, granulomatose avec polyangéite), de l’hypertension pulmonaire des connectivites qui semblent plus fréquentes que chez les Européens. Les néphropathies du lupus systémiques sont décrites dans la population Guadeloupéenne montrant une grande fréquence des néphropathies prolifératives. Le protocole EUROLUPUS qui permet le traitement de ces néphropathies prolifératives du lupus systémique avec de faibles doses de cyclophosphamide et de corticoïdes, est évalué en Martinique sur 30 patients alors qu’il ne l’a jamais été dans une population d’origine Africaine. Il semble y être aussi efficace que chez les patients d’origine Européenne, alors que les néphropathies y ont un pronostic meilleur. La maladie de Sjögren primaire est décrite en Martinique très proche de ce qu’on trouve en Europe sur le plan du tableau clinique et évolutif alors que cela n’est l’objet d’aucune étude dans une population d’origine noire Africaine. Nous avons par ailleurs montré en Martinique l’amélioration de la prise en charge du lupus systémique en Martinique au travers de la régression au fil du temps d’une des complications de la corticothérapie les plus pénibles pour les patients, l’ostéonécrose aseptique. La sclérodermie systémique est décrite à base de population avec épidémiologie dans les deux départements de Guadeloupe et Martinique, montrant des caractéristiques proches de celles retrouvées chez les AfroAméricains. Nous avons aussi montré la fréquence et la gravité des atteintes ORL des myopathies inflammatoires sur ces 2 départements avec une fréquence inhabituelle de certaines maladies auto-immunes dont le lupus systémique et les myosites inflammatoires associées aux anticorps anti-SRP, et l’absence de myosite à inclusion. Au total, nous apportons une somme de connaissance descriptive de ces maladies auto-immunes et systémiques permettant la mise en place de recherches plus fondamentales avec des bases solides par rapport aux profils hétérogènes de ces maladies. / Auto-immunes and systemic diseases are priorities for researchers since 15 years. This is related to the emergence of biological therapies, associated to great efficacy. Although, these diseases are heterogeneous, depending of different parameters such as ethnicity or geography. In the African descent population, we encounter unusual or particular manifestations of these diseases. Also, the knowledge of epidemiology and population based descriptions are crucial to properly initiate works on these populations, but also to understand a particularly complex physiopathology by using differences between populations. We describe in this work the population based characteristics of pure cutaneous lupus and systemic lupus, including an epidemiology of the incidence of the lowest incidence ever found in a population of African heritage. We also describe a population based series of anti-synthetase syndrome, confirming that the presentation is totally different compared to caucasians, and allows in Martinique the incidence, never explored before. We also provide the first evaluation of Kikuchi-Fujimoto disease in a population of African origin, and the first incidence ever realized. We do the same evaluation of the epidemiology of Behcet’s disease in a black origin population that shows that this disease was at a similar frequency in Martinique and in Europe. Micropolyangeitis, polyarteritis, eosinophilic granulomatosis with polyangeitis and Granulomatosis with polyangeitis were evaluated in an epidemiologic study in Martinique, with addition of some cases from other French American region for a more powerful characteristics description. These diseases seem less frequent than in Europe, associated with less severity except for micropolyangeitis. EUROLUPUS, a protocol with low dose IV cyclophosphamide and low dose steroids, used to treat proliferative nephritis of systemic lupus is shown to have the same efficacy in Martinique than in patients of European origin. Primary Sjögren syndrome, evaluated in Martinique, is very similar in expression than what is found in Europe. The decrease overtime of aseptic osteonecrosis, a steroid side effect, is a witness of better control of systemic lupus activity with less usage permitted by protocols and new immunosuppressive drugs such as mycophenolate. Systemic sclerosis is described as very close to African American in a population based study in Martinique and Guadeloupe. We finally show that the rare ENT involvement of idiopathic inflammatory myositis is frequent in our population, associated with poor outcome, and surprisingly frequently related to systemic lupus and necrotizing myositis associated to SRP antibody but not to inclusion body myositis. To conclude, we allow an amount of description of these diseases in our region, including pioneer studies. This works tends to be the basis for studies to be continued in a more fundamental way in our countries.