A doença inflamatória intestinal (DII) e a esclerose sistêmica (ES) são doenças inflamatórias crônicas de difícil diagnóstico e tratamento. A etiologia da DII e da ES ainda não é completamente compreendida, mas sabe-se que fatores genéticos, imunológicos e ambientais estão envolvidos na sua patogênese. A DII possui dois principais subtipos clínicos: a doença de Crohn (DC) e a retocolite ulcerativa (RCU), caracterizados pela inflamação do intestino delgado e/ou cólon. Evidências sugerem que o aumento do estresse oxidativo desempenha um papel importante na fisiopatologia da DII. A ES é uma doença inflamatória autoimune rara, caracterizada pela fibrose progressiva da pele e de órgãos internos. A hipótese de que o aumento do dano oxidativo pode iniciar o dano vascular e desencadear os eventos patológicos observados na ES vem sendo investigada. Genes e enzimas envolvidos na metabolização (Fase I) e detoxificação (Fase II) de xenobióticos são utilizados como marcadores de susceptibilidade para o desenvolvimento de doenças que possuem fatores ambientais como fatores de risco. Em uma reação de Fase I, as enzimas do Citocromo P450 (CYP) inserem um átomo de oxigênio em um substrato deixando-o eletrofílico e reativo, criando um sítio para posterior conjugação pelas enzimas de Fase II. As enzimas Glutationa S-tranferases (GST) de Fase II catalisam a conjugação da glutationa com uma grande variedade de compostos eletrofílicos, detoxificando substâncias endógenas e exógenas. A atividade catalítica aumentada das enzimas CYP, bem como a falha na detoxificação de metabólitos pelas GST pode contribuir para o aumento do estresse oxidativo. O objetivo deste estudo foi investigar o papel de polimorfismos nos genes que codificam enzimas de metabolização (CYP1A*2C e CYP2E1*5B) e detoxificação (GSTT1 nulo, GSTM1 nulo e GSTP1 Ile105Val) na susceptibilidade a estas doenças. O grupo de pacientes com DII era constituído por 235 indivíduos e o grupo controle por 241 indivíduos, todos eurodescendentes. Na ES, 122 pacientes (99 eurodescendentes e 23 afrodescendentes) e 329 controles (241 eurodescendentes e 87 afrodescendentes) foram analisados. Os polimorfismos CYP foram genotipados por PCR-RFLP, enquanto que os polimorfismos em GSTT1 e GSTM1 foram genotipados por PCR multiplex e PCR-RFLP para GSTP1. As frequências alélicas e genotípicas foram comparadas entre pacientes e controles usando o teste de Qui-Quadrado. A respeito dos resultados das análises em DII, as frequências alélicas e genotípicas dos polimorfismos CYP1A1*2C, CYP2E1*5B e GSTP1 Ile105Val, bem como as frequências genotípicas do polimorfismo de presença/ausência de GSTM1, foram similares nos três grupos de pacientes (DII, DC e RCU) quando comparados ao grupo controle (P>0,05). Observouse uma frequência significativamente aumentada do genótipo nulo de GSTT1 no grupo de pacientes com DII quando comparado ao grupo controle [0,28 vs 0,18; χ² com Yates P=0,02; OR=1,71 (IC 95% 1,09 –2,71)]. Quando separamos o grupo de pacientes em DC ou RCU, esta frequência permaneceu significativamente aumentada somente no grupo de pacientes com RCU comparado ao grupo controle [0,29 vs 0,18; χ² com Yates P=0,035; OR=1,84 (IC 95% 1,03 –3,24)]. Com relação aos resultados das análises na ES, uma frequência significativamente aumentada do genótipo *1A/*1A (P=0,03; 0,74 vs. 0,61) e do alelo *1A (P=0,013; 0,86 vs 0,78; OR=0,57, IC 95% 0,36–0,90) do polimorfismo CYP1A1*2C foi observada entre os indivíduos controles eurodescendentes. Em contrapartida, a frequência do alelo *2C estava significativamente aumentada entre os pacientes de mesma etnia (P=0,013; 0,22 vs 0,14; OR=1,75, IC 95% 1,11–2,74). Com relação às frequências alélicas e genotípicas dos polimorfismos CYP2E1*5B e GSTP1 Ile105Val, e as frequências genotípicas do polimorfismo de presença/ausência de GSTM1, nenhuma diferença significativa foi observada quando os grupos de pacientes de ambas as etnias foram comparados aos grupos controle (P>0,05). Uma frequência significativamente aumentada do genótipo nulo de GSTT1 [0,29 vs 0,18; χ² com Yates P=0,035; OR=1,85 (IC 95% 1,03–3,29)], bem como uma alta frequência da dupla deleção de GSTT1/GSTM1 [0,19 vs 0,08; χ² com Yates P=0,007; OR=2,62 (IC 95% 1,25 –5,46)], foi observada no grupo de pacientes comparado aos controles (eurodescendentes). Estas associações não se repetiram entre indivíduos afrodescendentes. Concluindo, nossos resultados sugerem que o genótipo nulo de GSTT1 está associado à susceptibilidade a DII e pode influenciar na definição do curso da doença para a RCU. Além disso, o genótipo nulo de GSTT1 sozinho ou em combinação com o genótipo nulo de GSTM1 é um fator genético de susceptibilidade para a ES, enquanto que o genótipo *1A/*1A ou a presença do alelo *1A do polimorfismo CYP1A1*2C pode exercer um papel protetor contra o desenvolvimento da ES em indivíduos eurodescendentes. / Inflammatory bowel disease (IBD) and systemic sclerosis (SSc) are chronic inflammatory diseases of difficult diagnosis and treatment. The etiology of IBD and SSc is not completely understood but it is known that genetic, immunologic and environmental factors are involved in its pathogenesis. Crohn’s disease (CD) and ulcerative colitis (UC) are the two major subtypes of IBD, characterized by inflammation of the small intestine and/or colon. Evidences suggest that the increase of oxidative stress plays an important role in the pathophysiology of IBD. SSc is a rare autoimmune inflammatory disease of the connective tissue characterized by progressive fibrosis of the skin and internal organs. The hypothesis that the increase of oxidative stress can initiate vascular damage and triggers the pathological events in SSc has been investigated. Genes and enzymes involved in metabolism (Phase I) and detoxification (Phase II) of xenobiotics are used as markers of susceptibility to the development of diseases that have environmental factors as risk factors. In a Phase I reactions, the Cytochrome P450 (CYP) enzymes insert an oxygen atom in a substrate that making it more electrophilic and reactive, and creating a site for subsequent conjugation by Phase II enzymes. Phase II Glutathione S-transferases (GSTs) enzymes catalyze the conjugation of glutathione with a variety of electrophilic compounds, detoxifying endogenous and exogenous substances. A higher catalytic activity of CYP enzymes, as well as the failure in detoxifying of metabolites by GST enzymes may to contribute for the increase of oxidative stress. The aim of this study was investigated the role of polymorphisms in genes coding Phase I enzymes (CYP1A*2C and CYP2E1*5B) and Phase II (GSTT1 null, GSTM1 null and GSTP1 Ile105Val) in susceptibility to these diseases. IBD group was constituted by 235 patients and the control group by 241 individuals, all European-derived. In SSc group, 122 patients (99 European-derived and 23 African-derived) and 329 controls (241 European-derived and 87 African-derived) were analyzed. The CYP polymorphisms were genotyped by PCR-RFLP, whereas polymorphisms in GSTM1 and GSTT1 were genotyped by multiplex PCR and PCRRFLP for GSTP1. Allelic and genotypic frequencies were compared between patients and controls using the Chi-square test. Concerning IBD, allelic and genotypic frequencies of CYP1A1*2C, CYP2E1*5B and GSTP1 Ile105Val polymorphisms, as well as genotypic frequencies of GSTM1 presence/absence polymorphism were similar in all groups patients (IBD, CD, and UC) and controls (P>0.05). We observed a significantly increased frequency of GSTT1 null genotype in IBD group as compared to controls [0.28 vs. 0.18, χ ² with Yates P=0.02, OR=1.71 (95% CI 1.09 – 2.71)]. When patients were classified in CD or UC group, this frequency remained significantly increased only among UC patients [0.29 vs. 0.18, χ ² with Yates P=0,035, OR=1.84 (95% CI 1.03 – 3.24)] as compared to controls. Regarding results in SSc, a frequency significantly increased of *1A/*1A genotype (P=0.03; 0.74 vs. 0.61) and *1A allele (P=0.013; 0.86 vs 0.78; OR=0.57, 95% CI 0.36–0.90) from CYP1A1*2C polymorphism was observed among European-derived controls. On the other hand, the frequency of *2C allele was significantly increased among patients of same ethnic group (P=0.013; 0.22 vs 0.14; OR=1.75, 95% CI 1.11–2.74). The allelic and genotypic frequencies of CYP2E1*5B and GSTP1 Ile105Val polymorphisms, as well as genotypic frequencies of GSTM1 presence/absence polymorphism were similar between SSc patients and controls of both ethnic groups (P>0.05). We observed a significantly increased frequency of GSTT1 null genotype [0.29 vs. 0.18, χ ² with Yates P=0.035, OR=1.85 (95% CI 1.03–3.29)], as well as an increased frequency of GSTT1/GSTM1 double-null in SSc patients as compared to controls [0.19 vs. 0.08; χ ² with Yates P=0.007, OR=2.62 (95% CI 1.25 – 5.46)]. These associations were exclusive to European-derived individuals. In conclusion, our results suggest that the GSTT1 null genotype is associated with susceptibility to IBD and may influence in defining the course of the disease for RCU. Furthermore, the GSTT1 null genotype alone or combined with GSTM1 null genotype is a susceptibility genetic factor to SSc, while the *1A/*1A genotype or the presence of *1A allele from CYP1A1*2C polymorphism may plays a protector role in SSc development in Brazilian Europeanderived individuals.

A doença inflamatória intestinal (DII) e a esclerose sistêmica (ES) são doenças inflamatórias crônicas de difícil diagnóstico e tratamento. A etiologia da DII e da ES ainda não é completamente compreendida, mas sabe-se que fatores genéticos, imunológicos e ambientais estão envolvidos na sua patogênese. A DII possui dois principais subtipos clínicos: a doença de Crohn (DC) e a retocolite ulcerativa (RCU), caracterizados pela inflamação do intestino delgado e/ou cólon. Evidências sugerem que o aumento do estresse oxidativo desempenha um papel importante na fisiopatologia da DII. A ES é uma doença inflamatória autoimune rara, caracterizada pela fibrose progressiva da pele e de órgãos internos. A hipótese de que o aumento do dano oxidativo pode iniciar o dano vascular e desencadear os eventos patológicos observados na ES vem sendo investigada. Genes e enzimas envolvidos na metabolização (Fase I) e detoxificação (Fase II) de xenobióticos são utilizados como marcadores de susceptibilidade para o desenvolvimento de doenças que possuem fatores ambientais como fatores de risco. Em uma reação de Fase I, as enzimas do Citocromo P450 (CYP) inserem um átomo de oxigênio em um substrato deixando-o eletrofílico e reativo, criando um sítio para posterior conjugação pelas enzimas de Fase II. As enzimas Glutationa S-tranferases (GST) de Fase II catalisam a conjugação da glutationa com uma grande variedade de compostos eletrofílicos, detoxificando substâncias endógenas e exógenas. A atividade catalítica aumentada das enzimas CYP, bem como a falha na detoxificação de metabólitos pelas GST pode contribuir para o aumento do estresse oxidativo. O objetivo deste estudo foi investigar o papel de polimorfismos nos genes que codificam enzimas de metabolização (CYP1A*2C e CYP2E1*5B) e detoxificação (GSTT1 nulo, GSTM1 nulo e GSTP1 Ile105Val) na susceptibilidade a estas doenças. O grupo de pacientes com DII era constituído por 235 indivíduos e o grupo controle por 241 indivíduos, todos eurodescendentes. Na ES, 122 pacientes (99 eurodescendentes e 23 afrodescendentes) e 329 controles (241 eurodescendentes e 87 afrodescendentes) foram analisados. Os polimorfismos CYP foram genotipados por PCR-RFLP, enquanto que os polimorfismos em GSTT1 e GSTM1 foram genotipados por PCR multiplex e PCR-RFLP para GSTP1. As frequências alélicas e genotípicas foram comparadas entre pacientes e controles usando o teste de Qui-Quadrado. A respeito dos resultados das análises em DII, as frequências alélicas e genotípicas dos polimorfismos CYP1A1*2C, CYP2E1*5B e GSTP1 Ile105Val, bem como as frequências genotípicas do polimorfismo de presença/ausência de GSTM1, foram similares nos três grupos de pacientes (DII, DC e RCU) quando comparados ao grupo controle (P>0,05). Observouse uma frequência significativamente aumentada do genótipo nulo de GSTT1 no grupo de pacientes com DII quando comparado ao grupo controle [0,28 vs 0,18; χ² com Yates P=0,02; OR=1,71 (IC 95% 1,09 –2,71)]. Quando separamos o grupo de pacientes em DC ou RCU, esta frequência permaneceu significativamente aumentada somente no grupo de pacientes com RCU comparado ao grupo controle [0,29 vs 0,18; χ² com Yates P=0,035; OR=1,84 (IC 95% 1,03 –3,24)]. Com relação aos resultados das análises na ES, uma frequência significativamente aumentada do genótipo *1A/*1A (P=0,03; 0,74 vs. 0,61) e do alelo *1A (P=0,013; 0,86 vs 0,78; OR=0,57, IC 95% 0,36–0,90) do polimorfismo CYP1A1*2C foi observada entre os indivíduos controles eurodescendentes. Em contrapartida, a frequência do alelo *2C estava significativamente aumentada entre os pacientes de mesma etnia (P=0,013; 0,22 vs 0,14; OR=1,75, IC 95% 1,11–2,74). Com relação às frequências alélicas e genotípicas dos polimorfismos CYP2E1*5B e GSTP1 Ile105Val, e as frequências genotípicas do polimorfismo de presença/ausência de GSTM1, nenhuma diferença significativa foi observada quando os grupos de pacientes de ambas as etnias foram comparados aos grupos controle (P>0,05). Uma frequência significativamente aumentada do genótipo nulo de GSTT1 [0,29 vs 0,18; χ² com Yates P=0,035; OR=1,85 (IC 95% 1,03–3,29)], bem como uma alta frequência da dupla deleção de GSTT1/GSTM1 [0,19 vs 0,08; χ² com Yates P=0,007; OR=2,62 (IC 95% 1,25 –5,46)], foi observada no grupo de pacientes comparado aos controles (eurodescendentes). Estas associações não se repetiram entre indivíduos afrodescendentes. Concluindo, nossos resultados sugerem que o genótipo nulo de GSTT1 está associado à susceptibilidade a DII e pode influenciar na definição do curso da doença para a RCU. Além disso, o genótipo nulo de GSTT1 sozinho ou em combinação com o genótipo nulo de GSTM1 é um fator genético de susceptibilidade para a ES, enquanto que o genótipo *1A/*1A ou a presença do alelo *1A do polimorfismo CYP1A1*2C pode exercer um papel protetor contra o desenvolvimento da ES em indivíduos eurodescendentes. / Inflammatory bowel disease (IBD) and systemic sclerosis (SSc) are chronic inflammatory diseases of difficult diagnosis and treatment. The etiology of IBD and SSc is not completely understood but it is known that genetic, immunologic and environmental factors are involved in its pathogenesis. Crohn’s disease (CD) and ulcerative colitis (UC) are the two major subtypes of IBD, characterized by inflammation of the small intestine and/or colon. Evidences suggest that the increase of oxidative stress plays an important role in the pathophysiology of IBD. SSc is a rare autoimmune inflammatory disease of the connective tissue characterized by progressive fibrosis of the skin and internal organs. The hypothesis that the increase of oxidative stress can initiate vascular damage and triggers the pathological events in SSc has been investigated. Genes and enzymes involved in metabolism (Phase I) and detoxification (Phase II) of xenobiotics are used as markers of susceptibility to the development of diseases that have environmental factors as risk factors. In a Phase I reactions, the Cytochrome P450 (CYP) enzymes insert an oxygen atom in a substrate that making it more electrophilic and reactive, and creating a site for subsequent conjugation by Phase II enzymes. Phase II Glutathione S-transferases (GSTs) enzymes catalyze the conjugation of glutathione with a variety of electrophilic compounds, detoxifying endogenous and exogenous substances. A higher catalytic activity of CYP enzymes, as well as the failure in detoxifying of metabolites by GST enzymes may to contribute for the increase of oxidative stress. The aim of this study was investigated the role of polymorphisms in genes coding Phase I enzymes (CYP1A*2C and CYP2E1*5B) and Phase II (GSTT1 null, GSTM1 null and GSTP1 Ile105Val) in susceptibility to these diseases. IBD group was constituted by 235 patients and the control group by 241 individuals, all European-derived. In SSc group, 122 patients (99 European-derived and 23 African-derived) and 329 controls (241 European-derived and 87 African-derived) were analyzed. The CYP polymorphisms were genotyped by PCR-RFLP, whereas polymorphisms in GSTM1 and GSTT1 were genotyped by multiplex PCR and PCRRFLP for GSTP1. Allelic and genotypic frequencies were compared between patients and controls using the Chi-square test. Concerning IBD, allelic and genotypic frequencies of CYP1A1*2C, CYP2E1*5B and GSTP1 Ile105Val polymorphisms, as well as genotypic frequencies of GSTM1 presence/absence polymorphism were similar in all groups patients (IBD, CD, and UC) and controls (P>0.05). We observed a significantly increased frequency of GSTT1 null genotype in IBD group as compared to controls [0.28 vs. 0.18, χ ² with Yates P=0.02, OR=1.71 (95% CI 1.09 – 2.71)]. When patients were classified in CD or UC group, this frequency remained significantly increased only among UC patients [0.29 vs. 0.18, χ ² with Yates P=0,035, OR=1.84 (95% CI 1.03 – 3.24)] as compared to controls. Regarding results in SSc, a frequency significantly increased of *1A/*1A genotype (P=0.03; 0.74 vs. 0.61) and *1A allele (P=0.013; 0.86 vs 0.78; OR=0.57, 95% CI 0.36–0.90) from CYP1A1*2C polymorphism was observed among European-derived controls. On the other hand, the frequency of *2C allele was significantly increased among patients of same ethnic group (P=0.013; 0.22 vs 0.14; OR=1.75, 95% CI 1.11–2.74). The allelic and genotypic frequencies of CYP2E1*5B and GSTP1 Ile105Val polymorphisms, as well as genotypic frequencies of GSTM1 presence/absence polymorphism were similar between SSc patients and controls of both ethnic groups (P>0.05). We observed a significantly increased frequency of GSTT1 null genotype [0.29 vs. 0.18, χ ² with Yates P=0.035, OR=1.85 (95% CI 1.03–3.29)], as well as an increased frequency of GSTT1/GSTM1 double-null in SSc patients as compared to controls [0.19 vs. 0.08; χ ² with Yates P=0.007, OR=2.62 (95% CI 1.25 – 5.46)]. These associations were exclusive to European-derived individuals. In conclusion, our results suggest that the GSTT1 null genotype is associated with susceptibility to IBD and may influence in defining the course of the disease for RCU. Furthermore, the GSTT1 null genotype alone or combined with GSTM1 null genotype is a susceptibility genetic factor to SSc, while the *1A/*1A genotype or the presence of *1A allele from CYP1A1*2C polymorphism may plays a protector role in SSc development in Brazilian Europeanderived individuals.

Title: The effect of aerobic training in patients with systemic sclerosis - literature review Objective: Main aim of this diploma thesis is to evaluate the effect of aerobic training in individuals with systemic sclerosis, to assess whether aerobic training has an impact on quality of life of these patients, and find out which methods are used to assess aerobic fitness in these individuals. Furthermore, the work is focused on summarizing the existing knowledge about the disease itself. Methodics: Thesis is written in the form of a systematic review according to the specified methodological parameters. Results: Studies have shown that aerobic training or aerobic training in combination with resistant training has a positive effect on the aerobic capacity of individuals with systemic scleroderma, the trend to improve quality of life was found in all studies and the methods used to determine aerobic fitness in all studies were cardiopulmonary stress tests. In the case of three studies, a six-minute walk test was also evaluated, the results of which were determined in two studies as the primary values for determining the effectiveness of training. Keywords: systemic sclerosis, scleroderma, physical exercise, aerobic exercise, aerobic training

Introduction: This work focused on two rare rheumatic diseases systemic sclerosis (SSc) and idiopathic inflammatory myopathies (IIM). Skin and musculoskeletal involvement in patients with SSc leads to disability and loss of functional abilities of an individual. Chronic inflammation of the muscles, subsequent muscle atrophy and permanent muscle damage in patients with IIM are the cause of a decrease in muscle strength and endurance. Moreover, both diseases also affect internal organs and manifest often with impaired lung and heart function. All of these involvements in both diseases lead to a decrease in the quality of life of patients. The data on efficacy of non-pharmacological care in SSc and IIM are very limited due to the heterogeneity of the studied interventions and/or outcomes. However, due to limitations in pharmacological therapy, non-pharmacological interventions could help bring patients back into their everyday life and improve their quality of life. Objectives: The main objective of this project was to evaluate the impact of physical intervention on disease course and activity in a substantial number of SSc and IIM patients, with the aim of minimizing the limitations of available studies, thereby improving the quality and reliability of the obtained results. Methods: This is a...

No description available.

Systemisk skleros (SSc) är en autoimmun rheumatisk sjukdom som kännetecknas av fibros i huden och/eller de interna organen, vaskulopati och en autoimmun reaktion från immunförsvaret, med eller utan specifika autoantikroppsprofiler. Diagnostisering och sjukdomsbehandling försvåras av sjukdomens heterogena natur. Det finns därför ett behov av pålitliga autoantikroppsbiomarkörer som kan bistå vid diagnostisering av patienter. Autoantikroppar som förekommer i serum kan avslöja sjukdomstillståndet hos patienter samt indikera en prognos om de korreleras till ett specifikt klinisk symtom. Syftet med denna studie var att identifiera autoantikroppar som kanditater till nya biomarkörer inom systemisk skleros i hopp om att dessa ska kunna förbättra stratifiering av patienter, samt att addera kunskap om autoantikroppsreaktivitet inom sjukdomen. Autoantikroppsprofilerna i 107 serumprover, där 55 tillhörde SSc-patienter och 52 tillhörde inflammatoriska kontroller, analyserades i två faser med en planar antigen array för en initial objektiv identifiering av möjliga autoantikroppskandidater, som sedan verifierades i en suspension bead array. Resultaten konfirmerar reaktivitet mot kända autoantigen, så som centromer protein B (CENPB) och DNA topoisomeras I (TOP1), samt identifierar fosfatidylinositol-5-fosfat 4-kinas typ 2 beta (PIP4K2B) som en ny, potentiellt specifik, autoantikroppskandidat för sjukdomen. Tripartite motif containing 21 (TRIM21) som är ett känt autoantigen hos flera systemiska autoimmuna sjukdomar visar potential för att kunna stratifiera sjukdomen. Resultaten i denna studie adderar ny information till kontexten inom autoantikroppsreaktivitet hos patienter med systemisk skleros som efter en mer omfattande dataanalys förhoppningsvis kommer att vara användbar inom diagnostisering av patienter samt för att skräddarsy behandling av sjukdomen. / Systemic sclerosis (SSc) is a highly heterogeneous rheumatic autoimmune disease that is characterized by fibrosis of the skin and/or visceral organs, vasculopathy, and an irregular immune response with or without specific autoantibody profiles. The heterogenic nature of the disease creates a challenge in diagnosis and clinical management of patients. There is thus a need for reliable autoantibody biomarkers that could aid in patient stratification. Serum autoantibodies are indicative of the disease state and may reveal prognosis if correlated to a specific clinical feature. This study aimed to discover novel autoantibody biomarker candidates with the hopes of improving patient stratification and to provide additional knowledge on the autoantibody reactivity in systemic sclerosis. By using a two-phase study design, an autoantibody profiling of 107 serum samples, consisting of 55 SSc samples and 52 inflammatory controls, was performed using the planar antigen array for initial discovery and a suspension bead array for verification. Resulting data confirms reactivity to known targets such as centromere protein B (CENPB) and DNA topoisomerase I (TOP1), while also identifying phosphatidylinositol-5-phosphate 4-kinase type 2 beta (PIP4K2B) as a potential novel target that is specific to the disease. Tripartite motif containing 21 (TRIM21), a known target among several systemic autoimmune diseases, show potential as a target for patient stratification. The results of this study add new information to the context of autoantibody reactivity in systemic sclerosis, which after more extensive data analysis, could be useful in improving the stratification of patients and in tailoring treatment.

Objectives: The aim of this systematic review was to assess the oral-health-related quality of life (OHRQoL) of adult patients with rheumatic diseases. Material and Methods: A systematic literature search was performed, including clinical studies on adults (aged at least 18 years) with a verified diagnosis of rheumatic disease. Results: 26 out of 41 clinical studies including rheumatoid arthritis (RA, seven studies), systemic sclerosis (SSc, five), Sjögren syndrome (SS, eight), Behcet disease (BD, four), systemic lupus erythematosus (SLE, one) and ankylosing spondylitis (AS, one) were found. In 15 studies, a healthy control group was recruited. The short form of the Oral Health Impact Profile (OHIP 14) was most frequently applied. The majority of studies (14/15) reported worse OHRQoL in patients with rheumatic disease compared to healthy individuals. In particular, patients with SS (salivary flow and composition) or BD (oral ulcers) showed a relation between OHRQoL and disease-specific oral manifestations. Most studies investigating subscales of OHRQoL (5/6) found the subscale physical disability to be predominantly affected in patients with rheumatic diseases. About half of the studies reported impaired psychosocial aspects. Conclusion: Patients with rheumatic diseases exhibit reduced OHRQoL, especially in diseases with oral manifestations like SS and BD. Physical affections due to oral diseases and psychosocial impairments caused by disease-related parameters must be recognized within patient-centered dental care.

Hintergrund: Systemische Sklerose (SSc) ist eine seltene, progressive Bindegewebserkrankung mit derzeitig begrenztem Wissen über die Zusammenhänge zwischen klinischen Anzeichen, körperlichen Einschränkungen, Lebensqualität und depressiven Symptomen. Während die Prävalenz von Depressionen in der deutschen Allgemeinbevölkerung bei 8,5% (Stein et al., 2014) und in der polnischen Allgemeinbevölkerung bei 4,8% liegt (Hapke et al., 2019), schwankt sie bei Patienten mit SSc zwischen 23% und 46% (Matsuura et al., 2003; Müller et al., 2012, „Corrigenda“, 2022; Jewett et al., 2013; Kwakkenbos et al., 2013; Nguyen et al., 2014; Faezi et al., 2017; March et al., 2019). Dies legt nahe, dass eine Definition der Determinanten von Depression und Lebensqualität erforderlich ist. Hypothese: Das Ziel der Studie bestand darin, soziodemographische, klinische, psychologische und therapeutischen Parameter sowie die gesundheitsbezogene Lebensqualität, subjektiver Gesundheitszustand, Depressionsneigung, körperliche Einschränkungen, Schmerzen, Krankheitssymptome und -merkmale, subjektive und objektive Krankheitsaktivität von Patienten mit SSc mittels einer quantitativen Analyse zu erfassen und Abhängigkeiten untereinander darzulegen. Des Weiteren sollte geprüft werden, ob bei den untersuchten Patienten mit SSc eine höhere Prävalenz für Depressionsneigung, ein häufigeres Vorliegen von körperlichen Einschränkungen, verminderte gesundheitsbezogene Lebensqualität und verminderter subjektiver Gesundheitszustand im Vergleich zur allgemeinen Bevölkerung vorliegt und welche Einflussfaktoren diese beeinträchtigen. Die sich hieraus ergebenden Erkenntnisse könnten die zukünftige Behandlung von Patienten mit systemischer Sklerose wesentlich beeinflussen. Methoden: Es wurde eine Querschnittsanalyse von 79 Patienten in Dresden und 10 Patienten in Breslau zwischen 2016 und 2018 durchgeführt, sodass länderspezifische Charakteristika identifiziert und verglichen werden konnten. Darüber hinaus wurde eine Längsschnittanalyse von 33 Patienten aus Dresden mit Daten aus dem Jahr 2008 und aus 2018 ausgewertet, um den Verlauf der Parameter zu beurteilen. Mittels eines Patientenfragebogens wurden unter anderem soziodemographische Daten, Schmerzangaben, sowie subjektive Krankheitsschwere (PGA), körperliche Einschränkung durch die Erkrankung (HAQ), gesundheitsbezogene Lebensqualität (EQ-5D-3L), subjektiver Gesundheitszustand (EQ-5D-VAS) und Depressionsneigung (CES-D) erfasst. Mittels Arztfragebogen wurden unter anderem die Diagnoseform, Dauer der Erkrankung, Organbeteiligung, Symptome, Therapie und mittels EUSTAR-Score die Krankheitsaktivität erfasst. Die Datenanalyse erfolgte deskriptiv und explorativ. Kreuztabellen, Chi-Quadrat-Test und T-Test wurden für Berechnungen verwendet, die Pearson-Korrelation zur Messung von Abhängigkeiten und logistische Regressionsanalysen für kategorisierte Parameter. Ergebnisse: Da die limitierte kutane systemische Sklerose die häufigste Diagnose darstelle, waren vor allem muskulokutane Symptome führend. Bei den Breslauer Patienten zeigten sich zudem häufiger Lungen- und Ösophagusbeteiligungen, eine höhere Krankheitsaktivität sowie höhere subjektive Krankheitsschwere. Die Dresdner Patienten gaben hingegen stärkere Schmerzen an. Die körperlichen Einschränkungen durch die Erkrankung, gesundheitsbezogene Lebensqualität und subjektiver Gesundheitszustand waren bei den Breslauer Patienten ausgeprägter und die Depressionsneigung im Vergleich zu den Dresdner Patienten erhöht. Beide Kohorten zeigten im Vergleich zur durchschnittlichen Bevölkerung höhere Raten an Patienten mit Depressionsneigung, eine niedrigere gesundheitsbezogene Lebensqualität und einen schlechteren subjektiven Gesundheitszustand. Es konnten jeweils hochsignifikante Zusammenhänge zwischen gesundheitsbezogener Lebensqualität, subjektivem Gesundheitszustand, körperlichen Einschränkungen, Depressionsneigung und Schmerzen gezeigt werden. Bei den Dresdner SSc-Patienten konnten weitere signifikante Korrelation der körperlichen Einschränkung mit dem Vorliegen einer ausgeprägten Sklerodermie (mRSS>14) und eines schlechten subjektiven Gesundheitszustandes mit der Beteiligung des Kauorgans gezeigt werden. Es fanden sich weiterhin signifikante Korrelationen von Depressionsneigung bei den SSc-Patienten in Dresden mit pulmonaler Hypertonie, Dyspnoe sowie Muskelschwäche. Letzteres war auch bei den Breslauer SSc-Patienten feststellbar ebenso wie weitere signifikante Korrelationen zwischen der Depressionsneigung und Kontrakturen, Pits sowie erhöhter Erkrankungsaktivität (EUSTAR>3). In der Längsschnittstudie der 33 Dresdner SSc-Patienten zeigte sich eine signifikante Zunahme der Krankheitsaktivität, der Schmerzangabe, der körperlichen Einschränkung durch die Erkrankung sowie der Patientenzahl mit Depressionsneigung, wobei eine in 2008 festgestellte Depressionsneigung mit einer BMI-Zunahme über den Krankheitsverlauf einherging. Es wurde eine Zunahme der subjektiven Krankheitsschwere sowie eine Abnahme der gesundheitsbezogenen Lebensqualität und des subjektiven Gesundheitszustandes beobachtet. Schlussfolgerungen: Diese Studie zeigt, dass fast die Hälfte der SSc-Patienten unter Depressionsneigung litt, was etwa fünfmal mehr ist als der durchschnittliche Wert in der deutschen Allgemeinbevölkerung. Im Verlauf der Erkrankung nahmen die Depressionsneigung, Schmerzen und körperliche Einschränkungen zu. Die gesundheitsbezogene Lebensqualität und der Gesundheitszustand nahmen ab, was darauf hindeutet, dass eine frühzeitige Erkennung der Krankheit und eine präventive interdisziplinäre Behandlung der körperlichen und psychischen Symptome erforderlich sind.:1. Abbildungsverzeichnis IV-V 2. Tabellenverzeichnis VI 3. Abkürzungsverzeichnis VII-VIII 4. Einleitung 1-11 4.1 Medizinische Kenntnisse zur Systemischen Sklerose 1-9 4.1.1 Manifestation, Prävalenz, Inzidenz 1 4.1.2 Klassifikation und Symptomatik 2-4 4.1.3 Pathogenese 4-6 4.1.4 Diagnostik 6-7 4.1.5 Therapie 8-9 4.2 Systemische Sklerose und Depression 10-11 4.3 Ziele der Studie 11 5. Methoden 12-18 5.1 Allgemeine Voraussetzungen und Zustimmung der Ethikkommission 12 5.2 Studiendesign 12 5.3 Einschluss der Patienten 12-13 5.4 vorbestehende Daten 13 5.5 Daten weiterer Studienzentren 13 5.6 Methoden zur Datenerhebung 13-16 5.6.1 Patientenfragebogen 13-15 5.6.2 Arztfragebogen 16 5.7 Statistische Analyse 17-18 6.Ergebnisse 19-40 6.1 Allgemein 20 6.2 Längsschnittstudie Dresden 20-27 6.2.1 Soziodemographische Daten 20 6.2.2 Charakteristika der Erkrankung, Diagnostik und Therapie 20-22 6.2.3 Schmerzen und deren Verlauf 22-23 6.2.4 Subjektive Krankheitsschwere und deren Verlauf 23 6.2.5 Körperlichen Einschränkung und deren Verlauf 24 6.2.6 Gesundheitsbezogene Lebensqualität und deren Verlauf 24-25 6.2.7 Subjektiver Gesundheitszustand und dessen Verlauf 25 6.2.8 Depressive Symptome, BMI und deren Verlauf 25-27 6.3 Querschnittstudie Dresden 28-37 6.3.1 Soziodemographische Daten 28 6.3.2 Charakteristika der Erkrankung, Diagnostik und Therapie 28-29 6.3.3 Schmerzen 29-31 6.3.4 Subjektiven Krankheitsschwere 32 6.3.5 Körperlichen Einschränkung und deren Einflussfaktoren 32 6.3.6 Gesundheitsbezogene Lebensqualität und deren Einflussfaktoren 32-34 6.3.7 Subjektiver Gesundheitszustand und dessen Einflussfaktoren 34-35 6.3.8 Depressive Symptome und deren Einflussfaktoren 36-37 6.4 Querschnittstudie Breslau 38-40 6.4.1 Soziodemographische Daten 37-38 6.4.2 Charakteristika der Erkrankung, Diagnostik und Therapie 38 6.4.3 Schmerzen 38 6.4.4 Subjektive Krankheitsschwere 39 6.4.5 Körperlichen Einschränkung und deren Einflussfaktoren 39 6.4.6 Gesundheitsbezogene Lebensqualität und deren Einflussfaktoren 39 6.4.7 Subjektiver Gesundheitszustand und dessen Einflussfaktoren 39 6.4.8 Depressive Symptome und deren Einflussfaktoren 40 7.Diskussion 41-54 7.1 Allgemein 40 7.2 Längsschnittstudie Dresden 41-44 7.3 Querschnittstudie Dresden und Breslau 44-51 7.4 Stärken und Grenzen der Studie 52-53 7.5 Auswirkungen auf die klinische Praxis und die zukünftige Forschung 53 7.6 Weiterführende Überlegungen 53-54 8. Zusammenfassung 55-59 9. Literaturverzeichnis 60-70 10. Anhang 71-116 10.1 Abbildungen 70-83 10.2. Tabellen 84-116 11. Anlagen 117-122 11.1 Darstellung des Eigenanteils 117 11.2 Erklärung zur Eröffnung des Promotionsverfahrens 118-119 11.3 Erklärung über die Einhaltung der aktuellen gesetzlichen Vorgaben im Rahmen einer Dissertation 120 11.4 Curriculum vitae 121 11.5 Verzeichnis der wissenschaftlichen Veröffentlichungen 122 12. Danksagung 123

The human gamma-delta (gd) TCR+ T-cell subset may undergo specific antigen-driven activation and clonal expansion, in the context of systemic sclerosis (SSc) pathogenesis. The purpose of this study was; 1) To determine whether gd TCR+ T-cells are clonally expanded in skin biopsies and peripheral blood from patients with SSc; and 2) To develop approaches for identification of the antigens recognized by these clonally-expanded gd TCR+ T-cells. Total RNA was isolated from the skin biopsies and peripheral blood of patients with SSc (n=8). After cDNA synthesis, the g- and d-chain TCR transcripts were amplified by PCR, cloned and sequenced for analysis. Full length copies of the TCR transcripts were constructed, expressed in a TCR-negative Jurkat T-cell line using retroviral gene transduction, and verified by RT-PCR and flow cytometry for gd TCR expression. Putative antigen recognition, by the transduced gd TCR+ Jurkat T-cell lines, was assessed via; 1) Measuring intracellular calcium flux in the transduced cells after stimulation with putative SSc antigens, including DNA topoisomerase I, centromere proteins A and B, hsp 27, hsp 90 and the viral lysate of human cytomegalovirus; and 2) Cytotoxicity against human endothelial cell lines (HUVEC and HLMVEC) via measurement of lactate dehydrogenase release from the targets. We report the presence of substantial, statistically-significant, proportions of identical g- and d-chain transcripts in skin biopsies and PBMC of patients with SSc, demonstrating the presence of antigen-driven clonal expansions. Jurkat T-cells, transduced with the clonally-expanded gd TCR transcripts from a patient, showed no evidence of cytotoxicity against the human endothelial cell lines, or calcium flux in response to stimulation with the putative SSc antigens assessed. In conclusion, extensive clonal expansions of g- and d-chain TCR transcripts were identified in skin biopsies and peripheral blood of patients with SSc, demonstrating the presence of oligoclonal populations of gd TCR+ T-cells in these patients. These gd TCR+ T-cells have undergone proliferation and clonal expansion in vivo in response to as yet unidentified antigens. Furthermore, an approach has been developed for the identification of the antigens recognized by the clonally-expanded gd TCR transcripts, which can be expanded to additional patients with SSc. / Microbiology and Immunology

Résumé : Dans la sclérodermie systémique (ScS), les contractures aux mains, pour lesquelles il n'existe aucun traitement prouvé, sont courantes et associées à de l'incapacité de la main, globale et au travail. Toutefois, quelques études sur les effets d'interventions comprenant des techniques manuelles ont montré des résultats prometteurs. Ainsi, le but de l'étude était d'explorer les effets d’un traitement ostéopathique sur la fonction de la main, des symptômes globaux de la maladie et le statut fonctionnel de personnes atteintes de ScS. Une série d'études à cas uniques (A[indice inférieur 1]-B-A[indice inférieur 2]) fut réalisée. Six participantes atteintes de ScS ont été recrutées parmi la cohorte du Groupe de recherche canadien sur la sclérodermie à deux sites (Hôpital général juif de Montréal et Centre hospitalier universitaire de Sherbrooke). Les participantes ont reçu neuf séances hebdomadaires d’ostéopathie semi-standardisées, ciblées sur les membres supérieurs, le thorax et la base du crâne. Des mesures répétées pendant les trois phases de l'étude ont été prises à une fréquence bihebdomadaire pour la raideur aux mains (RM) et les symptômes de douleur, dyspnée et fatigue; et hebdomadaire pour l'amplitude de mouvement des doigts (AMD), la fonction de la main (FM) et l'incapacité globale (IG). L'épaisseur/rigidité de la peau main/avant-bras (ÉPMA), l'incapacité au travail (IT) et la qualité de vie reliée à la santé (QVS) ont été mesurées à trois temps (avant et après l'intervention, ainsi qu'au suivi à un mois). Les variables à mesures répétées ont été représentées sur des graphiques linéaires soumis à des analyses visuelles, complétées du test Sheward's two Standard Deviation Band. Les différences ont été calculées pour les variables mesurées à trois temps. Toutes les participantes (n=6) ont montré une amélioration des variables reliées à la fonction manuelle (RM, AMD et FM), sauf pour l'ÉPMA (n=4). La majorité des participantes ont montré une amélioration des symptômes (douleur n=6, fatigue n=4 et dyspnée n=3/4) et des variables reliées au statut fonctionnel (IG n=5/5, IT n=4, score résumé physique n=6 et mental n=4 de la QVS). La plupart des effets se sont maintenus au suivi à un mois. Lorsque la comparaison était possible, presque toutes les améliorations observées ont été supérieures aux différences minimales cliniquement importantes suggérées pour cette population. Ces résultats suggèrent que l'ostéopathie pourrait être efficace pour réduire l'incapacité découlant des contractures aux mains de personnes souffrant de ScS, et devraient être vérifiés dans un essai clinique randomisé. // Abstract : In systemic sclerosis (SSc), hand contractures are common and associated with hand, global and work disability. There are no known effective treatments, although there have been a few promising studies with manual therapies. Our aim was to explore the effects of osteopathy on hand function, disease symptoms and functional status in SSc patients. A series of single case studies (A[subscript 1]-B-A[subscript 2] was undertaken. Six female SSc patients with hand contractures were recruited among subjects enrolled in the Canadian Scleroderma Research Group cohort at 2 sites (Jewish General Hospital, Montreal and Centre hospitalier universitaire de Sherbrooke, Sherbrooke). Participants received 9 weekly semi-standardized sessions of osteopathy targetted on upper limbs, thorax and cranial base. Repeated measures were taken during the three phases of the study, twice a week for hand stiffness and disease symptoms of pain, dyspnea and fatigue; and once a week for range of motion of fingers, hand disability and global disability. Upper limbs skin score, work disability and health-related quality of life were measured at baseline, after treatments and at 1-month follow-up. Data for each variable with repeated measures were represented on simple line graphs and visually interpreted, completed by the Sheward's two Standard Deviation Band test. Differences were calculated for variables measured at 3 time points. All participants (n=6) showed improvement in variables related to hand function (hand stiffness, range of motion of fingers and hand disability), except for upper limbs skin score (n=4). The majority of participants showed improvement in disease symptoms (pain n=6, fatigue n=4, et dyspnea n=3/4) as well as variables related to functional status (global disability n=5/5, work disability n=4, physical n=6 and mental n=4 component summary of health-related quality of life). Most improvements were maintained at 4 week follow up. When the comparison was possible, almost all observed improvements were higher than the minimal clinically important differences suggested for this population. These findings suggest that osteopathy may be effective in reducing disability from hand contractures in SSc. A randomized controlled trial is needed to confirm these results.