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.

Submitted by Renata Lopes (renatasil82@gmail.com) on 2016-07-14T11:38:20Z No. of bitstreams: 1 lilianaandradechebli.pdf: 509558 bytes, checksum: 46eb6aa1950b8cf02f40073b054ed6c3 (MD5) / Approved for entry into archive by Diamantino Mayra (mayra.diamantino@ufjf.edu.br) on 2016-07-19T14:23:32Z (GMT) No. of bitstreams: 1 lilianaandradechebli.pdf: 509558 bytes, checksum: 46eb6aa1950b8cf02f40073b054ed6c3 (MD5) / Made available in DSpace on 2016-07-19T14:23:32Z (GMT). No. of bitstreams: 1 lilianaandradechebli.pdf: 509558 bytes, checksum: 46eb6aa1950b8cf02f40073b054ed6c3 (MD5) Previous issue date: 2011-10-17 / Colite ulcerativa é uma doença inflamatória intestinal idiopática da mucosa colônica caracterizada clinicamente por episódios intermitentes de exacerbações alternados com períodos de remissão. Os corticosteroides permanecem como uma das drogas mais efetivas no tratamento das exacerbações moderadas a graves da colite ulcerativa. Entretanto, eles não são adequados para terapia de manutenção devido à falta de eficácia na prevenção de recorrências. Além disso, seu uso associa-se frequentemente com vários efeitos adversos e, aproximadamente, 25% dos pacientes que respondem aos corticosteroides serão incapazes de tolerar sua retirada sem que apresentem recorrências sintomáticas. Consequentemente, ―dependência de esteróides‖ em pacientes com colite ulcerativa é um problema de grande relevância na prática e manutenção da remissão sem esteróides é meta importante a ser alcançada. Diversas modalidades terapêuticas podem ser empregadas em pacientes com colite ulcerativa córtico-dependente (CUCD). Tradicionalmente, a escolha é entre a cirurgia ou o escalonamento do tratamento clínico, que geralmente envolve o uso de imunossupressores. O tratamento com azatioprina (AZA) tem tido amplo uso neste cenário. Entretanto, estudos no longo prazo avaliando a eficácia da AZA na CUCD são inexistentes. Os objetivos deste estudo foram avaliar em pacientes com CUCD, a eficácia da AZA no longo prazo para manutenção da remissão clínica sem esteróides, bem como a segurança desta droga neste contexto. Neste estudo de coorte prospectivo observacional, pacientes adultos com CUCD foram recrutados para tratamento com AZA durante o período de 36 meses. AZA foi ajustada para a dose alvo de 2-3 mg/Kg/dia. A redução da dose de esteróides durante o estudo seguiu um esquema previamente padronizado. A avaliação primária de eficácia foi a taxa anual de pacientes que alcançaram resposta sustentada a AZA sem esteróides. Resposta sustentada foi definida como a retirada completa dos corticosteroides e manutenção da remissão clínica sem a necessidade de se reintroduzir esteróides durante pelo menos seis meses adicionais. As principais avaliações de eficácia secundária foram: dose cumulativa anual de esteróides, número anual de recorrências da colite após introdução da AZA e efeitos adversos. Em base intenção de tratar, a proporção de pacientes permanecendo em remissão sem esteróides em 12, 24, e 36 meses foi 0.55, 0.52, e 0.45, respectivamente. Significante diminuição na taxa de recidivas clínicas assim como no requerimento para esteróides foram observados durante três anos de tratamento com AZA comparado com o ano prévio (P=0.000 para ambos). Pacientes com e sem resposta sustentada foram similares de acordo com demografia, extensão da doença, dose de AZA, uso de esteróides e 5-ASA. Apenas a duração menor da doença (<36 meses) associou-se à remissão sem esteróides (P=0.02, OR 3.12 95% IC 1.89-7.64). AZA foi bem tolerada e o perfil risco-benefício favorável. Neste estudo, AZA mostrou eficácia sustentada para manutenção da remissão clínica sem esteróides e para poupar esteróides durante três anos de terapia em pacientes com CUCD. Pacientes com colite ulcerativa de início mais recente são aqueles que mais provavelmente alcançarão remissão sustentada sem esteróides no final de 12 meses enquanto em uso de AZA. Isto parece se manter por até 36 meses. / Ulcerative colitis (UC) is a lifelong, immune-mediated inflammatory condition of the colonic mucosa, which is characterized by a relapsing and remitting course. Corticosteroids remain one of the most effective therapies for inducing remission in patients with moderate-to-severe UC. Nonetheless, corticosteroids are not used in maintenance therapy, mainly because undesirable side effects outweigh the possible benefits. Furthermore, approximately 25% of the patients is unable to support its withdrawal without relapsing, suggesting that the need to start steroid therapy in UC is associated with a dismal long-term prognosis. Thus, corticosteroid dependence in patients with UC is a pivotal clinical problem and maintenance of steroid-free remission is an important current evolving treatment goal. Patients with steroid dependent UC are usually given a choice between colectomy or stepped-up medical treatment, which traditionally involves prescription of an immunosuppressive drug. Azathioprine (AZA) therapy has found widespread use for this setting in clinical practice. However, studies assessing the efficacy of azathioprine in steroid-dependent ulcerative colitis (SD-UC) are scarce. The purpose of this trial was to explore the efficacy and safety of AZA in maintaining long-term steroid-free remission in SD-UC patients and the factors associated to sustained response. In this observational cohort study 42 subjects with SD-UC were recruited for AZA therapy during a 3-year period. AZA was adjusted for a target dose of 2-3 mg/Kg/day. Steroid therapy was tapered off following a standardized regimen. The primary endpoint was the annual rate of steroid-free response to AZA. Secondary endpoints included clinical recurrence, yearly steroid dose, and safety of treatment. On an intention-to-treat basis, the proportion of patients remaining in steroid-free remission at 12, 24, and 36 months was 0.55, 0.52, and 0.45, respectively. A significant decrease in the flare-ups rate and in requirement for steroids were observed during 3 years on AZA compared with the previous year (P=0.000 for both). Patients with and without sustained response were comparable according to demographics, extent of disease, dose of AZA, steroids and 5-ASA use. Only disease duration <36 months was associated to off-steroids remission (P=0.02, OR 3.12 95% CI 1.89-7.64). The AZA benefit-risk profile was favorable. In this open-label observational trial AZA showed sustained efficacy for maintenance of clinical remission off steroids and steroid sparing through 3 years of therapy in SD-UC. Patients with earlier UC are those who most probably will have sustained steroid-free remission at the end of 12 months while on AZA. This appears to sustain until 36 months.

Submitted by Renata Lopes (renatasil82@gmail.com) on 2016-10-04T13:18:43Z No. of bitstreams: 1 andreluistavarespinto.pdf: 5221976 bytes, checksum: aa9e110f12103765df1122351932b9b8 (MD5) / Approved for entry into archive by Diamantino Mayra (mayra.diamantino@ufjf.edu.br) on 2016-10-04T13:50:42Z (GMT) No. of bitstreams: 1 andreluistavarespinto.pdf: 5221976 bytes, checksum: aa9e110f12103765df1122351932b9b8 (MD5) / Made available in DSpace on 2016-10-04T13:50:42Z (GMT). No. of bitstreams: 1 andreluistavarespinto.pdf: 5221976 bytes, checksum: aa9e110f12103765df1122351932b9b8 (MD5) Previous issue date: 2010-03-30 / A doença de Crohn é uma afecção intestinal inflamatória crônica, multissistêmica e de caráter recorrente. Sua etiopatogênese permanece ainda desconhecida, mas considera-se haver um cenário fisiopatológico caracterizado, principalmente, pela inibição da imunidade inata com exacerbação da imunidade adaptativa, com atividade inflamatória mucosa intensificada. Por isso, os corticosteróides constituem a base fundamental do tratamento farmacológico na indução da remissão clínica na doença, graças às suas potentes ações como supressores do processo inflamatório. Entretanto, os proibitivos efeitos colaterais da corticoterapia prolongada associados à alta freqüência da cortico-dependencia na doença estimulou a busca de alternativas terapêuticas para manutenção da remissão no longo prazo. Nesse contexto, os imunossupressores, particularmente, os análogos da purina, azatioprina (AZA) ou 6mercaptopurina ocupam um papel central no tratamento de manutenção na doença, com efeitos “poupadores de esteróides”. A utilização desses agentes para manter a remissão clínica na doença é apoiada por evidências de estudos clínicos controlados e randomizados. No entanto, a maioria desses estudos não avaliou especificamente os doentes corticodependentes, não sendo claramente conhecida a ação dos análogos da purina nesse grupo de pacientes. Portanto, os objetivos do nosso estudo foram verificar a eficácia no longo prazo, da AZA em uma população exclusivamente portadora de doença de Crohn dependente de esteróides, assim como identificar os possíveis fatores preditivos associados à resposta clínica sustentada. Além disso foi verificada também a segurança dessa terapia, através da análise da incidência de eventos adversos. Para tanto, um total de 106 indivíduos adultos com doença de Crohn cortico-dependente foram prospectivamente incluídos para tratamento com AZA (2-3 mg/Kg/dia), durante o período de acompanhamento de até 10 anos. A proporção de doentes em remissão sustentada livre de esteróides ao final de 12, 24, 36, 48 e 60 meses foi de 0.61, 0.73, 0.72, 0,70 e 0.70 respectivamente. Depois disso, essa taxa anual foi sendo gradualmente reduzida, alcançando um nadir aos 108 meses de acompanhamento. O tempo médio de retirada completa dos esteróides foi de seis meses. Características demográficas, aquelas relacionadas à doença e a dose de AZA não se correlacionaram com remissão sustentada. Apenas a reduzida contagem leucocitária média durante o acompanhamento foi associada com a remissão livre de corticóides (P=0.01). Efeitos adversos graves relacionados à terapia com AZA foram incomuns. / The Crohn´s disease is a chronic, inflammatory, multisystem bowel disorder with a relapsing course. Her etiology remains unknown but probably there´s a scenario characterized by inibition of innate immunity and exacerbation of the adaptative immunity with exacerbated mucosal inflammatory activity. Then, the corticosteroids have been the mainstay of pharmacologic treatment for inducing clinical remission in the disease. However, the prohibitive side effects of prolonged corticosteroid therapy associated with high frequency of the corticosteroid- dependency in the disease taken to alternative treatments for long- term maintenance of clinical remission. The immunomodulators, especially, the purine analogs, azathioprine(AZA) or 6- mercaptopurine are the major option for this indication, with corticosteroid- sparing proprieties. The use of these agents is supported by randomized, controlled clinical studies. However, these trials have not evaluated the specific issue of the steroid dependence. Thus, our objectives in this study were to asses the efficacy and safety of AZA therapy in patients strictly with steroid-dependent Crohn`s disease and possibly, factors associated with sustained clinical remission. Therefore, 106 adults patients with steroiddependent Crohn`s disease were prospectively included for treatment with AZA (23mg/Kg/day) during the period of follow up as long as 10 years. The proportion of patients remaining in sustained steroid-free remission at 12, 24, 36, 48 and 60 months was 0.61, 0.73, 0.72, 0.70 and 0.70, respectively. Thereafter, the annual rate of weaning from steroids decreased gradually, reaching a nadir of 0.41 at 108 months. Median time to complete steroid withdrawal was 6 months. Demographics, disease-related data and the AZA dose did not correlate with sustained remission. Only the reduced mean leukocyte count during the follow up was associated with remission free steroids (P= 0.01). Serious adverse effects related to AZA therapy were uncommon.

Submitted by Renata Lopes (renatasil82@gmail.com) on 2017-06-14T14:16:56Z No. of bitstreams: 1 lilianaandradechebli.pdf: 4797149 bytes, checksum: 48711245cd6bc4dca1d8093d1e776787 (MD5) / Approved for entry into archive by Adriana Oliveira (adriana.oliveira@ufjf.edu.br) on 2017-06-29T12:12:52Z (GMT) No. of bitstreams: 1 lilianaandradechebli.pdf: 4797149 bytes, checksum: 48711245cd6bc4dca1d8093d1e776787 (MD5) / Made available in DSpace on 2017-06-29T12:12:52Z (GMT). No. of bitstreams: 1 lilianaandradechebli.pdf: 4797149 bytes, checksum: 48711245cd6bc4dca1d8093d1e776787 (MD5) Previous issue date: 2009-08-06 / CNPq - Conselho Nacional de Desenvolvimento Científico e Tecnológico / Colite ulcerativa é uma condição inflamatória imuno-mediada da mucosa colônica, caracterizada por curso intermitente e recorrente. Corticosteróides permanecem como uma das terapias mais efetivas para induzir remissão em pacientes com colite ulcerativa moderada a severa. Todavia, corticosteróides não são usados como terapia de manutenção, principalmente porque os efeitos colaterais indesejáveis superam seus possíveis benefícios. Além disso, em um ano, menos da metade dos pacientes com colite ulcerativa que requerem corticosteróides terão resposta sustentada, aproximadamente um terço dos pacientes necessitarão de colectomia e um quarto não tolerarão a retirada do mesmo sem que apresentem recidiva da doença. Assim, dependência de corticóides em paciente com colite ulcerativa é problema clínico fundamental e manutenção da remissão sem esteróides é uma importante meta terapêutica no presente. Em pacientes com colite ulcerativa córtico-dependente, usualmente é colocado a escolha entre colectomia ou escalonamento do tratamento clínico, o qual tradicionalmente envolve a prescrição de droga imunossupressora. A terapia com tiopurinas tem tido amplo uso neste cenário na prática clínica. Entretanto, estudos avaliando a eficácia da azatioprina (AZA) na colite ulcertiva córtico-dependente são escassos. Os objetivos deste estudo foram avaliar em pacientes com colite ulcerativa dependente de esteróides, a eficácia da AZA na manutenção da remissão clínica sem esteróides, bem como os possíveis fatores associados à resposta sustentada a esta droga. Neste estudo de coorte observacional, pacientes adultos com colite ulcerativa dependente de esteróides foram recrutados para tratamento com AZA durante o período de 12 meses. AZA foi ajustada para a dose alvo de 2-3 mg/Kg/dia. A redução da dose de esteróides durante o estudo seguiu um esquema previamente padronizado. A avaliação primária de eficácia foi a taxa anual de pacientes que alcançaram resposta sustentada a AZA sem esteróides. Avaliações secundárias incluíram o número anual de recorrências clínicas, dose mediana de esteróides utilizadas durante o ano e segurança do tratamento. O total de 42 pacientes foi incluído. Na análise intenção de tratar, a proporção de pacientes permanecendo em remissão sustentada sem esteróides no final de 12 meses foi de 0,55. Observou-se significante redução na taxa de recorrências clínicas, assim como no requerimento de esteróides durante 12 meses de tratamento com AZA quando comparado com o ano anterior ao uso desta droga. (P=0,000 para ambas as comparações). Apenas a duração da doença < 36 meses antes do início da AZA foi associada à remissão clínica sem esteróides (P=0,02, OR 3,12 95% IC 1,89-7,64). AZA foi bem tolerada e o seu perfil risco-beneficio favorável. AZA mostrou eficácia sustentada para a manutenção da remissão clínica sem esteróides, bem como efeito poupador de esteróides durante 12 meses de terapia em pacientes com colite ulcerativa dependente de esteróides. Os pacientes com colite ulcerativa de início mais precoce são aqueles que mais provavelmente alcançarão remissão sustentada sem esteróides durante o uso de AZA. / Ulcerative colitis (UC) is a lifelong, immune-mediated inflammatory condition of the colonic mucosa, which is characterized by a relapsing and remitting course. Corticosteroids remain one of the most effective therapies for inducing remission in patients with moderate-to-severe UC. Nonetheless, corticosteroids are not used in maintenance therapy, mainly because undesirable side effects outweigh the possible benefits. Furthermore, at one year, less than half of UC patients who require steroids have a sustained response, nearly one-third of patients require colectomy, and approximately a quarter is unable to support its withdrawal without relapsing. Thus, corticosteroid dependence in patients with UC is a pivotal clinical problem and maintenance of steroid-free remission is an important current evolving treatment goal. Patients with steroid dependent UC are usually given a choice between colectomy or stepped-up medical treatment, which traditionally involves prescription of an immunosuppressive drug. Thiopurine therapy has found widespread use for this setting in clinical practice. However, studies assessing the efficacy of azathioprine (AZA) in steroid-dependent ulcerative colitis (UC) are scarce. The purpose of this trial was to explore the efficacy of AZA in maintaining steroid-free remission in steroid-dependent UC patients as well as the factors associated to sustained response. In this observational cohort study adult subjects with steroid-dependent UC were recruited for AZA therapy during a 12 months period. AZA was adjusted for a target dose of 2-3 mg/Kg/day. Steroid therapy was tapered off following a standardized regimen. The primary endpoint was the rate of patients with sustained steroid-free response to AZA at the end of 12 months. Secondary endpoints included clinical recurrence, yearly steroid dose, and safety of treatment. A total of 42 patients were included. On an intention-to-treat basis, the proportion of patients remaining in sustained steroid-free remission at 12 months was 0.55. A significant decrease in the flare-ups rate as well as in requirement for steroids were observed during 12 months while on AZA compared with the previous year (P=0.000). Only disease duration of <36 months before the initiation of AZA was associated to off-steroids remission (P=0.02, OR 3.12 (95% CI 1.89-7.64)). AZA was well tolerated and its benefit-risk profile favorable. AZA showed sustained efficacy for maintenance of clinical remission off steroids and steroid sparing through 12 months of therapy in patients with steroid dependent UC. Patients with earlier UC are those who most probably will have sustained steroid-free remission while on AZA.

No description available.

Bakgrund: Inflammatorisk tarmsjukdom är en kronisk tarmsjukdom som ofta drabbar unga patienter och som ofta kräver livslång behandling. Vid avbrott av behandling drabbas patienten ofta av skov som kan vara svårbehandlade. På sikt kan obehandlad inflammatorisk tarmsjukdom leda till kolorektalcancer. Syfte: Syftet var att belysa patientens erfarenhet och behov av stöd och information vid inflammatorisk tarmsjukdom. Metod: En litteraturöversikt enligt Friberg, (2017) har genomförts. Artiklarna söktes fram via databaserna; PubMed, Cinahl complete och Academic Search Complete. Litteraturöversikten grundar sig på åtta vårdvetenskapliga studier, varav fyra utfördes med mixad metod, tre med kvalitativ metod och en med kvantitativ metod. Resultat: Resultatet presenteras utifrån två teman och fem underteman som framkom i analysen av studierna; Det första temat var Information till patient med IBD, med tre underteman; Informationens innehåll till patient med IBD, Hur läkemedlsinformation kan ges till patient med IBD och Behov av utbildning för sjuksköterskor för att tillmötesgå patientens behov av information. Det andra temat var Relation mellan sjuksköterska och patient med tillhörande underteman; Patientens behov av att ha en relation med sin sjuksköterska och Patientens behov av en relation med sjuksköterska från barn till vuxenvård. Diskussion: Resultatet diskuteras utifrån tidigare forskning samt utifrån Travelbees omvårdnads teori. Det fanns stöd för att patienten har ett behov av information och en relation med sjuksköterska. / Background: Inflammatory bowel disease is a chronic intestinal disease that often requires a lifelong treatment. With the occurrence of an interruption the patient may be stricken by episodes that is difficult to treat. Eventually an untreated inflammatory bowel disease could evolve to colorectal cancer. Aim: The aim was to describe the patient’s experiences and its need for support and information regarding the inflammatory bowel disease. Method:A literature review according to Friberg, (2017) have been carried through. The literature review is established on eight scientifically studies, which out of four was carried on with mixed methods, three with a quality method and one on quantitative method. The articles were provided via the data platforms; PubMed, Cinahl Complete and Academic Search Complete. Results: The result is presented under two major themes and five sub themes. First theme being: Information of disease and treatment with three sub themes; Content of information for a patient with IBD, how information about treatement is given to a patient with IBD and the need of education to nurses to fulfill the patient’s need of information and the second theme being: relationship between nurse and the patient and two sub themes being; The patient’s need of a good relation to its nurse and the patient’s need of a good relationship with the nurse from child to adult care. Discussion: The result has been discussed towards prior studies a to wards prior studies a towards Travelbees theory in care taking. There is support for believing that the patient needs information and a good relation towards the nurse.

No description available.

Living with inflammatory bowel disease (IBD) affects physical, psychological and social dimensions, limiting the ability to engage in daily activities. Persons with IBD may need frequent and lifelong contacts with the healthcare (HC), highlighting the importance of quality care. High quality HC for persons with IBD involves a partnership between the HC professionals and the person living with the disease. Information is essential, the more a person knows about their disease, the more concordant and satisfied with their treatment they are likely to be. The overall aim of this thesis was to describe the knowledge need, life situation and perception of HC among persons living with IBD, in order to develop a questionnaire to evaluate the quality of HC. This thesis is based on three studies that are presented in four papers. Qualitative methods were used to describe aspects of life situation in relation to the disease, whereas quantitative method was used to develop a questionnaire measuring quality of care. Study I and II have an inductive qualitative design. In study I, qualitative interviews with 30 people were performed to describe the knowledge need and experience of critical incidents in daily life while living with IBD. The interviews in study I were analyzed using content analysis (results presented in Paper I) and critical incident technique (results presented in Paper II). In study II, the perceptions of HC among persons living with IBD was explored in five focus group interviews and two individual interviews, in total n=26. Study III aimed to develop and evaluate a questionnaire, measuring quality of care among persons with IBD, including 318 persons with IBD and 8 professionals. The knowledge need among persons with IBD focused on managing symptoms and course of the disease and learning to assimilate the information in order to manage everyday life. Losing bowel control was of great concern for most of the informants in the study. Many of the informants said that “the bowel ruled their life” and that it influenced them to a great extent in their daily lives. The perception of HC among persons with IBD meant being met with respect and mutual trust, receiving information at the right time, shared decision-making, competence and communication, access to care, accommodation, continuity of care and the pros and cons of specialized care. The quality of care questionnaire QoC-IBD was constructed in five dimensions, building on the results from Study I and II. The dimensions were trust and respect, decision-making, information, continuity of care and access to care consisting of 21 questions in total. QoC-IBD is a short, self-administrated questionnaire that measures experiences of healthcare among persons with IBD with promising validity and reliability. To improve quality of care, HC is recommended to consider individual care needs and take the person’s daily life and social context into account. The QoC-IBD questionnaire measures the subjective experience of quality of care. Further testing in clinical practice is necessary to evaluate if QoC-IBD can be used to evaluate the care given and areas of improvement in HC for persons living with IBD.

La maladie de Crohn (MC) et la rectocolite hémorragique (RCH) sont les deux principales formes cliniques des maladies inflammatoires chroniques de l’intestin (MICI) responsables d’une atteinte inflammatoire de la paroi du tube digestif avec des ulcérations extensives. Ce sont des maladies fréquentes en Europe et en Amérique du Nord avec plus de 2.5 millions de malades. Du fait de l’augmentation importante de leur prévalence, de leur morbidité, du retentissement sur la qualité de vie des malades et du coût de leur prise en charge médicale, les MICI sont devenues un problème majeur de santé publique. Au cours de ces maladies, l’inflammation intestinale peut être contrôlée par les traitements médicamenteux ou la chirurgie sans pour autant obtenir de guérison complète et définitive. Bien que leur origine reste mal connue, l’hypothèse actuelle présente les MICI comme des maladies multifactorielles, secondaires à une réponse immunitaire muqueuse anormale dirigée contre la flore intestinale, survenant chez des individus génétiquement prédisposés et entrainant une inflammation intestinale. Le but du travail était d’explorer les mécanismes à l’origine de cette inflammation intestinale associée au développement des MICI en étudiant plus particulièrement certains facteurs environnementaux, moléculaires et microbiens. Nous avons étudiés tout d’abord l’aluminium comme facteur environnemental en démontrant qu’il pouvait participer au développement et à l’aggravation de l’inflammation intestinale sur des modèles de colite chez la souris. Nous avons ensuite étudié un facteur moléculaire important pour l’apoptose des cellules, la caspase-8. Nous avons montré que cette caspase-8 maintenait l’homéostasie intestinale des cellules épithéliales intestinales et que sont absence entraînait une inflammation intestinale ressemblant à la maladie de Crohn. Finalement nous nous sommes intéressés à un facteur microbien, Saccharomyces cerevisiae CNCM I-3856 qui est une levure. Nous avons démontré que cette levure était capable d’induire un effet anti-inflammatoire et analgésique chez l’animal en activant PPAR&#947; dans le colon. Chez l’homme nous avons montré dans une étude randomisée que Saccharomyces cerevisiae CNCM I-3856 réduisait les douleurs abdominales chez les patients atteints du syndrome de l’intestin irritable. En conclusion, l’exploration de ces trois facteurs environnementaux, moléculaires et microbiens permet de mieux comprendre le développement de l’inflammation intestinale. La perspective de ce travail est le développement dans un futur proche des nouvelles thérapeutiques ciblées permettant de lutter contre l’inflammation intestinale. / Crohn's disease (CD) and ulcerative colitis (UC) are the two main clinical forms of chronic inflammatory bowel disease (IBD) responsible for intestinal inflammation with extensive ulceration of the mucosa. These are common diseases in Europe and North America with over 2.5 million patients. Due to the significant increase in their prevalence, their morbidity, the impact on quality of life of patients and the cost of their medical care, IBD has become a major public health problem. In these diseases, intestinal inflammation may be controlled by drug treatment or surgery without obtaining a complete and final cure. Although their origin remains unclear, the current hypothesis presents IBD as multifactorial diseases secondary to an abnormal mucosal immune response directed against the intestinal flora, occurring in genetically predisposed individuals and causing intestinal inflammation. The aim of this work was to explore the mechanisms behind this intestinal inflammation associated with the development of IBD studying some particular environmental, molecular and microbial factors. We studied first the aluminum as an environmental factor and demonstrated that he could participate in the development and exacerbation of intestinal inflammation in models of colitis in mice. We then studied an important factor in molecular cell apoptosis, caspase-8. We have shown that caspase-8 was maintaining intestinal homeostasis in intestinal epithelial cells and that absence of caspase-8 leads to intestinal inflammation mimicking Crohn's disease. Finally we studied a microbial factor, Saccharomyces cerevisiae CNCM I-3856 which is yeast. We demonstrated that this yeast was capable of inducing an anti-inflammatory and analgesic effect in animals by activating PPARgamma in the colon. In humans we have shown in a randomized study that Saccharomyces cerevisiae CNCM I-3856 reduced abdominal pain in patients with irritable bowel syndrome. In conclusion, the exploration of these three environmental molecular and microbial factors helps to better understand the development of intestinal inflammation. The perspective of this work is the development in the near future of new targeted therapies directed against intestinal inflammation.

The purpose of this study was to investigate how children with Inflammatory Bowel Disease (IBD) and their families perceived their school experiences in Québec. IBD is one of many “invisible” chronic diseases. It is considered invisible because it occurs internally without significant observable external symptoms. However, children with IBD experience painful and fluctuating physical symptoms caused by intestinal inflammation, as well as the side effects from medications. As a result, they require special accommodations while they attend public or private school. The Québec Education Act (2010) stipulates that adequate services for a diverse student population must be provided. Consequently, the research sought to answer the following questions: What are the experiences of parents and children with IBD enrolled in general education classrooms? And, what are the experiences of their brother or sister? To research these questions, a case study method was used with five families. The two instruments used to collect the data were, (1) individual semi-structured interviews that followed a modified version of Seidman’s (2006) in-depth interviewing approach and (2) drawings of the family by siblings. The data were analyzed inductively. This study was the first to use a qualitative approach with multiple methods that were guided by Bronfenbrenner’s ecological systems theory (1979) and Turnbull and Turnbull’s family systems theory (2001). The findings revealed that, unlike many studies on families of children with special needs, these families with a child with IBD functioned relatively well. At the microsystem level, mothers assumed responsibility as the primary caregiver. Siblings experienced their own challenges, such as feelings of parental neglect. Nonetheless, they also maintained nurturing roles. Within the mesosystem level, the home and school relationship was impacted. Parents and children with IBD experienced school personnel who lacked awareness of IBD and provided insufficient classroom support, especially at public schools. Hence, parents-(predominantly mothers) played an integral role in advocating for necessary accommodations on their child’s behalf. In contrast to many studies on children with disabilities, children with IBD in this research had many friends in and outside of school. In the exosystem, parents struggled with feelings of guilt at having to balance employment and the high financial expense of caring for a child with IBD. They relied on assistance from government services and their IBD association. At the macrosystem level, family members believed that children with IBD were perceived negatively by society because of the lack of public awareness and the stigma that surrounds the topic of incontinence. This study makes contributions to systems theories and provides practical recommendations to school personnel and parents.