Background Pulmonary arterial hypertension (PAH) is a rare progressive disease with no known cure. Of various aetiologies, PAH in association with connective tissue disease (PAH-CTD) is the most rapidly progressive and difficult to treat. Management of PAH has evolved significantly in the past ten years since the introduction of oral therapies. Evidence for the efficacy of these agents outside randomised controlled trials is limited, but guidelines exist. Aim To measure the impact of first-line monotherapy with bosentan or sildenafil and the introduction of prescribing guidelines on outcomes in PAH-CTD. Methods Following a retrospective analysis of consecutive, incident, treatment-naive PAH-CTD cases identified by the ASPIRE registry, influences on outcome measures have been compared. First-line monotherapy episodes for 247 patients was analysed against four distinct endpoints: change in exercise capacity, WHO functional class, time on monotherapy and all-cause mortality. Results Treatment with bosentan or sildenafil resulted in clinical stability at 2 years for nearly 1/4 patients. No difference was identified between the groups in terms of either exercise capacity or WHO functional class. Sildenafil patients were found to remain on monotherapy longer than those prescribed bosentan. Patients prescribed sildenafil have improved survival over those treated with bosentan. Unexpected baseline differences in between groups may confound the results as the haemodynamics of the bosentan patients were more severe. Conclusions A significant number of patients with PAH-CTD remain clinically stable on monotherapy at 2 years. Both agents seem equally effective in this aggressive form of PAH. A novel endpoint “TOM” may be of value in future research assessing response to treatment.

Diss. (sammanfattning) Stockholm : Karol. inst., 2002. / Härtill 6 uppsatser.

Background Pulmonary arterial hypertension (PAH) is a rare progressive disease with no known cure. Of various aetiologies, PAH in association with connective tissue disease (PAH-CTD) is the most rapidly progressive and difficult to treat. Management of PAH has evolved significantly in the past ten years since the introduction of oral therapies. Evidence for the efficacy of these agents outside randomised controlled trials is limited, but guidelines exist. Aim To measure the impact of first-line monotherapy with bosentan or sildenafil and the introduction of prescribing guidelines on outcomes in PAH-CTD. Methods Following a retrospective analysis of consecutive, incident, treatment-naive PAH-CTD cases identified by the ASPIRE registry, influences on outcome measures have been compared. First-line monotherapy episodes for 247 patients was analysed against four distinct endpoints: change in exercise capacity, WHO functional class, time on monotherapy and all-cause mortality. Results Treatment with bosentan or sildenafil resulted in clinical stability at 2 years for nearly 1/4 patients. No difference was identified between the groups in terms of either exercise capacity or WHO functional class. Sildenafil patients were found to remain on monotherapy longer than those prescribed bosentan. Patients prescribed sildenafil have improved survival over those treated with bosentan. Unexpected baseline differences in between groups may confound the results as the haemodynamics of the bosentan patients were more severe. Conclusions A significant number of patients with PAH-CTD remain clinically stable on monotherapy at 2 years. Both agents seem equally effective in this aggressive form of PAH. A novel endpoint “TOM” may be of value in future research assessing response to treatment.

京都大学 / 新制・課程博士 / 博士(医学) / 甲第23773号 / 医博第4819号 / 新制||医||1057(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 金子 新, 教授 杉田 昌彦, 教授 松田 秀一 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

Diss. (sammanfattning) Stockholm : Karol. inst., 2003. / Härtill 6 uppsatser.

Patients with connective tissue diseases (CTD) such as systemic lupus erythematosus (SLE) have an increased risk for infections. This study investigated the outcome and characteristics of CTD patients under intensive care unit (ICU) treatment for sepsis

La prolongation de l’intervalle électrocardiographique QT est un facteur de risque d’arythmie ventriculaire et de mort subite. Cette anomalie, retrouvée chez certains patients atteints de lupus érythémateux disséminé, pourrait contribuer à la mortalité cardiovasculaire élevée dans cette population. L’anti-Ro/SSA, un auto-anticorps retrouvé chez environ 30% des patients atteints de lupus, est associé à la présence de blocs cardiaques chez le nouveau-né et pourrait aussi augmenter le risque de prolongation pathologique de l’intervalle QT chez l’adulte. Le présent mémoire est constitué de cinq chapitres traitant de l’association potentielle entre l’anticorps anti-Ro/SSA et la prolongation de l’intervalle QT. Le premier chapitre constitue une introduction permettant de mettre en contexte les éléments essentiels à la compréhension du projet d’étude. Le deuxième chapitre constitue une revue de l’état des connaissances actuelles sur le lien potentiel entre anti-Ro/SSA et intervalle QT. Le troisième chapitre présente le projet d’étude par l’intermédiaire d’un article publié dans Arthritis Care and Research. Dans cette étude, les patients de la cohorte de lupiques du Centre Universitaire de santé McGill ont subi des électrocardiogrammes dans l’objectif d’estimer l’association entre l’anti-Ro/SSA et les anomalies électrocardiographiques, en tenant compte d’autres facteurs démographiques et cliniques. L’association entre la prolongation de l’intervalle QT et la présence de l’anti-Ro/SSA a été démontrée (rapports de cotes ajustés de 5.1 à 12.6) et les patients porteurs de l’anti-Ro/SSA pourraient donc bénéficier de dépistage électrocardiographique systématique. Les points faibles et forts de cet article sont discutés dans le quatrième chapitre et des perspectives de recherches futures sont finalement abordées. / QT interval prolongation on the electrocardiogram is a risk factor for ventricular arrhythmias and sudden cardiac death. This abnormality is found in patients with systemic lupus erythematosus and could contribute to the high cardiovascular mortality rate in this population. Anti-Ro/SSA is an auto-antibody presents in about 30% of lupus patients and is associated with congenital cardiac block. This auto-antibody could also increase the risk of pathologic prolongation of the QT interval in adults. This master’s thesis is comprised of five chapters discussing the potential association between anti-Ro/SSA antibody and QT interval prolongation. The first chapter is an introduction to the essential elements for the understanding of the study project. The second chapter is a literature review of the potential link between anti-Ro/SSA and QT interval prolongation. The third chapter presents the study project through an article published in Arthritis Care and Research. In this study, patients from the McGill lupus cohort were invited to undergo electrocardiograms in order to estimate the association between anti-Ro/SSA antibody and electrocardiographic abnormalities, while taking into account the other potentially associated demographic and clinical factors. This study shows an association between anti-Ro/SSA and prolonged QT interval (Odds ratios: 5.1 to 12.6) and patients positive for anti-Ro/SSA may thus benefit from electrocardiographic testing. Strengths and weaknesses of this article are discussed in the fourth chapter and future research areas are finally explored.

Selecionamos consecutivamente 63 pacientes com doença mista do tecido conectivo (DMTC) (Kasukawa, 87) para determinar a relevância do padrão SD. Ter uma capilaroscopia periungueal (CPU) até cinco anos antes do início do estudo foi o principal critério de inclusão. Na entrada, avaliamos o envolvimento de órgãos e os auto-anticorpos. A idade média e o tempo de doença foram 45,3 + 10 e 8,45 + 5,42 anos, respectivamente. O padrão SD foi observado em 41 pacientes na entrada (65%) e em 45 na CPU prévia (71,5%), p = 0,20. Dez pacientes (16%) alteraram a CPU, 7 normalizaram e 3 desenvolveram padrão SD. O tempo de doença, número e freqüência de órgãos envolvidos foram semelhantes em pacientes com e sem padrão SD. Em contraste, a análise de cada parâmetro do padrão SD mostrou uma freqüência significativamente menor de áreas avasculares (AA) moderadas/graves na entrada, comparada com a CPU anterior (26,5 e 53%, p = 0,013). Além disto, 76% dos pacientes com doença intersticial pulmonar (TCAR) tiveram AA na entrada, enquanto apenas 24% dos pacientes com esta alteração não apresentavam este achado à CPU (p = 0,017). Adicionalmente, reduzida densidade capilar foi freqüentemente observada em pacientes submetidos à terapia imunossupressora, quando comparados com o grupo sem este tratamento (66,7 e 33,3%, p = 0,001). A CPU na DMTC é um processo dinâmico e a análise de cada parâmetro do padrão SD parece ser um bom indicador de doença intersticial pulmonar e gravidade de doença. / For determining the clinical relevance of SD-pattern in MCTD, sixty-three MCTD patients (Kasukawa´s criteria) were consecutively selected. The main inclusion criterion was availability of previous nailfold capillaroscopy (NC) 5 years before inclusion. At entry, organ involvement and autoantibody evaluation were performed. The mean age and disease duration were 45.3 + 10 and 8.45 + 5.42 years, respectively. SD-pattern was observed in 41 patients at entry (65%) and in 45 at previous NC (71.5%), p = 0.20. Ten patients (16%) changed NC, 7 normalized, and 3 developed SD-pattern. Disease duration, number and frequency of organ involvement were similar in patients with and without SD-pattern. In contrast, analysis of each SD-pattern parameter revealed a significant lower frequency of moderate/severe avascular areas (AA) at entry compared to previous examination (26.5 vs. 53%, p = 0.013). Moreover, 76% of patients with interstitial lung disease (HRCT) had AA at entry, whereas only 24% of patients with this alteration did not have this NC finding (p = 0.017). Furthermore, reduced capillary density was frequently observed in patients taking immunosuppressive therapy than those without (66.7 vs. 33.3%, p = 0.001). NC in MCTD is a dynamic process and analysis of each SD-pattern parameter seems to be a good indicator of lung involvement and disease severity

Selecionamos consecutivamente 63 pacientes com doença mista do tecido conectivo (DMTC) (Kasukawa, 87) para determinar a relevância do padrão SD. Ter uma capilaroscopia periungueal (CPU) até cinco anos antes do início do estudo foi o principal critério de inclusão. Na entrada, avaliamos o envolvimento de órgãos e os auto-anticorpos. A idade média e o tempo de doença foram 45,3 + 10 e 8,45 + 5,42 anos, respectivamente. O padrão SD foi observado em 41 pacientes na entrada (65%) e em 45 na CPU prévia (71,5%), p = 0,20. Dez pacientes (16%) alteraram a CPU, 7 normalizaram e 3 desenvolveram padrão SD. O tempo de doença, número e freqüência de órgãos envolvidos foram semelhantes em pacientes com e sem padrão SD. Em contraste, a análise de cada parâmetro do padrão SD mostrou uma freqüência significativamente menor de áreas avasculares (AA) moderadas/graves na entrada, comparada com a CPU anterior (26,5 e 53%, p = 0,013). Além disto, 76% dos pacientes com doença intersticial pulmonar (TCAR) tiveram AA na entrada, enquanto apenas 24% dos pacientes com esta alteração não apresentavam este achado à CPU (p = 0,017). Adicionalmente, reduzida densidade capilar foi freqüentemente observada em pacientes submetidos à terapia imunossupressora, quando comparados com o grupo sem este tratamento (66,7 e 33,3%, p = 0,001). A CPU na DMTC é um processo dinâmico e a análise de cada parâmetro do padrão SD parece ser um bom indicador de doença intersticial pulmonar e gravidade de doença. / For determining the clinical relevance of SD-pattern in MCTD, sixty-three MCTD patients (Kasukawa´s criteria) were consecutively selected. The main inclusion criterion was availability of previous nailfold capillaroscopy (NC) 5 years before inclusion. At entry, organ involvement and autoantibody evaluation were performed. The mean age and disease duration were 45.3 + 10 and 8.45 + 5.42 years, respectively. SD-pattern was observed in 41 patients at entry (65%) and in 45 at previous NC (71.5%), p = 0.20. Ten patients (16%) changed NC, 7 normalized, and 3 developed SD-pattern. Disease duration, number and frequency of organ involvement were similar in patients with and without SD-pattern. In contrast, analysis of each SD-pattern parameter revealed a significant lower frequency of moderate/severe avascular areas (AA) at entry compared to previous examination (26.5 vs. 53%, p = 0.013). Moreover, 76% of patients with interstitial lung disease (HRCT) had AA at entry, whereas only 24% of patients with this alteration did not have this NC finding (p = 0.017). Furthermore, reduced capillary density was frequently observed in patients taking immunosuppressive therapy than those without (66.7 vs. 33.3%, p = 0.001). NC in MCTD is a dynamic process and analysis of each SD-pattern parameter seems to be a good indicator of lung involvement and disease severity

La prolongation de l’intervalle électrocardiographique QT est un facteur de risque d’arythmie ventriculaire et de mort subite. Cette anomalie, retrouvée chez certains patients atteints de lupus érythémateux disséminé, pourrait contribuer à la mortalité cardiovasculaire élevée dans cette population. L’anti-Ro/SSA, un auto-anticorps retrouvé chez environ 30% des patients atteints de lupus, est associé à la présence de blocs cardiaques chez le nouveau-né et pourrait aussi augmenter le risque de prolongation pathologique de l’intervalle QT chez l’adulte. Le présent mémoire est constitué de cinq chapitres traitant de l’association potentielle entre l’anticorps anti-Ro/SSA et la prolongation de l’intervalle QT. Le premier chapitre constitue une introduction permettant de mettre en contexte les éléments essentiels à la compréhension du projet d’étude. Le deuxième chapitre constitue une revue de l’état des connaissances actuelles sur le lien potentiel entre anti-Ro/SSA et intervalle QT. Le troisième chapitre présente le projet d’étude par l’intermédiaire d’un article publié dans Arthritis Care and Research. Dans cette étude, les patients de la cohorte de lupiques du Centre Universitaire de santé McGill ont subi des électrocardiogrammes dans l’objectif d’estimer l’association entre l’anti-Ro/SSA et les anomalies électrocardiographiques, en tenant compte d’autres facteurs démographiques et cliniques. L’association entre la prolongation de l’intervalle QT et la présence de l’anti-Ro/SSA a été démontrée (rapports de cotes ajustés de 5.1 à 12.6) et les patients porteurs de l’anti-Ro/SSA pourraient donc bénéficier de dépistage électrocardiographique systématique. Les points faibles et forts de cet article sont discutés dans le quatrième chapitre et des perspectives de recherches futures sont finalement abordées. / QT interval prolongation on the electrocardiogram is a risk factor for ventricular arrhythmias and sudden cardiac death. This abnormality is found in patients with systemic lupus erythematosus and could contribute to the high cardiovascular mortality rate in this population. Anti-Ro/SSA is an auto-antibody presents in about 30% of lupus patients and is associated with congenital cardiac block. This auto-antibody could also increase the risk of pathologic prolongation of the QT interval in adults. This master’s thesis is comprised of five chapters discussing the potential association between anti-Ro/SSA antibody and QT interval prolongation. The first chapter is an introduction to the essential elements for the understanding of the study project. The second chapter is a literature review of the potential link between anti-Ro/SSA and QT interval prolongation. The third chapter presents the study project through an article published in Arthritis Care and Research. In this study, patients from the McGill lupus cohort were invited to undergo electrocardiograms in order to estimate the association between anti-Ro/SSA antibody and electrocardiographic abnormalities, while taking into account the other potentially associated demographic and clinical factors. This study shows an association between anti-Ro/SSA and prolonged QT interval (Odds ratios: 5.1 to 12.6) and patients positive for anti-Ro/SSA may thus benefit from electrocardiographic testing. Strengths and weaknesses of this article are discussed in the fourth chapter and future research areas are finally explored.