Wegener´s granulomatosis (WG) is an unusual, serious, systemic vasculitis with specific clinical findings. The studies in this thesis aim at broadening our understanding of the aetiology and outcome of WG. Patients with WG were identified in the In-patient Register 1975-2001. During this time the incidence increased three-fold, and neither ANCA-related increased awareness, nor diagnostic drift, seem to fully explain this trend, but it is still unclear if a true rise in incidence exists. Anti- neutrophil cytoplasmic antibodies (ANCA) have been presented as highly specific for vasculitis. In a series of consecutive cANCA/PR3-ANCA positive patients, we investigated the positive predictive value for ANCA, and the outcome of patients with a positive cANCA/PR3-ANCA but not vasculitis. These patients have a low future risk of developing vasculitis, possibly indicating that ANCA, in this setting, reflects neutrophil activating properties not specific to vasculitis. By linkage of the WG-cohort, and randomly selected population controls, to the Multi-generation register, we identified all first-degree relatives and spouses of patients and controls, totally encompassing some 2,000 patients and 70,000 relatives. Familial aggregation of WG was the exception, with absolute risks of < 1 per 1000.However, relative risks in first-grade relatives amounted to 1.56 (95% CI 0.35-6.90) such that a moderate familial aggregation cannot be excluded. In the WG-cohort, cancer occurrence and risk was compared to that of the general population. Patients with WG have an overall doubled risk of cancer, with particularly increased risks of bladder-cancer, haematopoietic cancers including lymphomas and squamous skin-cancer. In a case-control study nested within the WG-cohort, treatment with cyclophosphamide was compared among bladder-cancer patients and matched cancer-free controls. Absolute risk of bladder cancer as high as 10% some years after diagnosis were found, and this risk can partly be attributed to cyclophosphamide-treatment, with a dose-response relationship.

Background: The enhancement of quality of life (QOL) is a principal health care objective. Surprisingly, few studies have investigated this outcome in ANCA associated vasculitis (AAV), a complex chronic disease. Existing studies have, however, identified fatigue as a specific problem amongst this population. Although its aetiology is unknown, there is evidence, from other populations, to support a neural basis for this symptom. Aims: This study aimed to characterise QOL and its determinants amongst patients with AAV. A secondary study examined the association of AAV related fatigue with alterations of the brain. Methods: An AAV case-control study was conducted, incorporating a comparison and within-case analysis, using two groups of population and chronic disease controls. All participants completed a questionnaire comprising measures of QOL and putative determinants of QOL impairment. Concurrently, putative clinical determinants were collected from cases. The secondary study recruited AAV cases based on fatigue status. A further group with idiopathic fatigue was recruited from the general population. All subjects underwent magnetic resonance (MR) brain scanning incorporating structural and physiological imaging. Results: Compared to population controls, cases were substantially more likely to report low QOL and levels were equable to disease controls. Potentially modifiable biological and psycho-social factors were independently associated with poor QOL, of which fatigue was found to be of principal importance. In the secondary study, structural and physiological differences were observed between AAV patients with and without fatigue, as well as fatigued population subjects. Conclusions: AAV patients experienced significant QOL impairment. A bio-psychosocial approach to AAV health care is likely to improve QOL outcomes, although a better understanding of specific mechanisms is necessary to fully manage these problems. MR techniques have suggested a neural basis for AAV related fatigue. In the future they may help delineate the mechanisms of fatigue and consequently improve QOL in AAV.

Submitted by Edileide Reis (leyde-landy@hotmail.com) on 2015-04-08T22:07:57Z No. of bitstreams: 1 Isabella Vargas de Souza Lima.pdf: 9375405 bytes, checksum: a3d913a7254631a76ea5f2fc0da63ddc (MD5) / Made available in DSpace on 2015-04-08T22:07:57Z (GMT). No. of bitstreams: 1 Isabella Vargas de Souza Lima.pdf: 9375405 bytes, checksum: a3d913a7254631a76ea5f2fc0da63ddc (MD5) Previous issue date: 2012 / É reconhecida a interface entre a reumatologia, particularmente no que diz respeito às doenças autoimunes, e a infectologia, seja pela hipótese de agentes infecciosos atuando como gatilho das disfunções imunológicas, seja pelo risco infeccioso atribuído aos tratamentos imunossupressores. Adicionalmente, tem sido observada a produção de alguns autoanticorpos no curso de infecções. Por exemplo: em pacientes com tuberculose (TB), foi demonstrada a produção de anticorpos descritos como de alta especificidade para artrite reumatóide (AR) como os anticorpos antipeptídeos citrulinados (ACPAs) e, do mesmo modo, foi demonstrada a presença de anticorpos anticitoplasma de neutrófilos (ANCA) dentre os quais antiproteinase 3 (anti-PR3) e antimieloperoxidase (anti-MPO), que são marcadores de vasculites sistêmicas. Objetivos: a) revisar as publicações sobre positividade dos ACPAs em doenças infecciosas, b) pesquisar a prevalência destes anticorpos assim como do ANCA em uma população de portadores de tuberculose. Métodos: a) inicialmente foi realizada uma revisão sistemática sobre os estudos avaliando a presença de ACPAs em doenças infecciosas; b) posteriormente, um grupo de 50 pacientes com TB pulmonar não tratada ou com até 30 dias do início do tratamento foi avaliado quanto à presença de sintomas reumatológicos e, principalmente, quanto à positividade de anticorpos ACPAs, incluindo antipeptídeo citrulinado cíclico (anti-CCP) e antivimentina citrulinada modificada (anti-MCV) e quanto à positividade de ANCA por imunofluorescência indireta (IFI) e anticorpos anti-PR3 e anti-MPO por enzimaimunoensaio (ELISA). Resultados: a) a revisão sistemática foi publicada e encontra-se apresentada “Revisão de literatura” com o título Antibodies against cyclic citrullinated peptides in infectious diseases – a systematic review. Clin Rheumatol 2010, Dec 29(12): 1345-51. b) encontrou-se positividade de ACPAs em apenas dois (4%) dos 50 pacientes com TB e não houve positividade de ANCA por IFI ou a presença de anticorpos anti-PR3 ou anti-MPO por ELISA no soro desses pacientes. Estes resultados estão apresentados em dois artigos que foram submetidos para a revista Clinical Rheumatology (Canadá, fator de impacto 2011: 1,996), aguardando o parecer do corpo editorial. As versões submetidas encontram-se na sessão “Artigos”. Conclusões: embora estudos prévios tenham relatado a presença de ACPAs e ANCA em pacientes com TB, no presente estudo a positividade dos ACPAs foi baixa e não foi observada positividade para ANCA, anti-PR3 e anti-MPO, confirmando a alta especificidade destes testes para AR e vasculites sistêmicas, respectivamente.

Background: The International Classification of Function, Disability and Health (ICF) describes health using 1424 categories from 4 components: body functions (BF), body structures (BS), activities and participation (AP) and contextual factors (environmental (EF) and personal (PF)). In this study the ICF was used to describe and compare aspects of ANCA-Associated Vasculitis (AAV) measured in clinical trials and those important to clinicians and patients. Methods: Individual interviews and focus groups were used to capture the perspective of AAV patients. Clinicians’ perspective was obtained with an email-based questionnaire. Outcomes used in AAV randomized trials were extracted from results of a systematic review of literature. Identified concepts were mapped to the ICF according to previously published ICF linking rules, and the resulting lists of relevant AAV outcomes were compared descriptively. Results: Twelve individual interviews and 2 focus groups represented the patient perspective while responses from 27 clinicians yielded the clinicians’ perspective. Systematic literature review identified 67 clinical trials and 28 abstracts from which measured outcomes were extracted. All three perspectives demonstrated detailed coverage of ICF components BF and BS. In the component AP patients and clinicians identified similar ICF categories, a number of which were under-sampled by AAV trials. Contextual factors appear to be significantly more relevant to patients than clinicians and researchers. Conclusion: Patients and clinicians have different views of the relevance of various AAV outcomes, and these views differ from what is measured in clinical trials of AAV. This highlights the need for a broad and standardized approach to developing and selecting outcomes for complex medical conditions such as AAV.

No description available.