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1
Stassen, Patrica Maria. "ANCA-associated vasculitis triggers and treatment /." [S.l. : [Groningen : s.n.] ; University Library Groningen] [Host], 2008. http://irs.ub.rug.nl/ppn/.
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Chowdhury, Saifuddin M. Zahed. "Antineutrophil cytoplasmic antibodies and systemic vasculitis." Thesis, University of Newcastle Upon Tyne, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.327199.
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Berti, Alvise. "Autoreactive B Cells in ANCA-Associated Vasculitis." Doctoral thesis, Università degli studi di Trento, 2021. http://hdl.handle.net/11572/325394.
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Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a group of B-cell driven, autoimmune systemic vasculitides characterized by a relapsing course and the presence of ANCA autoantibodies which are instrumental in their pathogenesis. We aimed to investigate autoreactive proteinase 3 (PR3+) B cells involved in the development of human AAV. We previously developed a customized flow-cytometry method to identify autoreactive B cells among cryopreserved peripheral blood mononuclear cells (PBMC), using labeled PR3, one of the main AAV autoantigens, as a ligand. We therefore used multicolor flow cytometry in combination with bioinformatics and functional in vitro studies on 1) baseline samples of PBMC from 154 well-characterized participants of the RAVE trial (NCT00104299) with severely active PR3-ANCA+ AAV (PR3-AAV) and myeloperoxidase (MPO)-AAV, and 27 healthy controls (HC); 2) samples of matched bone marrow (BM) and peripheral blood from 8 non-vasculitis patients; and 3) 148 longitudinal samples from 23 PR3-AAV patients of the RAVE trial. Clinical data and outcomes from the trial and medical records were correlated with PR3+ B cells (total and subsets). In brief, we identified and phenotypically characterized autoreactive B cells in AAV and healthy controls, reporting their perturbations among the different B cell subsets, and their functional ability to produce PR3-ANCA autoantibodies in vivo and in vitro. We reported their maturation through central and peripheral tolerance checkpoints from BM to peripheral blood, leading to an accumulation of atypical autoreactive PR3+ memory B cells in PR3-AAV patients but not in MPO-AAV and HC. We also described the longitudinal association between autoreactive plasmablast redetection after anti-B cell
13 targeted therapy with the main disease outcome, relapse. Overall, our findings suggest the presence of defective central antigen-independent and peripheral antigen-dependent checkpoints in patients in PR3-AAV, elucidating the selection process of autoreactive B cells, and their association with disease relapse.
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McClean, Andrew. "Why are patients with ANCA-associated vasculitis fatigued?" Thesis, University of Birmingham, 2016. http://etheses.bham.ac.uk//id/eprint/6487/.
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Objective: To assess the severity and predictors of fatigue in ANCA-associated vasculitis (AAV), and the contribution of peripheral and central mechanisms. Methods: Fatigue, anxiety/depression, sleep quality and pain were measured in 152 patients with AAV, 68 patients with CKD, andTl healthy conffols. Muscle mass, strength and endurance, cardio-respiratory fitness, perception of exertion, high-sensitivity C-reactive protein (hsCRP), and dehydroepiandrosterone (DHEA) were measured in 48 patients with AAV and 4l healthy controls. Results: Fatigue in AAV was more severe than in CKD 1p:g.gl3) or controls (p<0.001), and correlated with anxiety/depression, sleep quality and pain (all p<0.001). There was no difference in muscle mass (p:0.979) or strength (p=0.315) between AAV and conhols, but muscle endurance time was shorter in AAV (p=0.006), with greater muscle reserve (p=0.038) indicating central activation failure. Perception of exertion (p=0.006) and cardio-respiratory fitness (p:0.029) were worse in AAV than controls. Only perception of exertion independently predicted AAV fatigue (p:0.01). Sleep disturbance predicted altered perception of exertion (p:0.017). hsCRP was higher (p0.01 1) and DHEAS levels were lower (p<0.001) in AAV than controls, but neither predicted fatigue. Conclusion: Fatigue in AAV is more severe than in CKD or health, is due to central mechanisms, and may be amenable to intervention.
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Trivedi, Sapna. "A genetic association study in ANCA associated vasculitis." Thesis, University of Cambridge, 2013. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.607655.
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Brown, Nina. "Improving outcomes for patients with ANCA associated vasculitis." Thesis, University of Manchester, 2017. https://www.research.manchester.ac.uk/portal/en/theses/improving-outcomes-for-patients-with-anca-associated-vasculitis(41ab7c31-2b89-4626-a6a9-4b19b99e4d7b).html.
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Background: ANCA Associated Vasculitis (AAV) is a relatively rare autoimmune condition with the potential to cause life-threatening organ inflammation and failure. Due to the relative rarity, and the heterogenous way in which the disease may present, delay to diagnosis is common. Although initial immunosuppressive treatment is usually effective at controlling disease, morbidity associated with treatment is high and disease relapses frequent, necessitating further immunosuppression exposure. Aims and Objectives: This body of work therefore seeks to address 2 of the main challenges faced by the AAV population; 1) identifying factors that may contribute to a delay to diagnosis and disease recognition 2) reducing morbidity associated with the disease and the treatment. Methods: Patient pathways, knowledge and uptake of protective therapy were explored through a national patient report study. Patient care guidelines to assist with morbidity prevention were informed through Delphi consensus methodology and comprehensive literature review. The development of software to support implementation of a rigorous systematic approach to the assessment of the vasculitis patients was achieved through collaboration with information technology, business development and system architecture and design experts. Results: Patient presentation including symptoms, initial mis-diagnosis and eventual diagnosis appear to influence time to diagnosis. There is substantial delay from symptom onset to diagnosis demonstrating the need for increased awareness and education. Equally patient awareness of treatment related morbidity is low with variable uptake of protective therapy. A Delphi study has produced consensus on which guidelines can be based to address some of these inadequacies. A software programme: "Vasculitis Care Optimisation Tool (VasCOT)", has been designed to support implementation of these guidelines. Discussion: The various approaches used in this body of work have so far allowed evaluation of areas where patient care needs to be improved. This in part will be addressed through the publication of national vasculitis care guidelines, informed by this work and the ongoing development of VasCOT.
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Smith, Rona Marie. "Biological therapy in the treatment of ANCA associated vasculitis." Thesis, University of Cambridge, 2016. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.709472.
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Henderson, Scott Russell. "Dissecting mechanisms of granuloma formation in ANCA-associated vasculitis." Thesis, University College London (University of London), 2018. http://discovery.ucl.ac.uk/10042084/.
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Anti-neutrophil cytoplasm antibodies (ANCA) are associated with a severe form of small vessel systemic vasculitis, in which they target two specific auto-antigens, proteinase-3 (PR3) and myeloperoxidase (MPO) found within neutrophils and monocytes. Granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA) are the main clinical syndromes, both characterized by kidney and lung disease, but granulomatous inflammation is almost exclusively found in GPA, and unlike other manifestations, remains difficult to treat. In GPA patients, PR3 is the predominant ANCA auto-antigen and neutrophil membrane PR3 expression is increased. There has been limited understanding of why granulomata are restricted to this patient subgroup. I have investigated the role of PR3 in driving giant cell and granuloma formation by generating a novel in vitro model. Using extensive tissue culture and microscopy techniques I have been able to demonstrate that PR3 induces both giant cell and granuloma formation in GPA patients’ cells. Giant cells are the precursors to granulomata and I have demonstrated that in GPA patients, monocytes firstly fuse with the persistence of PR3 and then later recruit lymphocytes to form an organized granuloma-like structure. I have developed a unique method of quantifying granuloma formation and I have been able to show that GPA patients show a statistically significant greater rate of PBMC aggregation both spontaneously and in the presence of PR3 compared to MPA patients and healthy controls. I have explored the potential mechanisms of granuloma formation in this patient subgroup. Specifically, IL-6 may be important in driving granuloma formation in GPA patients and supports the notion of PR3-mediated process. PR3 cleaves protease-activated receptor 2 (PAR2) and I have shown that the presence of a PAR2 agonist further augments cell fusion. These findings support the role of PR3-mediated monocyte activation and fusion with additional T cell aggregation. In summary, I have developed a novel system to test giant cell and granuloma formation in GPA patients, a potential platform to evaluate new therapeutic treatments.
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Basu, Neil. "The characterisation and determinants of quality of life in ANCA associated vasculitis." Thesis, University of Aberdeen, 2012. http://digitool.abdn.ac.uk:80/webclient/DeliveryManager?pid=189406.
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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.
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Rajp, Amit. "The immunogenetics of anti-neutrophil cytoplasmic antibody (ANCA) associated vasculitis." Thesis, University of Birmingham, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.273729.
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Chanouzas, Dimitrios. "Cytomegalovirus modulation of the immune system in ANCA associated vasculitis." Thesis, University of Birmingham, 2017. http://etheses.bham.ac.uk//id/eprint/7344/.
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Infection and cardiovascular disease represent the two most important sources of mortality in ANCA associated vasculitis (AAV). Expansions of CD4+CD28null T-cells that are only present in cytomegalovirus (CMV) positive individuals have previously been associated with increased infection and mortality in AAV, and cardiovascular disease in other inflammatory diseases. The work described in this thesis examines the hypothesis that subclinical CMV reactivation in AAV drives the expansion of CD4+CD28null T-cells thereby leading to the observed adverse outcomes. To investigate this, a proof of concept clinical trial of 6 months valaciclovir treatment or no additional therapy was designed and implemented in CMV seropositive AAV patients in remission. Valaciclovir treatment successfully blocked CMV reactivation and in turn this led to a reduction in the proportion of CD4+CD28null T-cells in the treated patients together with favourable changes in other associated CMV induced changes on the immune system. CD4+CD28null T-cells in AAV were identified as Th1, proinflammatory cytotoxic T-cells, able to target endothelial cells and were independently associated with increased arterial stiffness, an established marker of cardiovascular risk. These findings implicate subclinical CMV reactivation as a potentially reversible cause of vascular pathology in inflammatory disease and open novel therapeutic opportunities.
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Thorpe, Carolyn T. DeVellis Robert F. "Illness self-management among adults living with ANCA small vessel vasculitis." Chapel Hill, N.C. : University of North Carolina at Chapel Hill, 2006. http://dc.lib.unc.edu/u?/etd,703.
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Thesis (Ph. D.)--University of North Carolina at Chapel Hill, 2006.Title from electronic title page (viewed Oct. 10, 2007). "... in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Department of Health Behavior and Health Education." Discipline: Health Behavior and Health Education; Department/School: Public Health.
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Griffith, Megan Eleri. "Autoimmunity to proteinase 3 and myeloperoxidase in ANCA positive systemic vasculitis." Thesis, Imperial College London, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.264333.
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Coughlan, Alice. "The development of a humanised mouse model of ANCA associated vasculitis." Thesis, King's College London (University of London), 2013. https://kclpure.kcl.ac.uk/portal/en/theses/the-development-of-a-humanised-mouse-model-of-anca-associated-vasculitis(0207457f-ce89-4c39-b69d-b80e9cf7eff5).html.
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Anti-neutrophil cytoplasmic autoantibodies (ANCA), targeting the neutrophil protein granules myeloperoxidase (MPO) and proteinase 3 (PR3), activate neutrophils in vitro, and are associated with a systemic autoimmune vasculitis, in which a pauci-immune crescentic glomerulonephritis is common. The in vivo study of ANCA pathogenesis is severely limited, both by the lack of a robust anti-PR3 IgG induced disease model, and by the differences found between human and mouse biology. Therefore the development of a disease model based on humanised mice, defined as mice possessing human immune cells, has the potential to overcome these limitations, while also allowing the direct study of human ANCA in vivo. The aims of this thesis were 1) to establish in vitro assays of ANCA induced neutrophil activation, and thus allow the study of ANCA:neutrophil interactions and 2) to establish a humanised mouse model of ANCA vasculitis. ANCA were purified from patient plasma, and two human neutrophil respiratory burst assays were developed. Subsequently, it was shown that Granulocyte Colony Stimulating Factor (GCSF) primes neutrophils for an anti-MPO induced respiratory burst, and the inhibition of phosphoinositol 3-kinase p/5 abrogates the ANCA induced release of superoxide. Humanised mice were produced by the engraftment of human haematopoietic stem cells into irradiated, adult NOD-scid \\-2rf1’ mice. At least 8 weeks later a population of human neutrophils were identified by flow cytometry, and this population was expanded by treatment with GCSF. It was shown that these cells could respond to inflammatory stimuli in vivo, by modulating their expression of activation markers, and in vitro, by undergoing respiratory burst and degranulation. Patient derived ANCA was passively transferred into humanised mice that had been primed with GCSF and lipopolysaccharide. Mice were culled 7 days later, but there was no histological or biochemical evidence of disease. Thus, this work has identified GCSF and phosphoinositol-3-kinase p/8 as molecules of potential importance in ANCA vasculitis. Furthermore, the passive transfer of patient ANCA into humanised mice did not prove pathogenic in this study, and possible reasons for this are discussed. The demonstration of functional responses in human neutrophils does, however, suggest that this humanised mouse model has the potential be useful for the study of human neutrophils in vivo.
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Söderberg, Daniel. "The Contribution of Innate Immunity to the Pathogenesis of ANCA-associated Vasculitis." Doctoral thesis, Linköpings universitet, Avdelningen för läkemedelsforskning, 2016. http://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-132327.
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Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) constitute a group of vasculitides characterized by neutrophil-rich necrotizing inflammation of small vessels and the presence of ANCA in the circulation. Dying neutrophils surrounding the walls of small vessels are a histological hallmark of AAV. Traditionally it has been assumed that these neutrophils die by necrosis, but neutrophil extracellular traps (NETs) have recently been visualized at the sites of vasculitic lesions. NETs were first described to be involved in capture and elimination of pathogens but dysregulated production and/or clearance of NETs are thought to contribute to vessel inflammation in AAV; directly by damaging endothelial cells and indirectly by acting as a link between the innate and adaptive immune system through the generation of pathogenic PR3-ANCA and MPO-ANCA that can activate neutrophils. ANCA can, however, be found in all individuals and are therefore suggested to belong to the repertoire of natural antibodies produced by innate-like B cells, implying that not all ANCA are pathogenic. In paper I, we found neutrophils in patients to be more prone to undergo NETosis/necrosis spontaneously compared with neutrophils in healthy controls (HC), as well as that active patients possessed elevated levels of NETs in the circulation. Our results also suggest that ANCA during remission could contribute to the clearance of NETs as we observed an inverse relation between ANCA and NETs. In paper II, we observed neutrophils in patients to be more easily activated upon ANCA stimulation as they produced more ROS than neutrophils in HC. In paper III, we showed for the first time that cells of adaptive immunity (B and T cells) in addition to cells of innate immunity can release ET-like structures, in this case consisting of mitochondrial (mt) DNA. mtDNA can act as a damage-associated pattern molecule (DAMP) and promote inflammation, and increased levels of mtDNA has been observed in AAV. Our finding broadens our perspective of the possible roles of T and B cells in immunological responses, and should be further investigated in AAV. In paper IV, we observed reduced frequencies of MZ-like B cells, considered to be innate-like B cells that produce natural antibodies, and of the proposed regulatory B (Breg) cell populations CD24highCD27+ and CD25+CD27+ B cells in patients, particularly in those with active disease. We also observed the phenotypes of these different Breg cell populations to be different from the corresponding cells in HC. We hypothesize that the increased activation potential by neutrophils in AAV to produce ROS and undergo NETosis/necrosis contribute to the excessive inflammation as well as an increased antigen load of PR3 and MPO, and that this in combination with dysregulation of innate-like B cells and Breg cells could lead to break of tolerance to these antigens and production of pathogenic autoantibodies. ANCA can in turn activate neutrophils to release NETs, suggesting a vicious circle in disease development.
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De, Pellegrin Annamaria. "Role of ANCA in necrotizing vasculitis and in chronic inflammatory intestinal disease." Doctoral thesis, Università degli studi di Padova, 2008. http://hdl.handle.net/11577/3426734.
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Background: Wegener's granulomatosis (WG), Microscopic Poliangitis and Churg-Strauss Syndrome, the necrotizing vasculitis, are a group of inflammatory diseases of the
wall small-medium calibre blood vessels. This group of diseases are hystologically characterized by the presence of necrotic tissue with a consequent inflammatory infiltration and the formation of granulomas. GW is a disease which has periods of
remission and recurrence treated by therapeutic cycles associated with several side-effects. It is caracterized by the presence in serum of anti-neutrophil cytoplasm antibodies (ANCA). ANCA are auto-antibodies against enzymatic antigens
found in primary granules of neutrophyls and in peroxydase-positive lysosomes of monocytes.The two main antigens are serin proteinase-3 (PR3), a cytoplasmatic
protein and leucocyte myeloperoxydase (MPO). Indirect immunofluorescence permits to differentiate two distinct patterns, cytoplasmic (c-ANCA) and perinuclear (p-ANCA),
according to the involved antigen, accordingly PR3 and MPO.
Both patterns of ANCA presentation, mainly p-ANCA, are found in chronic inflammatory intestinal disease (IBD), noticeably Crohn's disease (CD) and ulcerative colitis (UC).
Study goal: To evaluate the prevalence of ANCA in a population of patients with WG and one with CIID. In these two groups we studied: presentation pattern, correlation among antibody titer, clinical phase and disease localization; the role of infective
agents as factors initiating ANCA production. Finally we correlated ANCA titers with response to treatment and disease complications. Patients and methods: we studied 13 patients with WG, some of which we had treated for over 7 years. In all patients ANCA levels were titred at the moment of diagnosis
and during recurrences. Cultures were performed during episdoes of infectious disease. 37 patients with IBD admitted to a general surgical department for colic resection or for treatment of anal abscesses or fistulas were also studied, of these 12 had UC and 15 CD. Patients were studied in 2 different stages: preoperatively and 3 months after surgery. We evalutated:ANCA dosage, erythrocyte sedimentation rate, CRP, fibrinogen levels, direct or anamnestic determination of infectious episodes. Serum ANCA levels were dosed according to indirect immunofluorescence and, if positive, their presence was confirmed by ELISA.
Results: ANCA were useful, if not decisive, in 85% of patients with WG, with titers ranging from 1:160 to 1:280. c-ANCA were 100% specific in patients with WG. ANCAs reappeared during follow-up in only 3 patients . Infectious episodes seemed to have been the factor causing recurrence. The presence of Staphylococcus aureus seems to favor the reappearance of ANCA in patients with WG while bactertial and/or viral infections may be responsible for ANCA-negative. p-ANCA were detected in 83% of patients with CU and in only 20% of patients with MC before surgery. After surgical treatment, ANCA were detected in 75% of patients with CU, while remain 20% in MC patients, but with lower titer.
Conclusions: also our study demonstrates to the usefulness of the search and dosage of the ANCA in the diagnosis and follow-up of the GW. P-ANCA had a clean prevalence
in the UC but they aren't useful in other chronic diseases. Also not playing a determining role in the diagnosis and not predicting in the prognosis of the IBD, ANCA turns out from our study a useful additional test in the diagnostic one
differentiates them between UC and MC.
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Dhaygude, Ajay. "Epidemiology, genetic differences and clinical outcomes of antineutrophil cytoplasmic autoantibody associated systemic vasculitis." Thesis, University of Manchester, 2012. https://www.research.manchester.ac.uk/portal/en/theses/epidemiology-genetic-differencesand-clinical-outcomes-ofantineutrophil-cytoplasmicautoantibody-associated-systemicvasculitis(1d4bf70b-3046-4997-9bdb-82206b6a8264).html.
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Introduction: The two subtypes of Antineutrophil Cytoplasmic autoantibody associated systemic vasculitis (AASV) cANCA and pANCA associated vasculitis are the commonest causes of rapidly progressive glomerulonephritis. In spite of recent advances in the pathogenesis and development of new therapeutic agents, long term outcomes are still poor with five year mortality of 25%. There are epidemiological, histological, clinical and outcome related differences between these two conditions. This strongly suggests that there must be differences between genetic factors and pathogenesis of these two conditions. There was also a perception amongst the clinicians that AASV is more common in the Greater Manchester area. Hence in this study I calculated the incidence of pauciimmune glomerulonephritis in Greater Manchester and analysed the genetic differences between cANCA and pANCA associated vasculitis. Methods: Five year incidence of pauciimmune glomerulonephritis was calculated in Greater Manchester between 1/1/1999 to 31/12/2003. I recruited 147 patients with ANCA associated vasculitis. Clinical data was collected. I studied single nucleotide polymorphisms (SNPs) of tumour necrosis factor alpha(TNFα), interleukin 8 (IL-8), transforming growth factor beta (TGFβ), platelet endothelial cell adhesion molecule 1 (PECAM-1), Chemokine (CC motif) ligand-5 C chemokine (CCL-5), interleukin 10 (IL-10) and interleukin 18 (IL-18) genes and compared the frequencies of genotypes and alleles in patients with cANCA and pANCA associated small vessel vasculitis and healthy volunteers. I also studied circulating cytokine profiles of IL-10 and IL-18. Results of IL-18 SNPs were validated in AASV cohort from South-East USA. Further I studied the gene expression patterns of active and remission state of AASV and metabolomics profile of cANCA and pANCA positive patients during active and remission state of vasculitis. Clinical outcomes (relapses and renal survival) were correlated with the genotypes. Results: I found a significantly higher incidence (9.8/million population) of pauciimmune glomerulonephritis in Greater Manchester compared to the previously published data from UK and USA (2.73 to 4.6/million). Renal function at the time of diagnosis predicted the long term renal survival. I also found a novel genetic association of increased frequency of high producer IL-18 SNPs 113T, 127C and 137G in pANCA positive patients compared to normal volunteers (p=0.04) and cANCA positive patients (trend- p=0.08). This was associated with increased levels of circulating IL-18 levels in these patients. This association was further confirmed in an independent cohort of AASV from USA. I also found a lower frequency of low producer GG genotype of IL-10 -1082 SNP (p=0.05) and this was associated with lower levels of circulating IL-10 in these patients compared to pANCA positive patients. I found significant difference in the metabolomics profiles of cANCA andpANCA positive patients. In paired plasma samples, levels of some metabolites were high during remission state compared to active vasculitis. Conclusions: These findings strongly support the hypothesis that there is an increased incidence of pauciimmune glomerulonephritis in Greater Manchester. There are genetic differences in cANCA and pANCA positive patients which may explain the different observed outcomes. Genome wide association study would strengthen these findings and should guide the vasculitis community to reclassify, assess and perhaps treat these two conditions separately.
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Slot, Marjan Carolien. "ANCA-associated vasculitis: factors involved in disease induction, survival and long-term complications." [Maastricht] : Maastricht : Maastricht University ; University Library, Universiteit Maastricht [host], 2007. http://arno.unimaas.nl/show.cgi?fid=11061.
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Freeley, Simon. "The role of complement and granulocyte colony stimulating factor in ANCA associated vasculitis." Thesis, King's College London (University of London), 2013. https://kclpure.kcl.ac.uk/portal/en/theses/the-role-of-complement-and-granulocyte-colony-stimulating-factor-in-anca-associated-vasculitis(997a1669-beac-4225-8a9a-51afc5004276).html.
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Hieutrophil cytoplasmic antibody (ANCA) associated vasculitis is a systemic disease i affects the kidneys, lungs, and other tissues. ANCA were first described in patients i focal necrotising glomerulonephritis in 1982, with myeloperoxidase )) and proteinase 3 (PR3) subsequently shown to be the antigenic targets responsible rthe perinuclear and cytoplasmic staining patterns, respectively. Infection is thought to erbate disease partially through the production of the proinflammatory cytokine TNFot i primes neutrophils for respiratory burst. In this thesis, the role of another cytokine, Milocyte-colony stimulation factor (GCSF) is examined both in vitro and in vivo. Previous i have implicated the complement system in ANCA vasculitis. Furthermore, TNFot •d neutrophils which have been activated with ANCA in vitro are known to release a >r into the supernatant which causes complement activation in normal serum. This w has yet to be identified, although many candidates such as the alternative pathway aonent properdin have been suggested. In this work it is shown that GCSF antrations are elevated in patients with acute ANCA vasculitis and that GCSF can prime ted neutrophils for anti-MPO induced respiratory burst. A passive antibody transfer i model of anti-MPO vasculitis was established and GCSF administration was shown to te disease. Experiments also explored other models of anti-MPO vasculitis based •PO-deficient mice. The mouse model was also used to investigate the effect of icy of either properdin or MASP2 in disease. Using the passive anti-MPO passive Sr model, properdin deficiency was shown to have no effect on the extent of disease ! MASP2-deficiency exacerbated disease by a mechanism which has yet to be identified. iwork has established GCSF as a key cytokine and possible therapeutic target, and I novel observations on complement in ANCA vasculitis.
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Booth, Anthony Deverell. "ANCA-associated systemic vasculitis: outcome, vascular dysfunction and the role of anti-TNFa therapy." Thesis, King's College London (University of London), 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.430463.
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Walls, Catriona A. "Development and characterisation of a 4-dimensional in vitro model of ANCA-associated vasculitis." Thesis, University of Aberdeen, 2017. http://digitool.abdn.ac.uk:80/webclient/DeliveryManager?pid=235935.
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ANCA-associated vasculitis is a group of devastating autoimmune diseases that predominantly target and destroy small blood vessels. The interaction of neutrophils and monocytes with the endothelial cell lining of blood vessels is imperative to understanding the pathophysiology of the disease. The nature and temporal dynamics of these interactions are mostly unknown and could provide a currently unmet clinical need for more reliable biomarkers of disease activity. This study describes the development of a 4-dimensional in vitro live cell imaging model allowing the interactions of leukocytes with endothelial cells to be analysed in the context of health and disease. Monocytes and neutrophils were isolated from peripheral venous blood of AAV patients and healthy donors. Cells were fluorescently labelled and imaged on a monolayer of human umbilical vein endothelial cells (HUVEC) using a spinning disc confocal microscope. Leukocyte migration, partial and full transmigration, route of transmigration, degranulation and the presence of leukocyte-derived particles inside endothelial cells were measured and the influence of ANCA or BVAS status considered. Following a series of preliminary experiments, it was determined that neutrophil degranulation and partial transmigration indicated early promise as potential biomarkers of disease activity. Several circulating serum analytes correlated with in vitro leukocyte functions, complementing these findings but also highlighting the prevalent immune dysfunction in the pathophysiology and development of the disease. Fatigue is a common symptom within the AAV community and the complex relationship between autoimmune fatigue and leukocyte functions was examined. The data in this thesis describes the development of a novel in vitro live cell imaging platform which can be used to investigate leukocyte functions as potential markers of disease activity as well as understanding their role in the pathophysiology of AAV.
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Hamour, Sally. "The role of IL-17 in the pathogenesis of glomerulonephritis and ANCA-associated vasculitis." Thesis, Imperial College London, 2013. http://hdl.handle.net/10044/1/14413.
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Immune-mediated glomerulonephritis and vasculitis accounts for over 10% of end-stage renal failure in the UK. The anti-neutrophil cytoplasm antibody(ANCA)-associated vasculitides (AAV) are a specific subset, characterised by the production of ANCA, and are idiopathic multi-system vasculitides affecting mainly small-calibre vessels and renal glomeruli. Extensive human and animal work by our group and others has attempted to dissect the mechanisms which underlie the pathogenesis of these conditions. Recently, an important development in our understanding of cellular immunity has been the identification of a subset of T-cells characterised by production of the pro-inflammatory cytokine interleukin-17 (IL-17). T-helper-17 (Th17) cells are implicated as critical mediators of autoimmune disease. I have attempted to characterise whether there is a role for Th17 cells in the pathogenesis of experimental glomerulonephritis and AAV. I have shown that IL-17-deficient mice are protected from nephrotoxic nephritis and have used cell transfer experiments to see whether disease susceptibility or protection can be conferred. Using bone marrow transplant experiments, I have also demonstrated (1) that haematopoietic cells are critical mediators of disease and (2) that local production of IL-17 has an unexpected protective role. In human work, using samples from patients with AAV, I have shown that IL-17 is over-expressed in serum from both acute and convalescent patients and is closely associated with levels of related cytokines such as IL-23. Patients with AAV have memory Th17 cells that respond to stimulation with ANCA autoantigens. IL-23 levels correlate with AAV disease activity. This work demonstrates a role for IL-17 and Th17 cells in experimental glomerulonephritis and AAV. IL-17 blockade is being trialled as a therapy for a number of autoimmune diseases. Improved understanding of the mechanisms of pathogenesis and protection by IL-17 in AAV and glomerulonephritis will enable better prediction of the effects of IL-17 blockade and bring benefits to patients.
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Pepper, R. J. "The role of calprotectin (S100A8/A9) in the pathogenesis of glomerulonephritis and ANCA-associated vasculitis." Thesis, University College London (University of London), 2013. http://discovery.ucl.ac.uk/1400216/.
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Glomerulonephritis is a common cause of end-stage renal failure and a feature of ANCA-associated vasculitis (AAV). AAV is an example of a small vessel vasculitis, characterised by inflammation of the endothelium and glomeruli in which the interaction between leukocytes and endothelial cells play a crucial role. Macrophages have been demonstrated to have a critical role during the initiation and progression of glomerulonephritis. Calprotectin (also termed S100A8/A9, mrp8/14), is a complex of 2 small calcium binding proteins that is abundantly expressed in neutrophils and monocytes as well as early infiltrating macrophages and is a ligand of Toll-like receptor 4 (TLR4) and the receptor for advanced glycation end-products (RAGE). There is growing evidence in animal models and patients with autoimmune diseases, of calprotectin being involved in the inflammatory response, as well as being a marker of activation of innate immunity. I have initially characterised the presence of calprotectin-positive cells in renal biopsies of patients with focal and crescentic AAV glomerulonephritis, therefore linking the presence of these cells with renal outcome. Patients with active AAV have elevated serum calprotectin levels, as well as significant expression on neutrophils and monocytes, which although decrease during remission, does not normalise. I have demonstrated that mrp14-/- mice are protected from nephrotoxic nephritis, which is abrogated by use of LPS during disease progression. Bone-marrow derived macrophages (BMDMs) release pro-inflammatory cytokines following stimulation with calprotectin; mediated by TLR4. Mrp14-/- BMDMs do not respond to the pro-inflammatory stimulus of S100A8/A9. The co-culture of endothelial cells (EC) and wild-type BMDMs is pro-inflammatory unlike that of mrp14-/- BMDM and ECs. Mrp14-/- mesangial cells also have a decreased pro-inflammatory response. This work demonstrates that calprotectin has a role in experimental glomerulonephritis as well as AAV patients. This may improve our understanding of the inflammatory response and identify a new novel treatment targets.
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Mooney, Janice. "What are the informational needs of patients with ANCA-associated vasculitis? : a mixed methods study." Thesis, University of East Anglia, 2014. https://ueaeprints.uea.ac.uk/50620/.
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Background: The ANCA-associated vasculitides (AAVs) are a group of rare, potentially life-threatening conditions which if untreated can be fatal. Little is known about the information needs of people with AAV. Objectives: To explore what it is like to be diagnosed with AAV and to find out the informational needs of this group. Study design: A mixed methods approach using focus groups and one-to-one interviews, then a questionnaire surveying the membership of Vasculitis UK (VUK) and the Vasculitis Clinical Research Consortium (VCRC). Results: Emergent themes from the first phase were: reaction to diagnosis, need for information on disease management and access to knowledgeable practitioners. There were 314 VUK, 273 VCRC respondents. Respondents rated information on diagnosis, prognosis, investigations, treatment, and side effects as extremely important. Information on patient support groups and psychosocial care was less important. There was no difference in the ratings of information needs based on group, sex, age, disease duration, disease, or method of questionnaire delivery. Conclusion: Receiving the diagnosis of a rare, potentially life-threatening disease causes anxiety and fear and can impede information retention and recall. People with AAV seek specific information concerning their disease, treatment regimes and side effects, and the results of investigations. Individuals preferred to receive this information from a doctor. Recommendations: Patients with AAV should be treated in a similar manner to patients with other chronic illnesses in which patient education is a fundamental part of care.
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Kettritz, Ralph. "Untersuchungen zu zellulären Mechanismen bei ANCA-assoziierten nekrotisierenden Vaskulitiden." Doctoral thesis, Humboldt-Universität zu Berlin, Medizinische Fakultät - Universitätsklinikum Charité, 2000. http://dx.doi.org/10.18452/13747.
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Gegenstand der vorliegenden Arbeit waren Untersuchungen zu zellulären Mechanismen ANCA-assoziierter systemischer Vaskulitiden. Es wurde dabei zunächst die ANCA-induzierte Aktivierung neutrophiler Granulozyten untersucht. Es konnte gezeigt werden, daß die Quervernetzung der ANCA-Antigene auf der Oberfläche neutrophiler Granulozyten die Generation von Sauerstoffradikalen auslöst. Der zweite Komplex beschäftigte sich mit der Regulation der Apoptose neutrophiler Granulozyten, die einen zentralen Mechanismus für die Auflösung von Entzündungen darstellt. Die Ergebnisse zeigen, daß die Apoptose neutrophiler Granulozyten durch IL-8 verzögert und durch TNF-alpha akzeleriert wird. Dabei führt die Interaktion mit extrazellulären Matrixsubstanzen wie Fibronektin zu einer weiteren Akzeleration der TNF-alpha-induzierten Apoptose. Die Bedeutung der Tyrosin Phosphorylierung für diesen Prozess wird gezeigt, und Ly-GDI, ein regulatorisches Protein für kleine GTPase-Proteine der Ras-Superfamilie, wurde als ein Substrat der Tyrosin-Kinasen charakterisiert. Letztlich konnten neue Kandidaten-Proteine für die Regulation der Lebensspanne neutrophiler Granulozyten identifiziert werden.Mechanisms of ANCA-associated vasculitis were studied. First, the activation of human neutrophils by ANCA was investigated. The data demonstrate the important role of cross-linking ANCA-antigens by the auto-antibodies on the cell surface for the initiation of a respiratory burst. The second issue was the regulation of neutrophil apoptosis that is central to the resolution of inflammation. These experiments indicate that apoptosis was delayed by IL-8 and accelerated by TNF-alpha. Interaction with extracellular matrix proteins, such as fibronectin resulted in further acceleration of apoptosis. The important role of protein tyrosine phosphorylation was demonstrated, and Ly-GDI, a regulator of GTPase-proteins of the ras-superfamily was characterized. Finally, proteins that may control the life span of neutrophils were identified.
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Flossmann, Oliver. "Determining outcomes and prognostic factors in ANCA associated vasculitis as a platform for the evaluation of newer treatments." Thesis, St George's, University of London, 2013. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.603596.
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Anti-neutrophil cytoplasm antibody (ANCA) associated vasculitis (AAV) is a multisystem disease with substantial morbidity and mortality despite modem treatment. Longer-term patient outcomes are inadequately defined and new safe therapies arc needed. The aims o[this thesis were to investigate long-term outcomes of patients with AAV, compare two different damage assessment scores and the study of a novel immune-suppressant, deoxyspcrgualin (DSG), in the treatment of relapsing and refractory disease. Survival was studied in 535 newly diagnosed patients recruited to four randomised controlled trials. After a median of 5.2 years 25% deaths occurred with a mortality rate ratio of 2.6 (95% Confidence Interval (Cl) 2.2-3.1 ) compared to an age and sex matched general population. Multivariable analysis showed severely impaired kidney function, advancing age, higher disease activity and white cell count and lower haemoglobin were significant negative prognostic factors. In the same cohort, 38% experienced a relapse. Higher risk for relapse was independently associated with anti-proteinase 3 (anti-PR3) antibodies and cardiovascular involvement whereas impaired kidney function conferred a lower risk. A comparison between the Vasculitis Damage Index (VDI) and the Combined Damage Assessment Index (CDA) showed good correlation between both indices. The CDA was more complex but captured more detail. An international expert panel developed recommendations for the conduct of clinical studies and therapeutic trials in AA V. The following areas were covered: disease definitions, disease activity states, outcome measures, eligibi lity criteria, trial design including relevant end-points and biomarkers. Areas for further research were identified. A prospective open label study in 44 patients with refractory or relapsing granulomatosis with polyangiitis (GPA) treated for six months with DSG showed that 95% achieved either partial Of complete remission. Adverse events were common but rarely led to treatment discontinuation. Prolonged administration of DSG in eleven patients was effective III the majority without the occurrence of unexpected toxicity.
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Pearce, Fiona A. "The epidemiology and natural history of ANCA-associated vasculitis in the UK : a response to the UK Strategy for Rare Diseases." Thesis, University of Nottingham, 2018. http://eprints.nottingham.ac.uk/50022/.
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Introduction: Rare diseases have gained recognition over the past decade as an important area for health service improvement. They affect 1 in 17 people over a lifetime, consume 14% of the NHS budget, and are an important cause of illness and death[1]. In 2013, the Department of Health published for the first time a “UK Strategy for Rare Diseases” which identified 5 key recommendations for improving the lives of people with rare diseases, and included the need for epidemiological studies. 75% of rare diseases are genetic in origin, and have onset in childhood. However, rheumatologists provide care for people with a number of rare diseases, amounting to an important component of the 25% of rare diseases which are believed to be non-genetic and present in adulthood. One of the main challenges in studying rare disease, is the difficulty in finding enough people with the disease to study. Recent linkage of databases of primary and secondary care health records in the UK provide an opportunity to study representative samples, large numbers of people, and the breadth of healthcare provision. In this thesis, I report 4 epidemiological studies in routinely collected healthcare data, conducted in an exemplar rheumatic disease, ANCA-associated vasculitis. Methods: I used routinely collected healthcare data from local hospitals, a large database of UK general practice records, and linked hospital episode statistics to identify cases of ANCA-associated vasculitis. The specific questions addressed in the studies were: 1. What are the current incidence, prevalence and mortality of ANCA-associated vasculitis in the UK, stratified by age, sex and ethnic group? I addressed this question in a local hospital cohort, and then in linked primary and secondary care records in England. I used projections of the population structure in 20 years’ time to predict the expected number of incident and prevalent cases. 2. What is the natural history of the most common type of ANCA-associated vasculitis (granulomatosis with polyangiitis) prior to diagnosis, and are there opportunities to diagnose it sooner in primary or secondary care? I conducted a case-control study in a large database of primary care records, and attempted to develop a model for GPs that predicted the risk of a person having granulomatosis with polyangiitis, such as is advocated by the UK Strategy for Rare Diseases. 3. What are the strongest aetiological factors in granulomatosis with polyangiitis in the UK? I compared the frequency of possible aetiological exposures between cases and population-based controls in a large database of prospectively collected primary care data. Results: 1. There were about 1300 new cases of ANCA-associated vasculitis in the UK in 2015, more than previously thought. The incidence has been stable since 2000, however the disease is more common in older people, therefore due to predicted aging of the UK population there will be 34% more cases in 2035. We are not able to detect any differences in incidence rates between people from different ethnic groups, but our studies lacked power for this question. 2. People with granulomatosis with polyangiitis consulted their GP more than healthy people prior to their diagnosis. However, they consulted with a wide variety of symptoms, and none were highly predictive of the diagnosis. In addition, the lower the prevalence of the disease, the lower the positive predictive value of a diagnostic model. Granulomatosis with polyangiitis is rare, so even with an exceptionally well-performing model (with a sensitivity of 100% and a specificity of 90%) only 2 of every 10,000 people flagged as ‘at risk’ would have granulomatosis with polyangiitis, and the rest would have false positive results. 3. People with granulomatosis with polyangiitis were 5 times more likely than population-based controls to have a previous diagnosis of bronchiectasis, and 2-3 times more likely to have a previous diagnosis of an autoimmune disease or chronic renal impairment. Conclusions: 1. Although incidence appears stable, commissioners need to expand services to diagnose and treat people with GPA, and other adult-onset rare diseases, over the next 20 years due to the predicted increase in the proportion of the population in the age-groups at highest risk. 2. In particular, over the next 20 years, the age structure of the Black and Minority ethnic population in the UK is predicted to change to have many more people in older age-groups, and the UK medical community need to be alert to an expected emergence of significant numbers of Black and Minority ethnic people with ANCA-associated vasculitis. 3. Computerised prompts to alert GPs to consider a diagnosis of rare disease are unlikely to work. Resources to improve early diagnosis and treatment of ANCA-associated vasculitis would be better targeted at secondary care where the majority of cases have contact in the year before diagnosis. 4. The novel association of bronchiectasis with developing granulomatosis with polyangiitis raises a new hypothesis for bronchiectasis as a possible aetiological factor in granulomatosis with polyangiitis.
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Milman, Nataliya. "Using the International Classification of Function, Disability and Health (ICF) to Compare Areas of ANCA-Associated Vasculitits (AAV) Measured in Clinical Trials to those Important to Patients with AAV and Clinicians who are Involved in their Care." Thesis, Université d'Ottawa / University of Ottawa, 2014. http://hdl.handle.net/10393/31827.
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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.
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Hinkofer, Lisa [Verfasser], and Elisabeth [Akademischer Betreuer] Weiß. "Distinction of vasculitis-associated ANCA subsets and their pathogenic role in a new mouse model with the humanized target antigen / Lisa Hinkofer. Betreuer: Elisabeth Weiß." München : Universitätsbibliothek der Ludwig-Maximilians-Universität, 2015. http://d-nb.info/1094516961/34.
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Djabarouti, Sarah. "Optimisation des traitements à base d'acide mycophénolique chez les patients atteints de maladies auto-immunes." Thesis, Bordeaux 2, 2009. http://www.theses.fr/2009BOR21699.
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L’acide mycophénolique (MPA) est un immunosuppresseur très prometteur dans le traitement des maladies auto-immunes (MAI) telles que le lupus érythémateux disséminé (LED) et les vascularites à ANCA, et disponible sous deux formes pharmaceutiques : le mycophénolate mofétil (MMF) et le mycophénolate sodique (EC-MPS). Les études menées chez les patients transplantés recommandent le dosage plasmatique et le suivi pharmacocinétique (PK) du MPA, dans un objectif d’optimisation thérapeutique. A ce jour, ce suivi est encore inexistant dans les MAI, et les données de corrélation concentrations-efficacité thérapeutique, sur lesquelles se base l’optimisation, demeurent toujours rares dans ce domaine. Les travaux présentés dans cette thèse s’inscrivent dans l’étude des corrélations PK/pharmacodynamie (PD) du MPA dans les MAI. Ces travaux ont permis de proposer des schémas et des outils d’optimisation des traitements à base de MPA pour ces patients. Pour cela, les concentrations plasmatiques du MPA et de son métabolite 7-O-glucuronide (MPAG) ont été déterminées pour 53 patients présentant de manifestations extra-rénales de MAI à l’aide d’une méthode de chromatographie couplée à la spectrométrie de masse. Les paramètres PK ont été estimés pour MMF et EC-MPS dans les deux groupes de MAI. D’après ces travaux, l’optimisation du MMF chez les patients atteints de MAI peut reposer sur le suivi de la concentration à 12 h (C12) en MPA. Un seuil de 3 mg/L est proposé afin de maintenir la rémission dans le LED, mais reste à définir dans les vascularites. Pour EC-MPS, une stratégie de prélèvements limités basée sur la mesure de la concentration maximale et la C12 est nécessaire pour estimer l’aire sous la courbe des concentrations entre 0 et 12 h du MPAMycophenolic acid (MPA), the active form of both mycophenolate mofetil (MMF) and enteric-coated mycophenolate sodium (EC-MPS), is an immunosuppressant increasingly used in the treatment of autoimmune diseases such as systemic lupus erythematosus (SLE) and ANCA-associated vasculitis. In transplant recipients, therapeutic drug monitoring (TDM) of MPA is widely used to prevent acute organ rejection. However, MPA TDM is currently not available in autoimmune diseases, as data on the pharmacokinetic (PK)/pharmacodynamic (PD) relationships are very sparse in this indication. Our aim was to study the possible PK/PD relationships of MPA in patients with non-renal manifestations of SLE or ANCA-associated vasculitis. An assay based on liquid chromatography coupled with mass spectrometry was applied to the PK study of MPA and its major glucuronide metabolite (MPAG) in 53 SLE and vasculitis patients receiving either MMF or EC-MPS. According to our results, in SLE patients with non-renal manifestations, TDM based on the measurement of MPA 12-h trough concentration (C12) would allow optimizing therapies with MMF. A 3-mg/L efficacy threshold could be proposed to prevent clinical flares under MMF maintenance therapy. For EC-MPS, a limited sampling strategy including MPA maximum concentration and C12 is necessary to estimate the area under the curve between 0 and 12-h of MPA
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Delbet, Jean-Daniel. "Étude de preuve de concept thérapeutique évaluant l'efficacité d'un anticorps monoclonal dans le traitement des glomérulonéphrites à croissant ciblant CLDN1 dans les cellules épithéliales pariétales glomérulaires." Electronic Thesis or Diss., Université Paris Cité, 2024. http://www.theses.fr/2024UNIP5227.
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Introduction : La glomérulonéphrite à croissant (cGN) est une forme avancée de glomérulopathie commune à plusieurs maladies rénales d'origine immunitaire. La cGN se caractérise par une prolifération des cellules épithéliales pariétales glomérulaires (PEC), formant des croissants dans la chambre urinaire et conduisant en l'absence de traitement à l'insuffisance rénale terminale. Dans le cadre de ma thèse, j'ai particulièrement étudié la claudine-1 (CLDN1), une protéine transmembranaire impliquée dans les jonctions serrées, qui peut être exposée en dehors de ces jonctions serrées et activer des voies profibrotiques. Nous savons que la CLDN1 est exprimée spécifiquement par les PEC dans le glomérule, étant donné l'importance de l'activation des PEC dans les lésions glomérulaires, un anticorps monoclonal ciblant la CLDN1 pourrait être une cible thérapeutique pertinente et innovante. Par ailleurs, des biomarqueurs spécifiques des PEC activées, tels que CD44 et CD9, ont été mis en évidence dans les cGN. Les souris déficientes en CD44 n'étant pas capables d'induire de cGN et la délétion spécifique de CD9 dans les PEC prévenant les lésions tissulaires de la cGN. Malgré leurs rôles primordiaux dans la physiopathologie des cGN, leur expression dans la pathologie glomérulaire humaine n'est pas connue, tout comme leur corrélation avec le pronostic rénal. Le premier objectif de cette thèse est donc d'étudier l'expression des biomarqueurs des PEC (CLDN1, CD9 et CD44) en fonction des lésions histologiques glomérulaires les cGN humaines (néphropathie à IgA (IgAN) et vascularite à ANCA (vANCA)), leur rapport avec la perte et la dédifférenciation podocytaire et avec le pronostic néphrologique des patients. Le deuxième objectif de cette thèse est d'étudier le potentiel bénéfice de cibler la CLDN1 avec l'anticorps anti-CLDN1 dans un modèle murin de cGN. Méthode : L'expression de CLDN1, CD9 et CD44 dans les tissus rénaux de patients atteints de IgAN et vANCA a été analysée grâce à une technique d'immunofluorescence multiplex (méthode OPAL). La corrélation entre l'expression de CLDN1, CD9 et CD44 et les critères cliniques (DFGe, protéinurie), les lésions histologiques, les biomarqueurs de dédifférenciation podocytaire (p57 et WT1) et le pronostic néphrologique a été étudiée. Une analyse en transcriptomique spatiale des croissants glomérulaires exprimant CLDN1 et CD44 dans les reins de patients atteints de cGN a été réalisée. Des études de preuve de concept utilisant des anticorps anti-CLDN1 ont été effectuées dans un modèle préclinique de cGN. Résultats : Dans les tissus (n=131) de patients atteints de vANCA et IgAN, l'immunofluorescence en multiplex a révélé une surexpression de CLDN1 dans les croissants glomérulaires ainsi que dans les lésions fibreuses. Au moment de la biopsie rénale diagnostique, l'expression de CLDN1 dans les glomérules était corrélée à la perte de podocytes (mesurée par l'expression de P57). L'augmentation de l'expression des cellules doubles positives (CLDN1+ et CD44+) était statistiquement significativement associée à un mauvais pronostic rénal chez les patients atteints de vANCA et d'IgAN avec un suivi médian de 2,5 et 6.9 ans respectivement. L'analyse en transcriptomique spatiale a mis en évidence l'association entre la présence de PEC « activées » (CLDN1+/CD44+) et l'augmentation de l'expression des gènes de la matrice extracellulaire. Dans le modèle murin de cGN, nous avons mis en évidence qu'un anticorps anti-CLDN1 avait la capacité de se lier aux PEC activés, sa cible thérapeutique, et de réduire significativement de l'albuminurie chez les souris traitées. Conclusion : Nos résultats suggèrent un rôle fonctionnel de CLDN1 dans la pathogenèse de la cGN, fournissant une preuve de concept préclinique pour les anticorps anti-CLDN1. Ces données suscitent des questions mécanistiques et suggèrent que des anticorps anti CLDN1 pourrait représente une approche thérapeutique novatrice chez les patients atteints de cGNIntroduction: Crescentic glomerulonephritis (cGN) is the final mode of kidney injury common to several immune-mediated kidney diseases. cGN is characterized by extensive glomerular parietal epithelial cells (PEC) proliferation, forming crescents in urinary space and leading, if untreated, to end-stage kidney disease (ESKD). In a pathological context, claudin-1 (CLDN1), a transmembrane protein involved in epithelial tight junctions, can be exposed outside the tight junctions and mediate pro-fibrotic pathways and extracellular matrix (ECM) remodeling as described in other cell types. CLDN1 is expressed explicitly by PEC in the glomerulus and given the importance of PEC activation in glomerular injury, we evaluated whether a monoclonal antibody targeting CLDN1 could represent a relevant and innovative therapeutic tool. Additionally, specific biomarkers of PEC activation, such as CD44 and CD9, have been studied in cGN. CD44-deficient mice display attenuated experimental cGN, and specific deletion of CD9 in PEC prevents tissue damage in experimental cGN. However, CD9 and CD44 expression in human glomerular cGN (IgA nephropathy (IgAN) and ANCA vasculitis (AAV)) is unknown, as is their correlation with podocyte loss, histological lesions, and renal outcome. The first objective of this study was to evaluate PEC biomarkers (CLDN1, CD9, and CD44) expression in human cGN, their association with glomerular histological lesions, podocyte loss and dedifferentiation, and renal outcome. The second objective is to evaluate the potential benefit of targeting CLDN1 with an anti-CLDN1 Ab in a cGN mouse model. Method: CLDN1, CD9, and CD44 expression in renal tissues of cGN patients was analyzed using kidney multichannel immunofluorescence staining and spatial transcriptomics. Correlation between CLDN1, CD9, and CD44 expression and clinical endpoints (eGFR, proteinuria), histological lesions, biomarkers of podocyte dedifferentiation (p57 and WT1), and renal outcome were studied. A spatially resolved molecular roadmap from CLDN1+/CD44+ crescentic glomeruli was conducted. Proof-of-concept studies using anti-CLDN1 monoclonal antibody were performed in the Matsugi model of cGN. Results: In tissues of 131 patients with IgAN and AAV, multichannel immunofluorescence revealed up-regulated CLDN1 expression by crescents and fibrous lesions. At the time of diagnostic kidney biopsy, glomerular CLDN1 expression was correlated with podocyte loss (measured by p57 expression) and glomerular fibronectin area. The increase of proportion of double-positive (CLDN1+ and CD44+) cells was statistically significantly associated with poor renal outcome (50% decline in estimated glomerular filtration rate (eGFR) or ESKD) in patients with ANCA vasculitis and IgA nephropathy, with a median follow-up of 2.5 and 6.9 years, respectively. Spatial transcriptomics analysis highlighted the association between CLDN1+/CD44+ crescentic glomeruli and extracellular matrix genes. In the cGN murine model, we demonstrated that anti-CLDN1 antibody could bind to activated PEC, its therapeutic target and significantly reduced albuminuria in treated mice. Conclusion: Our results suggest a functional role of CLDN1 in the pathogenesis of cGN providing a preclinical proof-of-concept for the use of anti-CLDN1 antibodies as a novel therapeutic approach in patients with cGN
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Jeannin, Guido <1978>. "Utilizzo del Rituximab nel trattamento della vasculiti ANCA associate." Doctoral thesis, Alma Mater Studiorum - Università di Bologna, 2012. http://amsdottorato.unibo.it/4578/1/Jeannin_Guido_tesi.pdf.
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Introduzione. Recenti studi hanno dimostrato che il Rituximab (RTX) è un’alternativa sicura ed efficace alla ciclofosfamide nell’indurre la remissione in pazienti con severa vasculite ANCA-associata (AAV) di nuova diagnosi o recidiva. Scopo dello studio era valutare l’efficacia e la sicurezza del RTX nei nostri pazienti con AAV.
Metodi. Studio retrospettivo delle caratteristiche cliniche, dei risultati e della tolleranza al RTX dei pazienti con AAV trattati presso il nostro centro da Gennaio 2006 a Dicembre 2011. Inizialmente veniva utilizzato lo schema convenzionale delle 4 somministrazioni settimanali da 375 mg/m2. Dal 2011 sulla base dell’esperienza maturata e dei nuovi dati della letteratura si decideva di non adottare uno schema fisso per le recidive, ma di somministrare una o due dosi secondo la severità della recidiva ed il rischio infettivo.
Risultati. Venivano trattati 51 pazienti con AAV, 15/51 (29%) di nuova diagnosi e 36/51 (71%) ad una recidiva. La maggior parte dei pazienti con nuova diagnosi presentavano una micropoliangioite con severo interessamento renale, 5/15 (33%) erano in dialisi dall’esordio. 32/36 (89%) pazienti trattati ad una recidiva presentavano una recidiva granulomatosa di Granulomatosi di Wegener (WG). Tutti ottenevano una remissione, più rapidamente per le manifestazioni vasculitiche. 2/5 pazienti in dialisi dall’esordio recuperavano la funzione renale. Si osservavano 11 recidive in 9 pazienti con GW mediamente dopo 23.1 mesi, tutti ottenevano nuovamente la remissione. Ad un follow-up medio di 20.1 mesi si registravano 4 decessi, 3 (3/15, 20%) nel gruppo di pazienti con nuova diagnosi, uno (1/36, 3%) nel gruppo trattato ad una recidiva. Quattro pazienti sospendevano il RTX per infezioni.
Conclusioni. Nella nostra casistica il RTX si è dimostrato efficace e sicuro nell’indurre la remissione in pazienti con severa AAV, sia all’esordio che alla recidiva. I pazienti con WG presentano maggior rischio di recidiva e dovrebbero pertanto essere mantenuti in terapia immunosoppressiva dopo RTX.Background. Recently Rituximab (RTX) has proved to be an effective and safe alternative to Cyclophosphamide for remission induction in newly diagnosed and relapsing anti-neutrophil cytoplasm antibody (ANCA)-associated vasculitis (AAV). The aim of this study was to evaluate the efficacy and safety of RTX in our cohort of AAV-patients. Method. A retrospective study of the main clinical characteristic, outcomes, and RTX tolerance of AAV patients treated in our centre from January 2006 to December 2011. Initially we adopted the conventional schedule of RTX administration (4 weekly doses of 375 mg/m2). Since 2011, basing on our previous experience and new literature data, we have decided to not use a fixed schedule to treat relapse but to administer 1 or 2 doses of RTX according to individual AAV severity and infective risk. Results. Fifty-one AAV-patients were treated, 15/51 (29%) with newly diagnosed AAV and 36/51 (71%) with relapsing AAV. The majority of newly diagnosed patients had microscopic polyangiitis (9/15, 60%) with severe renal involvement, 5/15 (33%) were on dialysis at diagnosis. 32/36 (89%) patients treated for relapse had Wegener’s Granulomatosis (WG) with granulomatous relapses. All patients achieved clinical remission, within 4-6 weeks for vasculitic manifestation, it took longer for granulomatous manifestation. 2/5 patients on dialysis recovered renal function. Eleven relapses were observed in 9 patients with WG after 23.1 months on average, which were successfully re-treated with RTX. At an average follow-up of 20.1 months four deaths were observed, 3 (3/15, 20%) in the newly diagnosed patients and one (1/36, 3%) in patients treated for relapse. Four patients stopped RTX for infection. Conclusion. In our cohort RTX was found to be safe and effective for remission induction of newly diagnosed and relapsing AAV-patients. WG has an increased risk of relapse and therefore after RTX patients with WG should be maintained with immunosuppressive therapy.
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Jeannin, Guido <1978>. "Utilizzo del Rituximab nel trattamento della vasculiti ANCA associate." Doctoral thesis, Alma Mater Studiorum - Università di Bologna, 2012. http://amsdottorato.unibo.it/4578/.
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Introduzione. Recenti studi hanno dimostrato che il Rituximab (RTX) è un’alternativa sicura ed efficace alla ciclofosfamide nell’indurre la remissione in pazienti con severa vasculite ANCA-associata (AAV) di nuova diagnosi o recidiva. Scopo dello studio era valutare l’efficacia e la sicurezza del RTX nei nostri pazienti con AAV.
Metodi. Studio retrospettivo delle caratteristiche cliniche, dei risultati e della tolleranza al RTX dei pazienti con AAV trattati presso il nostro centro da Gennaio 2006 a Dicembre 2011. Inizialmente veniva utilizzato lo schema convenzionale delle 4 somministrazioni settimanali da 375 mg/m2. Dal 2011 sulla base dell’esperienza maturata e dei nuovi dati della letteratura si decideva di non adottare uno schema fisso per le recidive, ma di somministrare una o due dosi secondo la severità della recidiva ed il rischio infettivo.
Risultati. Venivano trattati 51 pazienti con AAV, 15/51 (29%) di nuova diagnosi e 36/51 (71%) ad una recidiva. La maggior parte dei pazienti con nuova diagnosi presentavano una micropoliangioite con severo interessamento renale, 5/15 (33%) erano in dialisi dall’esordio. 32/36 (89%) pazienti trattati ad una recidiva presentavano una recidiva granulomatosa di Granulomatosi di Wegener (WG). Tutti ottenevano una remissione, più rapidamente per le manifestazioni vasculitiche. 2/5 pazienti in dialisi dall’esordio recuperavano la funzione renale. Si osservavano 11 recidive in 9 pazienti con GW mediamente dopo 23.1 mesi, tutti ottenevano nuovamente la remissione. Ad un follow-up medio di 20.1 mesi si registravano 4 decessi, 3 (3/15, 20%) nel gruppo di pazienti con nuova diagnosi, uno (1/36, 3%) nel gruppo trattato ad una recidiva. Quattro pazienti sospendevano il RTX per infezioni.
Conclusioni. Nella nostra casistica il RTX si è dimostrato efficace e sicuro nell’indurre la remissione in pazienti con severa AAV, sia all’esordio che alla recidiva. I pazienti con WG presentano maggior rischio di recidiva e dovrebbero pertanto essere mantenuti in terapia immunosoppressiva dopo RTX.Background. Recently Rituximab (RTX) has proved to be an effective and safe alternative to Cyclophosphamide for remission induction in newly diagnosed and relapsing anti-neutrophil cytoplasm antibody (ANCA)-associated vasculitis (AAV). The aim of this study was to evaluate the efficacy and safety of RTX in our cohort of AAV-patients. Method. A retrospective study of the main clinical characteristic, outcomes, and RTX tolerance of AAV patients treated in our centre from January 2006 to December 2011. Initially we adopted the conventional schedule of RTX administration (4 weekly doses of 375 mg/m2). Since 2011, basing on our previous experience and new literature data, we have decided to not use a fixed schedule to treat relapse but to administer 1 or 2 doses of RTX according to individual AAV severity and infective risk. Results. Fifty-one AAV-patients were treated, 15/51 (29%) with newly diagnosed AAV and 36/51 (71%) with relapsing AAV. The majority of newly diagnosed patients had microscopic polyangiitis (9/15, 60%) with severe renal involvement, 5/15 (33%) were on dialysis at diagnosis. 32/36 (89%) patients treated for relapse had Wegener’s Granulomatosis (WG) with granulomatous relapses. All patients achieved clinical remission, within 4-6 weeks for vasculitic manifestation, it took longer for granulomatous manifestation. 2/5 patients on dialysis recovered renal function. Eleven relapses were observed in 9 patients with WG after 23.1 months on average, which were successfully re-treated with RTX. At an average follow-up of 20.1 months four deaths were observed, 3 (3/15, 20%) in the newly diagnosed patients and one (1/36, 3%) in patients treated for relapse. Four patients stopped RTX for infection. Conclusion. In our cohort RTX was found to be safe and effective for remission induction of newly diagnosed and relapsing AAV-patients. WG has an increased risk of relapse and therefore after RTX patients with WG should be maintained with immunosuppressive therapy.
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Lima, Isabella Vargas de Souza. "Pesquisa de autoanticorpos utilizados no diagnóstico de artrite reumatóide e vasculites em pacientes com tuberculose." Escola de Medicina e Saúde Pública, 2012. http://www7.bahiana.edu.br//jspui/handle/bahiana/32.
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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.
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Costa, Mafalda Teixeira da. "Treatment of Renal ANCA-associated Vasculitis." Master's thesis, 2017. https://hdl.handle.net/10216/104483.
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Costa, Mafalda Teixeira da. "Treatment of Renal ANCA-associated Vasculitis." Dissertação, 2017. https://hdl.handle.net/10216/104483.
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Tieu, Joanna. "Optimising Management in ANCA-Associated Vasculitis." Thesis, 2021. https://hdl.handle.net/2440/135593.
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From early descriptions of vasculitis to our currently understanding of the vasculitides, there has been continual evolution of the concepts on pathogenesis, classification, management and the impacts on patients. This is a thesis by publication, with an overarching aim of optimising therapy in anti-neutrophil cytoplasm antibody (ANCA)- associated vasculitis (AAV). The first chapter provides an overarching background for the subsequent chapters, providing an historical perspective on disease, disease manifestations including AAV subgroups and some of the impacts of AAV to patients. Chapter 2 provides insights into the impacts of AAV in Australia. Using data-linkage of WA hospitalisation, emergency department and death registry data, mortality including cause of death in patients with AAV and polyarteritis nodosa (PAN) were compared against the general population and controls. Data-linkage of WA hospitalisation and cancer registry data enabled analysis of cancer rates in patients with AAV/PAN compared with the general population. Chapters 3 and 4 examines the use of rituximab in AAV in the United Kingdom. Chapter 3 includes a literature review examining the evidence for use of rituximab in the maintenance of remission in AAV, and the results of a Delphi exercise conducted to develop consensus guidelines on the use of rituximab for the maintenance of remission in AAV. Chapter 4 examines the longer-term outcomes of patients who have develop rituximab associated hypogammaglobulinaemia in a quaternary referral centre. Chapter 5 examines the health-related quality of life (HRQoL) of patients with a relapse of AAV amongst patients in the multi-centre RITAZAREM study. This presents an unpublished manuscript examining the HRQoL of these patients during the induction phase of this study and compares the HRQoL in patients who received two different glucocorticoid regimens for induction of remission. Finally, chapter 6 provides a discussion on the thesis and directions for future research.Thesis (Ph.D.) -- University of Adelaide, Adelaide Medical School, 2022
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Říhová, Zuzana. "ANCA - associated renal vasculitis - epidemiology, diagnostics and treatment." Doctoral thesis, 2006. http://www.nusl.cz/ntk/nusl-268905.
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Andrade, Andreia Cristina Cruz. "Glomerulonefrite associada a ANCA - papel do Rituximab." Master's thesis, 2021. http://hdl.handle.net/10316/98452.
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Trabalho Final do Mestrado Integrado em Medicina apresentado à Faculdade de MedicinaIntrodução: Apesar da eficácia global da terapêutica existente para as vasculites associadas a anticorpos anticitoplasma de neutrófilos (ANCA), tem havido uma procura constante no sentido de reduzir o risco dos seus efeitos secundários. O rituximab tem demonstrado eficácia semelhante ou superior à ciclofosfamida, sem aumento do número total de efeitos adversos. Com este estudo pretende-se comparar o tratamento com rituximab e ciclofosfamida nos doentes com glomerulonefrite associada a ANCA. Métodos: Realizámos um estudo observacional retrospetivo que incluiu 27 doentes com glomerulonefrite associada a ANCA que receberam tratamento com rituximab ou ciclofosfamida no Centro Hospitalar e Universitário de Coimbra entre 2013 e 2020. O objetivo principal foi comparar a evolução da função renal e necessidade de terapêutica substitutiva da função renal. Avaliámos também a eficácia de indução de remissão e incidência de recidiva e de complicações associadas ao tratamento. Resultados: A função renal à entrada era semelhante nos dois grupos. Verificou-se menor probabilidade de necessidade de terapêutica substitutiva da função renal (TSFR) no grupo rituximab (p=0,039). Nos doentes sem necessidade de TSFR observou-se um aumento da taxa de filtração glomerular semelhante aos 6, 12 e 24 meses (14; 24 e 15 ml/min/1.73m2 no grupo rituximab e 11; 16 e 17 ml/min/1.73m2 no grupo controlo). Não houve diferença significativa na indução de remissão completa (92% no grupo rituximab vs. 100% no grupo controlo; p=0,481) nem na incidência de recidiva: até aos 6 meses ocorreu 1 recidiva no grupo rituximab e após os 6 meses ocorreu 1 recidiva no grupo rituximab e 5 no grupo controlo. A prevalência de eventos adversos aos 6 meses foi de 62% no grupo rituximab e 36% no grupo controlo (p=0,180), e aumentou para 73% no grupo rituximab e 67% no grupo controlo aos 24 meses. Conclusão: Ambas as terapêuticas estiveram associadas a bons resultados em termos de função renal com melhoria da taxa de filtração glomerular, mas com destaque para a menor probabilidade de necessidade de terapêutica substitutiva da função renal a longo prazo no grupo sob rituximab. Não houve diferença na indução de remissão e incidência de recidiva e de eventos adversos.
Introduction: Despite the overall effectiveness of the existing therapy for anti-neutrophil cytoplasmic antibody-associated vasculitis, there has been a constant demand to reduce the risk of its side effects. Rituximab has been shown to have a similar or even better efficiency when compared to cyclophosphamide without increasing the number of adverse events. This study aims to compare the treatment with rituximab and cyclophosphamide in patients with ANCA-associated glomerulonephritis. Methods: We performed a retrospective, observational cohort study involving 27 patients with ANCA-associated glomerulonephritis that received treatment with rituximab or cyclophosphamide in Centro Hospitalar e Universitário de Coimbra between 2013 and 2020. The primary endpoint was comparing the renal function evolution and the need for renal replacement therapy. We also analysed the efficiency to induce remission, relapse incidence, and prevalence of treatment complications. Results: Renal function at the entry was similar in both groups. We observed a lower probability of the need for renal replacement therapy (RRT) in the rituximab group (p=0,039). For patients without the requirement of RRT, we noticed a similar increase of glomerular filtration rate at 6, 12 and 24 months (14; 24 and 15 ml/min/1.73m2 for the rituximab group and 11; 16 and 17 ml/min/1.73m2 for the control groups). There was no significant difference in the induction of complete remission (92% for the rituximab group vs. 100% for the control group; p=0,481) neither in the incidence of relapses: until 6 months occur 1 relapse in the rituximab group and after 6 months occur 1 relapse in the rituximab group and 5 in the control group. The prevalence of adverse events at six months was 62% in the rituximab group and 36% in the control group (p=0,180) and increases to 73% in the rituximab group and 67% in the control group at 24 months. Conclusion: Both treatments presented good results regarding kidney function with improved of glomerular filtration rate, however, rituximab showed to have a lower probability of requiring long-term renal replacement therapy. There were no differences in remission induction, relapse incidence and prevalence of adverse events.
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Hoffmann, Johanna Charlotte. "Untersuchung von Biomarkern bei Patienten mit Anca-assoziierter Vaskulitis." Doctoral thesis, 2018. http://hdl.handle.net/11858/00-1735-0000-002E-E40F-5.
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Kröplin, Juliane. "Analyse von kardiovaskulären Risikofaktoren bei Patienten mit ANCA-assoziierten Vaskulitiden unter besonderer Berücksichtigung von Lipoprotein (a)." Doctoral thesis, 2019. http://hdl.handle.net/21.11130/00-1735-0000-0003-C144-6.
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Esgalhado, Marília Maria Fontelas Simões. "Doenças auto-imunes : vasculite de Wegener." Master's thesis, 2017. http://hdl.handle.net/10400.26/20245.
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Dissertação para obtenção do grau de Mestre no Instituto Superior de Ciências da Saúde Egas MonizA vasculite de wegener ou granulomatose com poliangeíte, é uma patologia que têm como característica a inflamação e necrotização dos pequenos vasos, como os capilares. A sua etiologia é desconhecida, contudo existem suspeitas de mecanismos envolvidos nesta inflamação, como o caracter genético e imunológico. Esta tem como característica a presença de anticorpos ANCA, que atuam sobre os neutrófilos, e desencadeiam uma resposta inflamatória constante. A manifestação desta patologia pode advir de fatores internos ou externos, sendo assim classificada como primária ou secundária, respetivamente. Esta pode ser classificada como vasculite primária, quando os fatores que desencadeiam esta patologia são internos e não existe nenhuma razão específica para o aparecimento das manifestações clínicas, e secundária quando existem fatores externos como infeções, que desencadeiam o processo inflamatório. As manifestações clínicas da vasculite de wegener, podem manifestar-se através de todo o organismo, devido à presença de pequenos vasos, contudo as mais comuns são no sistema respiratório, principalmente a hemorragia pulmonar. O diagnóstico é difícil e geralmente pouco precoce e depende não só dos dados laboratoriais e imagiológicos, como do histórico clínico do doente e da familiarização do clínico com esta patologia. O diagnóstico tardio, irá dificultar o prognóstico do doente. O tratamento desta patologia, é individualizada e têm como base a administração de glucocorticóides e ciclofosfamida, no entanto, esta poderá ser alterada consoante o doente e a severidade das manifestações.
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Figueiredo, Carolina Silva. "Glomerulonefrite pauci-imune ANCA+." Master's thesis, 2017. http://hdl.handle.net/10451/31047.
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Trabalho Final do Curso de Mestrado Integrado em Medicina, Faculdade de Medicina, Universidade de Lisboa, 2017A vasculite associada a ANCA é um tipo de vasculite que envolve predominantemente os pequenos vasos em qualquer órgão. Os ANCA (antineutrophil cytoplasmic antibody) são anticorpos citoplasmáticos anti-neutrófilos, envolvidos nos mecanismos patogénicos da doença. A Granulomatose com Poliangeíte (GPA) é um subtipo de VAA, caraterizada por necrose, inflamação granulomatosa e vasculite, que ocorre preferencialmente no aparelho respiratório e rins, mas que pode envolver qualquer órgão. Apesar da etiologia de GPA permanecer desconhecida, acredita-se que tenha uma base autoimune e que seja despoletada por eventos ambientais em indivíduos geneticamente suscetíveis. Clinicamente, a GPA apresenta lesões com um espectro morfológico alargado. O acrónimo ELK é usado para descrever o comum envolvimento clínico do ouvido, nariz e garganta (ENT), pulmão (L) e rim (K). Os sintomas constitucionais estão geralmente presentes. O diagnóstico de GPA baseia-se na combinação de sintomas e sinais clínicos, dados laboratoriais e achados histológicos. O padrão ANCA típico associado à GPA é o c-ANCA reconhecedor do auto-antigénio PR3. Apesar do teste ANCA ser altamente específico, a biopsia renal continua a ser fundamental para a confirmação diagnóstica e para aferir a gravidade do envolvimento renal, o prognóstico e a intervenção terapêutica. O tratamento da GPA melhorou grandemente a taxa de sobrevida destes doentes e compreende doses altas de corticoesteroides em combinação com ciclofosfamida como terapia de indução, enquanto que para a terapia de manutenção, a azatioprina é o fármaco de escolha. O caso clinico apresentado refere-se a um doente com GPA com envolvimento predominante do pulmão e rim. A lesão renal sob forma de glomerulonefrite rapidamente progressiva permitiu, em conjunto com o historial clínico do doente, enquadrar a lesão renal no contexto de GPA e instituir terapêutica dirigida com sucesso.
ANCA-associated vasculitides is a type of vasculitis that predominantly involves small vessels in any organ. ANCA (antineutrophil cytoplasmic antibody) are anti-neutrophil cytoplasmic antibodies involved in the pathogenic mechanisms of the disease. GPA is a subtype of AAV, characterized by necrosis, granulomatous inflammation and vasculitis, that occurs preferentially in upper and lower respiratory tract system and in the kidneys, but may involve any organ. Although the etiology of GPA remains unknown, it is believed to have an autoimmune basis and may be triggered by environmental events in genetically susceptible individuals. Clinically, GPA’s manifestations are part of a wide morphological spectrum. The acronym ELK is used to describe the clinical involvement of the ear, nose and throat (ENT), lung (L) and kidney (K). Constitutional symptoms are commonly present. The diagnosis of GPA is based on the combination of symptoms and clinical signs, laboratory data and histological findings. The typical ANCA pattern associated with GPA is the c-ANCA recognizing the PR3 auto-antigen. Although the ANCA test is highly specific, renal biopsy remains essential for diagnostic confirmation and for assessing the severity of renal involvement, prognosis and a therapeutic approach. GPA treatment greatly improved the survival rate of these patients and consists of high doses of corticosteroids in combination with cyclophosphamide as induction therapy, whereas for maintenance therapy, azathiophrine is the drug of choice. The presented clinical case refers to a GPA disease with a predominant involvement of the lung and kidney. Renal damage as a rapidly progressive glomerulonephritis allowed, with the prior clinical history, setting the renal lesion in the context of GPA disease and to institute successful targeted therapy.
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Gomes, Margarida A. Pereira. "Granulomatose com poliangeíte." Master's thesis, 2014. http://hdl.handle.net/10451/24364.
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Trabalho Final do Curso de Mestrado Integrado em Medicina, Faculdade de Medicina, Universidade de Lisboa, 2014Vasculitides are systemic diseases characterised by the presence of vascular inflammation. They can be classified according to the American College of Rheumatology Criteria and to the Chapel Hill Consensus Conference Nomenclature of Vasculitides. These do not enable to make the diagnosis, but to place the patients in diagnostic subgroups. The diagnosis is given by a compatible fenotype, specific serology or imagiology and confirmation is set by biopsy. There are different scores that allow the measurement of the severity and damage caused by vasculitides. Granulomatosis with Polyangiitis is an auto-imune disease characterised by granulomatous inflammation of the respiratory airways and renal and pulmonary small vessel vasculitis. It is more common among caucasians and white male in Europe. The symptoms usually start between the ages of 45 and 65. It is associated with the presence of antineutrophil cytoplasmic antibodies (ANCA) aginst proteinase 3, yet its etiology is still unknown. The treatment is based on stage and disease activity. In severe disease it is administrated cyclophosphamide with glucocorticoids, which are then changed to less potent imunosupressors after the induction of remission. There are new biological therapies under investigation.
As vasculites são doenças sistémicas caracterizadas por inflamação vascular. Podem ser classificadas de acordo com critérios definidos pela American College of Rheumatology e pela Nomenclatura da Chapel Hill Consensus Conference. Estas classificações não permitem fazer o diagnóstico, mas sim agrupar os pacientes com vasculite em subgrupos de diagnóstico. O diagnóstico é feito com base num fenótipo compatível, serologia ou imagiologia específicas e confirmação por biópsia. Existem diversos scores que permitem avaliar a severidade e o dano provocado pelas vasculites. A Granulomatose com Poliangeíte é uma doença auto-imune caracterizada geralmente por inflamação granulomatosa das vias respiratórias e vasculite renal e pulmonar de pequenos vasos. É mais comum em caucasianos e na população europeia em homens. O aparecimento dos sintomas ocorre tipicamente entre os 45 e os 65 anos. É associada a anticorpos contra o citoplasma de neutrófilos (ANCA) contra a proteinase 3, contudo a sua etiologia ainda é desconhecida. O tratamento é feito de acordo com o estadio e actividade da doença. Na doença grave é feita a associação de ciclofosfamida e glicocorticóides, com posterior substituição para imunossupressores menos potentes após a indução da remissão. Existem novas terapias biológicas em estudo.
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Remtula, Sofia Piarali. "Granulomatose eosinofílica com poliangeíte : uma doença rara." Master's thesis, 2014. http://hdl.handle.net/10451/24570.
Full textAbstract:
Trabalho Final do Curso de Mestrado Integrado em Medicina, Faculdade de Medicina, Universidade de Lisboa, 2014Eosinophilic Granulomatosis with Polyangiitis is a rare systemic antineutrophil cytoplasmatic antibodies (ANCA) mediated vasculitis that affects small and medium-size vessels. Common clinical manifestations are late-onset asthma, marked blood eosinophilia and systemic necrotizing vasculitis. It can affect any organ with the respiratory system, the peripheral nervous system and the skin being the most frequently implicated.Treatment of Eosinophilic Granulomatosis with Polyangiitis is based in corticosteroids and immunosuppressive drugs and depends on disease severity.The correct management of this clinical condition is extremely important since the outcome greatly improves when the treatment is done timely and appropriately.
A Granulomatose Eosinofílica com Poliangeíte (GEP) é uma vasculite sistémica rara mediada por antineutrophil cytoplasmatic antibodies (ANCA) que afecta pequenos e médios vasos. As manifestações clínicas mais comuns são asma de início tardio, eosinofilia marcada e vasculite sistémica necrotizante. Pode atingir qualquer órgão, sendo os sistemas respiratório, nervoso periférico e a pele os mais comumente envolvidos. Os corticosteróides e os agentes imunosupressores constituem a base da terapêutica da Granulomatose Eosinofílica com Poliangeíte que é determinada de acordo com os critérios de gravidade. O tratamento desta entidade clínica é de extrema importância uma vez que o prognóstico melhora consideravelmente quando este é feito atempada e adequadamente.