This thesis aimed to understand the humoral autoimmune response and to translate our knowledge to improve the targeting of autoimmunity in AAV and SLE patients. Our studies demonstrate that NETs... Show moreThis thesis aimed to understand the humoral autoimmune response and to translate our knowledge to improve the targeting of autoimmunity in AAV and SLE patients. Our studies demonstrate that NETs have a pivotal role in both AAV and SLE patients. NETs function as autoantigens, can cause direct glomerular inflammation and can be part of immune-complexes in SLE. Importantly, AAV and SLE-induced NETs are disease specific processes that each encompassed their own unique properties. This should be taken into account when evaluating targeting of NETs in AAV and SLE. In SLE patients, NETs could be targeted through reducing the autoantibody repertoire, specifically high avidity anti-dsDNA and anti-C1q autoantibodies that drive immune complex formation. These autoantibodies were effectively targeted by combined treatment with RTX and BLM. During B-cell targeted therapy in AAV and SLE patients, the presence and reoccurrence of autoreactive B-cells and relevant autoantibodies are components of minimal residual autoimmunity (MRA), which often persists after B-cell therapy. Interestingly, both in AAV and SLE, double negative (DN) B-cells have a key role in the humoral autoimmune response and were associated with reoccurrence of autoantibodies. However, it remains to be established how MRA is associated with disease flares and to find the best way to use it as immunomonitoring tool to guide and personalize treatment. Show less
First, we described a method to quantify NETs which has the potential to monitor autoantigen load in the setting of autoimmune diseases where NETs play a role in its pathophysiology. The use of... Show moreFirst, we described a method to quantify NETs which has the potential to monitor autoantigen load in the setting of autoimmune diseases where NETs play a role in its pathophysiology. The use of confocal microscopy with multiple z-stacks, makes it a sensitive method. We provided a context of how NETs can be quantified in SLE and AAV. We demonstrated that not all NETs are created equally and translation of NET formation to a digital quantification creates a narrow view. We showed higher ex vivo NET formation in AAV patients with active disease compared to AAV patients with an underlying infection supporting that excessive NET formation is an autoimmune phenomenon. Also, we demonstrated that the observed excessive NET formation is independent of ANCAs.In the next part of this thesis, we focused on new treatments in lupus nephritis. Most importantly, the results of the Sybiose study are shown; a phase 2 proof-of-concept study that included 15 patients with severe, refractory SLE treated with rituximab and belimumab. We showed that RTX+BLM has the ability to reduce autoantibodies, thereby indirectly reducing excessive NET formation in SLE, presumably due to the targeting of autoreactive B cells. Further, we observed a clinical response in our patients while tapering immunosuppressive medication. Show less
This thesis focuses on renal involvement in ANCA-associated vasculitis (AAV), also named as ANCA-associated glomerulonephritis (AAGN). The studies mainly focus on clinico- and histopathologic... Show moreThis thesis focuses on renal involvement in ANCA-associated vasculitis (AAV), also named as ANCA-associated glomerulonephritis (AAGN). The studies mainly focus on clinico- and histopathologic parameters that are predictive for renal outcome. Predictive parameters for renal relapse in the native kidney are the histopathological classification of AAGN and interstitial infiltrates. The histopathological classification of AAGN is validated and the interobserver variability is investigated. It shows that this classification is predictive for renal outcome regarding the focal and sclerotic class, but needs more refinement for the crescentic and mixed class. The interobserver agreement between pathologists for this classification was moderate. Regarding renal transplantation, this thesis shows that this is a viable treatment option in patients with end-stage renal failure due to AAGN. The risk of renal disease recurrence in the renal graft is low, but once it has occurred, the risk of graft loss is considerable. In addition, this thesis presents an optimized assay for detecting anti-plasminogen autoantibodies in patients with AAV. The presence of these autoantibodies is validated in a cohort. The detection of these autoantibodies is important, because their presence seem to have a predictive value for renal outcome. This thesis also gives an overview of the clinical presentation, diagnosis and management of AAV. Show less
Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), including granulomatosis with polyangiitis (Wegener’s) (GPA) and microscopic polyangiitis (MPA), is a small-to-medium... Show moreAntineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), including granulomatosis with polyangiitis (Wegener’s) (GPA) and microscopic polyangiitis (MPA), is a small-to-medium vessel vasculitis that affect multiple organs and is life-threatening when untreated. In this thesis, several aspects of ANCA-associated vasculitis concerning genetics, clinical and histopathological classification, treatment and long-term outcome were investigated. Show less
ANCA-associated vasculitis (AAV) is a systemic autoimmune disease which is associated with increased risk of mortality and morbidity. The outcomes of patients with AAV have improved... Show moreANCA-associated vasculitis (AAV) is a systemic autoimmune disease which is associated with increased risk of mortality and morbidity. The outcomes of patients with AAV have improved substantially as a consequence of earlier detection of the disease and more sophisticated therapy regimens. Despite these advances, the disease influences the lives of patients substantially. Therefore, this thesis focused on prognosis and outcomes with the aim to further improve the outcomes of patients with AAV. Show less
