On the pathogenesis and clinical outcome of ANCA-associated vasculitis

Antineutrophil 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. LUMC / Geneeskund

ANCA-associated vasculitis – Should we change the standard of care?

Collaborative clinical trials over the last 25 years have revolutionised the care of patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis. This has led to production of management recommendations and standards of care. This paper reviews the existing standards and the recent evidence that has fed further evolution of standards of care. Pattern recognition remains vital to early diagnosis and therefore initiation treatment. While cyclophosphamide remains the treatment of choice, the advent of rituximab has been shown to be beneficial to patients with relapsing disease. It may be safer in young females and those with a risk of urothelial cancers. Methotrexate and mycophenolate mofetil may not be as good as previously thought for inducing remission. Azathioprine and rituximab are the standards for remission maintenance. There have been recent changes to the nomenclature of vasculitides. It is possible that these will continue to evolve over time to make them more meaningful and inform treatment and prognosis. In the absence of gold-standard biomarkers, we discuss the role of ANCA and histopathology, especially in the Indian setting. Follow-up and monitoring of these patients should include structured evaluation using validated clinical tools, assessing cardiovascular risk, vigilance for infections and other co-morbidities due to exposure to glucocorticoids and immunosuppression

Intertwin membrane perforation and umbilical cord entanglement after laser surgery for twin-twin transfusion syndrome: prevalence, risk factors and outcome

Introduction: Perforation of the intertwin membrane can occur as a complication of fetoscopic laser surgery for twin-twin transfusion syndrome (TTTS). Data on the occurrence and the risk of subsequent cord entanglement is limited. The objective of this study is to assess the prevalence, risk factors and outcome of intertwin membrane perforation and cord entanglement after laser surgery for TTTS. Methods: In this multicenter retrospective study, we included all TTTS pregnancies treated with laser surgery in two fetal therapy centers, Shanghai (China) and Leiden (The Netherlands) between 2002 and 2020. We evaluated the occurrence of intertwin membrane perforation and cord entanglement after laser, based on routine fortnightly ultrasound examination and investigated the risk factors and the association with adverse short- and long-term outcome. Results: Perforation of the intertwin membrane occurred in 118 (16%) of the 761 TTTS pregnancies treated with laser surgery and was followed by cord entanglement in 21% (25/118). Perforation of the intertwin membrane was associated with higher laser power settings, 45.8 Watt versus 42.2 Watt (p=0.029) and a second fetal surgery procedure 17% versus 6% (p<0.001). The group with intertwin membrane perforation had a higher rate of caesarean section (77% versus 31%, p<0.001) and a lower gestational age at birth (30.7 versus 33.3 weeks of gestation, p<0.001) compared to the group with an intact intertwin membrane. Severe cerebral injury occurred more often in the group with intertwin membrane perforation, 9% (17/185) versus 5% (42/930) respectively (p=0.019). Neurodevelopmental outcome at two years of age was similar between the groups with and without perforation of the intertwin membrane and between the subgroups with and without cord entanglement. Conclusion: Perforation of the intertwin membrane after laser occurred in 16% of TTTS cases treated with laser and led to cord entanglement in at least one in five cases. Intertwin membrane perforation was associated with a lower gestational age at birth and a higher rate of severe cerebral injury in surviving neonates.Research into fetal development and medicin

Genetic Variants in Antineutrophil Cytoplasmic Antibody-Associated Vasculitis: A Bayesian Approach and Systematic Review.

A number of genome-wide association studies (GWASs) and meta-analyses of genetic variants have been performed in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis. We reinterpreted previous studies using false-positive report probability (FPRP) and Bayesian false discovery probability (BFDP). This study searched publications in PubMed and Excerpta Medica Database (EMBASE) up to February 2018. Identification of noteworthy associations were analyzed using FPRP and BFDP, and data (i.e., odds ratio (OR), 95% confidence interval (CI), p-value) related to significant associations were separately extracted. Using filtered gene variants, gene ontology (GO) enrichment analysis and protein⁻protein interaction (PPI) networks were performed. Overall, 241 articles were identified, and 7 were selected for analysis. Single nucleotide polymorphisms (SNPs) discovered by GWASs were shown to be noteworthy, whereas only 27% of significant results from meta-analyses of observational studies were noteworthy. Eighty-five percent of SNPs with borderline p-values (5.0 × 10-8 < p < 0.05) in GWASs were found to be noteworthy. No overlapping SNPs were found between PR3-ANCA and MPO-ANCA vasculitis. GO analysis revealed immune-related GO terms, including "antigen processing and presentation of peptide or polysaccharide antigen via major histocompatibility complex (MHC) class II", "interferon-gamma-mediated (IFN-γ) signaling pathway". By using FPRP and BFDP, network analysis of noteworthy genetic variants discovered genetic risk factors associated with the IFN-γ pathway as novel mechanisms potentially implicated in the complex pathogenesis of ANCA-associated vasculitis

ANCA-associated vasculitis.

The anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAVs) are a group of disorders involving severe, systemic, small-vessel vasculitis and are characterized by the development of autoantibodies to the neutrophil proteins leukocyte proteinase 3 (PR3-ANCA) or myeloperoxidase (MPO-ANCA). The three AAV subgroups, namely granulomatosis with polyangiitis (GPA), microscopic polyangiitis and eosinophilic GPA (EGPA), are defined according to clinical features. However, genetic and other clinical findings suggest that these clinical syndromes may be better classified as PR3-positive AAV (PR3-AAV), MPO-positive AAV (MPO-AAV) and, for EGPA, by the presence or absence of ANCA (ANCA+ or ANCA-, respectively). Although any tissue can be involved in AAV, the upper and lower respiratory tract and kidneys are most commonly and severely affected. AAVs have a complex and unique pathogenesis, with evidence for a loss of tolerance to neutrophil proteins, which leads to ANCA-mediated neutrophil activation, recruitment and injury, with effector T cells also involved. Without therapy, prognosis is poor but treatments, typically immunosuppressants, have improved survival, albeit with considerable morbidity from glucocorticoids and other immunosuppressive medications. Current challenges include improving the measures of disease activity and risk of relapse, uncertainty about optimal therapy duration and a need for targeted therapies with fewer adverse effects. Meeting these challenges requires a more detailed knowledge of the fundamental biology of AAV as well as cooperative international research and clinical trials with meaningful input from patients

On the pathogenesis and clinical outcome of ANCA-associated vasculitis

Antineutrophil 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. </table

Histopathological classification of antineutrophil cytoplasmic antibody-associated glomerulonephritis: an update

IP1AImmunopathology of vascular and renal diseases and of organ and celltransplantatio