Comparison of outcomes using the rituximab originator MabThera with the biosimilar Truxima in patients with ANCA-associated vasculitis

Objectives: The use of rituximab (MabThera®), an anti-CD20 monoclonal antibody, is the most significant development in the management of anti-neutrophil cytoplasm antibody (ANCA)-associated vasculitis (AAV) since the introduction of cytotoxic therapy in 1950. Truxima® is the first anti-CD20 biosimilar approved for the same indications, and has been available in the UK since 2017. Significant cost savings have been reported when switching to biosimilars, which could lead to greater patient access to such treatment. Therefore, it is important to know whether patients’ clinical and laboratory parameters respond equally well to biosimilars as to reference medicines, tested in clinical trials. Method: We retrospectively reviewed the clinical outcomes and laboratory parameters in 257 consecutive patients treated with anti-CD20 depletion therapy using MabThera or Truxima, for induction and maintenance of remission, in two tertiary renal centres between 2010 and 2019. Results: We demonstrated no difference between patients treated with MabThera or Truxima in rates of remission, relapse, and hospitalization with infection when used for either induction or maintenance of remission of AAV. In one hospital subgroup analysis, we showed comparable levels of hypogammaglobulinaemia, B-cell depletion, and frequency of infusion reactions, with no significant differences. Conclusion: The efficacy and safety of the rituximab biosimilar Truxima are not inferior to the originator MabThera in patients with AAV. Truxima represents a cheaper and safe therapeutic alternative that could increase patient access to rituximab

Therapeutic Myeloperoxidase Inhibition Attenuates Neutrophil Activation, ANCA-Mediated Endothelial Damage, and Crescentic GN

BACKGROUND: Myeloperoxidase released after neutrophil and monocyte activation can generate reactive oxygen species, leading to host tissue damage. Extracellular glomerular myeloperoxidase deposition, seen in ANCA-associated vasculitis, may enhance crescentic GN through antigen-specific T and B cell activation. Myeloperoxidase-deficient animals have attenuated GN early on, but augmented T cell responses. We investigated the effect of myeloperoxidase inhibition, using the myeloperoxidase inhibitor AZM198, to understand its potential role in treating crescentic GN. METHODS: We evaluated renal biopsy samples from patients with various forms of crescentic GN for myeloperoxidase and neutrophils, measured serum myeloperoxidase concentration in patients with ANCA-associated vasculitis and controls, and assessed neutrophil extracellular trap formation, reactive oxygen species production, and neutrophil degranulation in ANCA-stimulated neutrophils in the absence and presence of AZM198. We also tested the effect of AZM198 on ANCA-stimulated neutrophil-mediated endothelial cell damage in vitro, as well as on crescentic GN severity and antigen-specific T cell reactivity in the murine model of nephrotoxic nephritis. RESULTS: All biopsy specimens with crescentic GN had extracellular glomerular myeloperoxidase deposition that correlated significantly with eGFR and crescent formation. In vitro, AZM198 led to a significant reduction in neutrophil extracellular trap formation, reactive oxygen species production, and released human neutrophil peptide levels, and attenuated neutrophil-mediated endothelial cell damage. In vivo, delayed AZM198 treatment significantly reduced proteinuria, glomerular thrombosis, serum creatinine, and glomerular macrophage infiltration, without increasing adaptive T cell responses. CONCLUSIONS: Myeloperoxidase inhibition reduced neutrophil degranulation and neutrophil-mediated endothelial cell damage in patients with ANCA-associated vasculitis. In preclinical crescentic GN, delayed myeloperoxidase inhibition suppressed kidney damage without augmenting adaptive immune responses, suggesting it might offer a novel adjunctive therapeutic approach in crescentic GN

Binding Truths: Atypical anti-GBM disease mediated by IgA anti-GBM antibodies targeting the α1 chain of type IV collagen

Anti−glomerular basement membrane (anti-GBM) disease presents with rapidly progressive glomerulonephritis, often associated with alveolar hemorrhage and characterized histologically by crescentic glomerulonephritis. Typically, there is linear deposition of Ig along the glomerular basement membrane (GBM), which, in the majority of cases, is due to IgG autoantibodies directed against the noncollagenous domain of the α3 chain of type IV collagen (α3[IV]NC1).1 Early disease recognition relies on detecting circulating IgG anti-GBM antibodies in serum samples. However, conventional assays do not detect IgA antibodies or those directed against other target antigens, including α5(IV) found in some Alport disease patients following renal transplantation.2 The presence and specificity of the antibody can be confirmed by Western blotting, usually at a reference center, although this is not routinely performed. We describe a case of anti-GBM disease mediated by IgA anti-GBM antibodies not detected by standard serological tests, and suggest a method of detection and monitoring that can be used in the right clinical context

Risk factors for severe outcomes in patients with systemic vasculitis & COVID‐19: a bi‐national registry‐based cohort study

OBJECTIVE: COVID-19 is a novel infectious disease with a broad spectrum of clinical severity. Patients with systemic vasculitis have an increased risk of serious infections and so may be at risk of severe outcomes following COVID-19. It is important to establish the risk factors for severe COVID-19 outcomes in these patients, including the impact of immunosuppressive therapies. METHODS: A multi-centre cohort was developed through the participation of centres affiliated with national UK and Ireland vasculitis registries. Clinical characteristics and outcomes were described. Logistic regression was used to evaluate associations between potential risk factors and severe COVID-19 outcome, defined as a requirement for advanced oxygen therapy, invasive ventilation, or death. RESULTS: Sixty-five cases of patients with systemic vasculitis who developed COVID-19 were reported (median age 70 years, 49% female) of whom 25 (38%) experienced a severe outcome. Most cases (55/65, 85%) had ANCA-associated vasculitis (AAV). Almost all patients required hospitalization (59/65, 91%), 7 patients (11%) were admitted to intensive care and 18 patients (28%) died. Background glucocorticoid therapy was associated with severe outcome (adjusted odds ratio [aOR] 3.7 (1.1-14.9, p=0.047)) as was comorbid respiratory disease (aOR 7.5 (1.9-38.2, p=0.006)). Vasculitis disease activity and non-glucocorticoid immunosuppression were not associated with severe outcome. CONCLUSION: In patients with systemic vasculitis, glucocorticoid use at presentation and comorbid respiratory disease were associated with severe outcomes in COVID-19. These data can inform clinical decision making relating to risk of severe COVID-19 in this vulnerable patient group

Involvement of the p62/NRF2 signal transduction pathway on erythrophagocytosis

This deposit is composed by the main article plus the supplementary materials of the publication.Erythrophagocytosis, the phagocytic removal of damaged red blood cells (RBC), and subsequent phagolysosome biogenesis are important processes in iron/heme metabolism and homeostasis. Phagolysosome biogenesis implies the interaction of nascent phagosomes with endocytic compartments and also autophagy effectors. Here, we report that besides recruitment of microtubule-associated protein-1-light chain 3 (LC3), additional autophagy machinery such as sequestosome 1 (p62) is also acquired by single-membrane phagosomes at very early stages of the phagocytic process and that its acquisition is very important to the outcome of the process. In bone marrow-derived macrophages (BMDM) silenced for p62, RBC degradation is inhibited. P62, is also required for nuclear translocation and activation of the transcription factor Nuclear factor E2-related Factor 2 (NRF2) during erythrophagocytosis. Deletion of the Nrf2 allele reduces p62 expression and compromises RBC degradation. In conclusion, we reveal that erythrophagocytosis relies on an interplay between p62 and NRF2, potentially acting as protective mechanism to maintain reactive oxygen species at basal levels and preserve macrophage homeostasis.Fundação para a Ciência e a Tecnologia grants: (HMSP-ICT/0024/2010, UID/Multi/04462/2013, SFRH/BD/62197/2009, SFRH/BD/90258/2012, SFRH /BD/51877/2012, SFRH/BD/52293/2013, PTDC/SAU-TOX/116627/2010, HMSP-ICT/0022/2010 ); European Union FEDER support: (COMPETE, QREN, PT2020 Partnership Agreement), ERC grant: (ERC-2011-AdG 294709-DAMAGECONTROL).info:eu-repo/semantics/publishedVersio

Risk Factors for Severe Outcomes in Patients With Systemic Vasculitis and COVID‐19: A Binational, Registry‐Based Cohort Study

Funder: Vifor Pharma; Id: http://dx.doi.org/10.13039/501100006484Objective: COVID‐19 is a novel infectious disease with a broad spectrum of clinical severity. Patients with systemic vasculitis have an increased risk of serious infections and may be at risk of severe outcomes following COVID‐19. We undertook this study to establish the risk factors for severe COVID‐19 outcomes in these patients, including the impact of immunosuppressive therapies. Methods: A multicenter cohort was developed through the participation of centers affiliated with national UK and Ireland vasculitis registries. Clinical characteristics and outcomes are described. Logistic regression was used to evaluate associations between potential risk factors and a severe COVID‐19 outcome, defined as a requirement for advanced oxygen therapy, a requirement for invasive ventilation, or death. Results: The cohort included 65 patients with systemic vasculitis who developed COVID‐19 (median age 70 years, 49% women), of whom 25 patients (38%) experienced a severe outcome. Most patients (55 of 65 [85%]) had antineutrophil cytoplasmic antibody–associated vasculitis (AAV). Almost all patients required hospitalization (59 of 65 [91%]), 7 patients (11%) were admitted to intensive care, and 18 patients (28%) died. Background glucocorticoid therapy was associated with severe outcomes (adjusted odds ratio [OR] 3.7 [95% confidence interval 1.1–14.9]; P = 0.047), as was comorbid respiratory disease (adjusted OR 7.5 [95% confidence interval 1.9–38.2]; P = 0.006). Vasculitis disease activity and nonglucocorticoid immunosuppressive therapy were not associated with severe outcomes. Conclusion: In patients with systemic vasculitis, glucocorticoid use at presentation and comorbid respiratory disease were associated with severe outcomes in COVID‐19. These data can inform clinical decision‐making relating to the risk of severe COVID‐19 in this vulnerable patient group