A novel glucocorticoid-free maintenance regimen for anti-neutrophil cytoplasm antibody–associated vasculitis

Pepper, Ruth J.; McAdoo, Stephen P.; Moran, Sarah; Kelly, Dearbhla M.; Scott, Jennifer; Hamour, Sally; Burns, Áine; Griffith, Megan; Galliford, Jack; Levy, Jeremy; Cairns, Thomas; Gopaluni, Seerapani; Jones, Rachel; Jayne, David; Little, Mark A.; Pusey, Charles D.; Salama, Alan D.

doi:10.1093/rheumatology/kez001

Cited by 55 publications

(37 citation statements)

References 28 publications

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“…There is still significant morbidity in vasculitis patients associated with current treatments, and there are also forms of CGN such as IgA nephropathy for which we have limited effective treatments. Glucocorticoid therapy is associated with significant long-term morbidity and recent trials in CGN have been designed to address the need for steroid minimisation (PEXIVAS, CLEAR, ADVOCATE and our recent steroid free maintenance AAV cohort study) [44][45][46][47] .…”

Section: Discussionmentioning

confidence: 99%

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

Antonelou

Michaëlsson

Evans

et al. 2019

JASN

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BackgroundMyeloperoxidase 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.MethodsWe 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.ResultsAll 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.ConclusionsMyeloperoxidase 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.

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Section: Discussionmentioning

confidence: 99%

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

Antonelou

Michaëlsson

Evans

et al. 2019

JASN

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“…There is a paucity of comparative data on the use of either cyclophosphamide or rituximab in patients with low glomerular filtration rate (for example, <20 ml/min/1.73 m 2 ), with a lower dose of cyclophosphamide together with rituximab being used in the RITUXVAS trial 198 . The use of this combination is controversial and may confer an additional risk of infection 199 .…”

Section: Other Immunosuppressive or Immunomodulating Drugsmentioning

confidence: 99%

ANCA-associated vasculitis

Kitching

Anders

Basu

et al. 2020

Nat Rev Dis Primers

591

507

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The anti-neutrophil cytoplasmic antibody (ANCA)associated vasculitides (AAVs) are diseases characterized by inflammation of blood vessels, endothelial injury and tissue damage. The three types of small-vessel vasculitis, namely granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA) and eosinophilic GPA (EGPA; previously known as Churg-Strauss syndrome), feature a loss of tolerance to neutrophil primary granule proteins, most often leukocyte proteinase 3 (PR3; also known as myeloblastin) or myeloperoxidase (MPO) (Table 1). The vessels involved in AAV are typically capillaries, arterioles and venules but small arteries and veins may also be affected. Autoimmunity is documented clinically by serum ANCAs to PR3 (PR3-ANCA) or MPO (MPO-ANCA), which are generally associated with the main syndromic AAV presentations (box 1). AAVs collectively represent one of several types of autoimmune vasculitis (Fig. 1). GPA and MPA can involve small blood vessels in any organ or tissue but commonly affect the upper and lower respiratory tract and the kidneys (box 2). Patients with AAV typically present with severe organ-threatening or life-threatening disease, although less severe presentations also occur. GPA is predominantly associated with PR3-ANCA and its clinical features typically include sinonasal disease, lower respiratory tract involvement with pulmonary haemorrhage and granulomatous inflammation, and glomerulonephritis. MPA is usually associated with MPO-ANCA and clinical features include more severe renal disease and some of the manifestations of GPA but without granulomatous inflammation. EGPA is characterized by asthma, eosinophilia and, in many (but not all) cases, vasculitis. EGPA is less common than GPA or MPA and, in some cases, is associated with ANCAs, mainly MPO-ANCA (Table 1). Although categorized as a form of AAV, EGPA has less overlap with the other AAVs than that between GPA and MPA with regard to its genetic, pathogenetic, and clinical features and its management and is typically considered a separate entity. Improvements in treatment and prognosis for patients with AAV have resulted from the translation of both preclinical and clinical research findings. Here, we provide an updated overview of the clinical and

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“…A two centre cohort study has reported 49 patients who received combination treatment with rituximab and low-dose IV cyclophosphamide and a rapid glucocorticoid taper, approximating a total steroid dose of 1 g administered over 2 weeks. Ninety percent of patients were in sustained remission at 12 months without requiring additional glucocorticoids, and there were reduced rates of serious infections and new onset diabetes compared with historical EUVAS controls [50]. There is also potential for novel therapeutics to replace steroids entirely.…”

Section: Pexivas and Steroidsmentioning

confidence: 99%

Is There a Role for Plasma Exchange in ANCA-Associated Vasculitis?

Prendecki

McAdoo

Pusey

2020

Curr Treat Options in Rheum

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Purpose of review This review summarises the evidence for the use of therapeutic plasma exchange (TPE) in anti-neutrophil cytoplasm antibody (ANCA)–associated vasculitis. TPE is an extra-corporeal treatment which efficiently removes IgG and other pathogenic small molecules from the blood. There are several mechanistic reasons why this should be of benefit in AAV including the well-described pathogenicity of ANCA. Recent findings The recently published PEXIVAS trial is the largest study of TPE in AAV to date. It did not show a benefit for adjunctive TPE on a primary end point of ESRD or death. There was no difference in serious adverse events between those treated with TPE and those treated with immunosuppressive drugs alone. Conclusions Based on the results of PEXIVAS, most patients with AAV should not be treated with adjunctive TPE. However, there are subgroups of patients with AAV for whom TPE may still be of benefit, including those with double positivity for anti-GBM antibodies and ANCA.

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A novel glucocorticoid-free maintenance regimen for anti-neutrophil cytoplasm antibody–associated vasculitis

Cited by 55 publications

References 28 publications

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

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

ANCA-associated vasculitis

Is There a Role for Plasma Exchange in ANCA-Associated Vasculitis?

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