Striking the Right Balance in Anti-neutrophil Cytoplasmic Antibody-Associated Vasculitis This symposium took place on 4th June 2021, as part of the European Alliance of Associations for Rheumatology (EULAR) virtual congress Speakers: Benjamin Terrier,¹ Joanna Robson,² Bernhard Hellmich³ 1. University of Paris and Hôpital Cochin, France 2. University of the West of England and Bristol Royal Infirmary, UK 3. University of Tübingen, Germany Disclosure: Terrier has been an advisory board member and/or received consulting fees/ travel expenses from AstraZeneca, Chugai, Grifols, GlaxoSmithKline, Janssen, LFB, Octapharma, Roche, and Vifor Pharma. Robson has received speaker’s fees from Roche and Vifor Pharma; and research support from Vifor Pharma. Hellmich has been an investigator in clinical trials for Ab2Bio, AbbVie, AstraZeneca, Bristol- Myers Squibb, Chemocentrix, GlaxoSmithKline, InflaRx, Kiniksa, Nippon Kayaku, Novartis, Roche, and Sanofi. He has acted as a consultant, advisory board member, and/or lecturer for AbbVie, Bristol-Myers Squibb, Boehringer Ingelheim, Chugai, GlaxoSmithKline, InflaRx, Novartis, Pfizer, Roche, and Vifor Pharma. He is also a member of the Guideline Committees for European Alliance of Associations for Rheumatology (EULAR) and the German Society of Rheumatology (DGRh). Acknowledgements: Writing assistance was provided by Helen Boreham. Support: The publication of this article was funded by Vifor Pharma. The views and opinions expressed are those of the presenters. Content was reviewed by Vifor Pharma for medical accuracy. Citation: Rheumatol. 2021;8[1]:43-50. Meeting Summary Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) causes irreversible short- and long-term damage to vital organs, particularly the kidneys and lungs. Current standard of care (SOC) for AAV, of which glucocorticoids (GC) are a lynchpin, has a number of important limitations: responses to therapy are variable, some patients fail to achieve and sustain remission, and treatment related adverse events (AE) are common. GCs in particular carry a heavy toxicity burden leading to increased organ damage and other serious AEs, as well as negatively impacting patients’ quality of life. During this symposium, leading vasculitis experts considered how to strike the right balance in AAV and achieve the dual clinical priorities of sustained disease control and minimisation of treatment-related toxicity. The emerging evidence for alternative complement pathway activation in AAV disease pathogenesis and its investigation as a potential therapeutic target were also discussed, with promising results from the landmark Phase III ADVOCATE trial having recently demonstrated the non-inferiority of the novel C5a-inhibitor avacopan versus SOC at Week 26 and the superiority at Week 52. Creative Commons Attribution-Non Commercial 4.0 JULY 2021 • RHEUMATOLOGY 43 The Pathogenesis of Vascular The neutrophil antigen PR3 has also been proven to play a key role in the inflammatory Lesions and the Alternative process that underpins AAV. Patients with AAV Complement Pathway show constitutive expression of membrane PR3 (mPR3), which acts as a danger signal Benjamin Terrier for macrophages and disrupts immune signalling. Apoptotic neutrophils expressing AAV are a type of small-vessel necrotising mPR3 induce a proinflammatory response by vasculitis that manifest as systemic diseases, macrophages, which then induces maturation with pulmonary; ear, nose, and throat; and renal and activation of dendritic cells, creating a involvement. The key pathological feature of favourable microenvironment for the persistence AAV is the presence of ANCA, which can target of inflammation.11-13 two neutrophil antigens, myeloperoxidase (MPO) and proteinase 3 (PR3). Granulomatosis The complement pathway has emerged as with polyangiitis is more commonly associated another potential culprit with a role in AAV with PR3, while microscopic polyangiitis and pathophysiology. In a murine model of MPO- eosinophilic granulomatosis with polyangiitis ANCA vasculitis induced by intravenous (previously known as Churg-Strauss) are typically injection of MPO-ANCA, mice pre-treated with associated with the MPO serotype. cobra venom factor (a toxin that depletes complement) did not develop renal disease.14 Terrier discussed how the pathogenic role This clearly illustrates the critical importance of of MPO-ANCA was first demonstrated two the complement pathway in disease initiation, decades ago. Treatment of mice with MPO- noted Terrier. Further work in mice with a ANCA purified from MPO-deficient mice or via different genetic background showed that those transfer of splenocytes into immunodeficient missing genes from the alternative complement mice was shown to induce a glomerular pathway, particularly C5 or factor B, were nephritic disease after 6 days. The glomeruli of protected from developing vasculitis in the these mice exhibited a fibrinoid necrosis with kidney, suggesting that ANCA-stimulated crescents with very few IgG deposits, indicating neutrophils release factors, which activate a pauci-immune glomerular nephritis as seen in complement via the alternative pathway.14 Mice the human disease.1 with deleted C5a pathway genes, particularly those coding for the C5a receptor, were similarly Further work then set out to explore the role of protected from MPO-ANCA glomerular nephritis neutrophils in disease pathology. An important and animals treated with CCX168, a molecule genome-wide association study demonstrated that specifically inhibits the C5a receptor, that there is a distinct genetic background developed less severe forms of the disease as according to ANCA specificity, with PR3 ANCA evidenced by decreased haematuria, proteinuria, patients, but not MPO-ANCA patients, showing and leukocyturia.15 polymorphisms of key genes encoding α-1 antitrypsin and PR3.2 Neutrophils have also Research into AAV also has probed the been established as a key effector of endothelial interaction between activated neutrophils and damage in AAV. Analysis of the characteristics of factor H. TNF-primed neutrophils exhibit a strong inflammatory reaction when bound to neutrophils in patients with AAV revealed specific endothelial cells, including respiratory burst gene expression profiles, specifically disturbed and degranulation. Binding factor H to these epigenetic control of PR3/MPO expression.3-5 In neutrophils acts to inhibit ANCA-induced vitro data demonstrated that MPO and PR3 are neutrophil activation. However, in patients with able to induce a proinflammatory environment AAV, factor H displays a deficient ability to in endothelial cells, including the production bind to neutrophils and inhibit their ANCA- of proinflammatory cytokines, while in vivo induced activation.16 experiments have shown that ANCA is able to stabilise the endothelial adhesion of neutrophils Integrating all of these different mechanistic and increase their transmigration, thereby aspects gives a clear insight into the driving inflammation.6-10 interconnected role of ANCA, neutrophils, and 44 RHEUMATOLOGY • JULY 2021 EMJ complement in AAV.17 Activation of neutrophils by From a historical perspective, mortality cytokines or C5a induces membrane expression of remained high when GCs were the only available MPO/PR3 antigens. These primed neutrophils treatments for AAV.19 Today, the increased risk then undergo activation by ANCA, inducing of infection associated with high-dose GCs an oxidative burst and endothelial damage. remains a key concern for clinicians and is Activated neutrophils in turn release factors that underscored by data from observational studies. activate the alternative complement pathway, A Japanese study showed that patients on high- leading to production of C5a and further dose GCs had a 50% cumulative incidence of amplification of the inflammatory response. The severe infections over the course of 1 year.20 result is a positive inflammatory feedback loop.17 In another retrospective, multicentre study Terrier noted that, from a therapeutic perspective, (n=114) from Europe and the USA, intravenous targeting activation of the alternative methylprednisolone significantly increased the complement pathway, in particular the key C5a/ risk of infection during the first 3 months (hazard C5a receptor interaction, could be clinically ratio: 2.7; 95% confidence interval: 1.4–5.3), even 21 beneficial and is one of the primary approaches after adjustment for confounding factors. currently under evaluation. Evidence from this same study also showed no benefit of methylprednisolone pulses versus Overall, Terrier concluded that emerging standard-dose GC therapy in terms of survival, evidence from murine models, human correlation renal recovery, or relapses.21 studies, and data from randomised controlled Robson showcased data from a recent trials support a key role for the alternative systematic literature review of 91 studies complement pathway in AAV. There are (published between 2000 and 2020), which also strong interactions between neutrophil included 18 randomised controlled trials and activation and their ability to activate the encompassed over 10,000 patients with AAV, complement pathway, creating the possibility of highlighting the severe AEs associated with combination therapies that target both. Potential GC use. Infections were found to be the therapeutic targets within the complement overwhelming risk, noted Robson, but other pathway include blockade of complement severe AEs were also of concern such