The paradigm shift in ANCA-associated vasculitis: prime time for the complement targeting

This editorial refers to ‘CanVasc consensus recommendations for the use of avacopan in antineutrophil cytoplasm antibody-associated vasculitis: 2022 addendum’, by Turgeon et al. 2023;62:2646–51. Treatment of ANCA-associated vasculitis (AAV) has changed in recent years [1]. Despite that, AAV is still characterized by an excess of mortality compared with the general population, with treatment-induced toxicity and organ damage (in particular, residual chronic kidney disease) being two of the main determinants [2]. There is therefore a strong need for new therapeutic strategies as well as a need for high responsiveness of national and international societies for quick updating of established guidelines when significant changes in the therapeutic scenario arises. Turgeon et al. [3] recently modified the Canadian Vasculitis Research Network (CanVasc) consensus recommendations by adding three new statements on avacopan therapy based on newly available evidence. Specifically, the authors developed these three new recommendations: The addition of oral avacopan (30 mg twice daily) can be considered for induction of remission in patients with newly diagnosed or relapsing GPA or MPA treated with CYC or RTX. After starting avacopan, a faster GC tapering protocol aiming for discontinuation by the end of week 4 should be considered. When initiated as part of induction therapy, avacopan can be continued for 1 year. The international phase 3, placebo-controlled ADVOCATE trial [4] demonstrated that avacopan, in addition to standard-of-care (SoC) therapy with RTX or CYC, was non-inferior to glucocorticoid (GC) in inducing remission at week 26 and superior to GC in sustaining remission at week 52. These results, together with the PEXIVAS study [5] and retrospective experiences of induction regimens combining RTX and CYC [6], radically change the prominent role of GCs in disease management and argue that ‘reduced’ GC treatment is possible in AAV. The avacopan story is indeed a nice example of a quick and effective translation from the bench to the bedside of a novel drug targeting a pathway that only recently has emerged as central in AAV pathogenesis. By blocking C5a receptor 1, avacopan stops in advance the ability of inflammatory cells, such as neutrophils, to cause damage in response to C5a activation. In fact, C5a primes neutrophils for subsequent ANCA-induced activation by upregulating the surface expression of the MPO and PR3 antigens. In murine models, genetic deletion of C5 (or a C5-inhibiting monoclonal antibody) has been shown to prevent necrotizing crescentic glomerulonephritis triggered by anti-MPO antibodies [7]. Furthermore, murine models have also demonstrated that the alternative complement pathway (but not the classic or lectin pathway) plays a crucial role in the pathogenesis of AAV: only factor B knockout mice showed no necrotizing crescentic glomerulonephritis, whereas C4 knockout mice developed disease similar to the wild-type mice [7]. In the ADVOCATE study, the mean and median GC burden of all sources was reduced by 63% and 86%, respectively, in the avacopan group compared with the GC group [4], leading to a substantial reduction in GC toxicity in all domains [4]. In a real-life setting, the beneficial effects and safety profile of avacopan have been confirmed, even in difficult-to-treat patients, although still in small numbers [8]. No less importantly, the reduction of cumulative GC exposure may globally improve the health-related quality of life of AAV patients [9]. Due to its compelling safety profile, in the era of alternative treatment to GC, avacopan is an attractive option apparently also able to lower relapse risk. In fact, although the study was not designed to answer questions regarding the role of avacopan as an agent for the maintenance of remission, during the 52 weeks of treatment the relapse rate for the group receiving RTX was 8% with avacopan and 20% with GC, as compared with 10% and 21%, respectively, in the group receiving CYC [4]. Particularly interesting is the impact of this new drug on renal function. In fact, avacopan has been shown to induce a continued improvement of kidney function between the 26-week and 52-week timepoints, especially in patients with lower estimated glomerular filtration rate (eGFR) [10]. In the ADVOCATE trial, a total of 50 patients had a baseline eGFR <20 ml/min/1.73 m2, i.e. 27 in the avacopan group and 23 in GC group. At week 52, 11 of 27 patients in the avacopan group had a ≥2-fold increase in eGFR vs 3 of 23 patients in the GC group (P = 0.03). In detail, eGFR increased on average 16.1 and 7.7 ml/min/1.73 m2 in the avacopan and GC groups, respectively (P = 0.003) [10]. Overall, the effect of avacopan appears to support kidney repair and reduce kidney inflammation through 12 months, although the mechanism behind this effect is still unclear. The difference between the avacopan and GC groups in terms of eGFR improvement within the first year is indeed significant and whether, once eGFR is stabilized, this is going to translate into a significant difference of the overall slope of eGFR reduction in the long term needs to be explored. More data are needed to clarify the role of avacopan in extrarenal manifestations. In the ADVOCATE study [4], pulmonary and ENT involvement was present in slightly less than half of the patients, and improved overall in both groups during follow-up. The avacopan group had numerically (but not statistically significant) lower rates of pulmonary and ENT involvement at weeks 26 and 52 compared with the GC group. However, further data will be needed to investigate this issue. Interestingly, in the subgroups analysis, with the limitation of reduced statistical power, while the remission rates at week 26 were similar across the different subgroups explored, at week 52 remission was more frequent in the avacopan group for patients with relapsing disease, ANCA MPO, induced with RTX and with a clinical diagnosis of MPA [4], suggesting the importance of a multitarget therapy (B cell and complement) in difficult-to-treat scenarios. Turgeon et al. [3] also provide a nice research agenda for the future, including 10 clinical questions of high importance that still need to be clarified in order to contribute to better defining the role of avacopan in clinical practice. Among those 10 points, the ideal duration of the treatment with avacopan and how this drug is going to impact the dosing and the schedule of administration of other immunosuppressive drugs are key aspects; in our opinion a significant point would also be to better clarify the mechanisms behind the renal benefits and whether these can be translated in other clinical contexts. In summary, the ADVOCATE trial [4] and real-world data [7] support the efficacy and safety of avacopan as adjunctive therapy in AAV; the significance of the impact of this new drug is such that it will drive the updating of current guidelines. Importantly, a new effective target in AAV has been identified, opening the way for multitarget therapy in AAV. Therefore, patients have a greater chance to improve disease control and quality of life. Data are available upon reasonable request by any qualified researchers who engage in rigorous, independent scientific research, and will be provided following review and approval of a research proposal and Statistical Analysis Plan (SAP) and execution of a Data Sharing Agreement (DSA). All data relevant to the study are included in the article. All the coauthors have made a substantial contribution to the concept of the article; drafted the article and revised it critically for important intellectual content; approved the version to be published; agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. No specific funding was received from any bodies in the public, commercial or not-for-profit sectors to carry out the work described in this article. Disclosure statement: The authors have declared no conflicts of interest.

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