Novel Treatment Paradigms: Complement Inhibition in Antineutrophil Cytoplasmic Autoantibody Vasculitis

Abstract

A growing body of evidence has highlighted the critical role of complement activation—particularly through the alternative pathway—in the pathogenesis of antineutrophil cytoplasmic autoantibody (ANCA) vasculitis. Foundational insights first emerged from landmark mouse model studies, which have been further substantiated by findings in human ANCA vasculitis. In addition, measuring complement activation fragments in circulation and urine may correlate with disease activity and may serve as sensitive biomarkers for disease monitoring. C5a and C5a receptor engagement has been shown to be particularly important for mediating disease and has been a central therapeutic target. Avacopan is an oral small molecule C5a receptor antagonist approved as adjunctive therapy to standard treatments for severe active ANCA vasculitis. Studies have shown that avacopan can reduce disease activity, proteinuria, and glucocorticoid exposure; and may even allow for greater kidney recovery in patients with ANCA vasculitis and severe renal insufficiency. Additional therapies targeting various components of the complement cascade are under investigation or in development, generating considerable excitement for novel treatment strategies in ANCA vasculitis. This review discusses key clinical developments and summarizes pivotal clinical trials evaluating complement inhibition in ANCA vasculitis. Although early results suggest that complement inhibitors may offer more effective and safer alternatives to established therapies, there are limitations and barriers that prevent their more widespread use. Further research is needed to better understand their efficacy and long-term safety and to inform how to optimize their integration into treatment paradigms for ANCA vasculitis.

ANCA vasculitis is a dynamic, relapsing-remitting autoimmune disorder targeting various vascular beds with a particular predilection for the kidneys and lungs.^1,2 It is characterized by inflammation of small- to medium-sized blood vessels resulting in significant morbidity and mortality. Central to its pathogenesis are autoantibodies directed against myeloperoxidase (MPO) and proteinase 3 (PR3), which activate neutrophils and monocytes, fueling vascular injury.^3,4 Extensive in vitro studies and animal model research have firmly established that these autoantibodies are not mere biomarkers but active drivers of disease, demonstrating their pathogenic role in initiating vascular damage.5, 6, 7, 8, 9

Autoantibody-mediated activation of neutrophils and monocytes triggers a cascade of innate immune mechanisms that, if left unchecked, result in fibrosis of injured tissue.^7,10 The complement system, a crucial arm of innate immunity, can be activated through 3 distinct pathways—classical, alternative, and lectin—each contributing to inflammatory amplification.¹¹

In this review, we delve into the emerging landscape of novel treatment paradigms that focus on complement inhibition in ANCA vasculitis. We explore the mechanistic rationale behind these approaches, review current clinical developments, and discuss their potential to affect the management of ANCA vasculitis, thereby offering hope for more targeted, effective, and safer therapies for this challenging disease.

Complement Activation in ANCA Vasculitis

The importance of complement activation in ANCA vasculitis was confirmed by a series of pivotal mouse model studies of pauci-immune necrotizing and crescentic glomerulonephritis induced by i.v. injection of mouse antimouse MPO IgG (MPO-ANCA).^12,13 These studies provided evidence that the alternative complement pathway, but not the classical or lectin pathway, was required for inducing MPO-ANCA glomerulonephritis.¹² The evidence that C5a and C5a receptor engagement is an important process remediating ANCA vasculitis comes from 2 different lines of investigation. The first comes from a murine study in which mice deficient in the C5a receptor did not develop anti-MPO–induced glomerulonephritis.¹⁴ Subsequently, the blockade of the C5a receptor with an antagonist that eventually became what we now know as avacopan, ameliorated the disease in a dose-dependent fashion.¹⁵

In Mice, Complement Activation is Critical. What is the Evidence for Complement Activation in Humans?

Complement activation occurs during most inflammatory events. The alternative pathway of complement is constantly activated at low levels through a process known as C3 tickover.^16,17 Systemic complement activation is believed to be important in diseases such as lupus nephritis and cryoglobulinemia where C3 and C4 levels are depressed. However, in conditions such as IgA nephropathy, the role of complement activation, and the potential benefits of therapeutic interventions targeting alternative complement pathway activation in reducing proteinuria, are increasingly evident.¹⁸ Notably, this occurs despite the absence of appreciable clinical changes in circulating C3 or C4. It has been proposed that IgA nephropathy is a tissue-specific autoimmune disease.¹⁹ Similarly, it has been suggested that in ANCA glomerulonephritis, immune complexes form only at the surface and within the microenvironment of primed or activated neutrophils and monocytes.¹³ Such localized inflammation and complement activation do not substantially reduce circulating levels of C3, unlike the marked reduction in C3 seen in lupus nephritis and cryoglobulinemic glomerulonephritis, where there are high levels of circulating immune complexes accompanied by systemic complement activation.

Multiple analyses provide substantial evidence that the alternative complement pathway is actively involved in human ANCA vasculitis. Activation of this pathway leads to the production of fragments, including Bb, C3a, C5a, and sC5b-9, which are significantly elevated during active disease. In patients from a single center with MPO-ANCA glomerulonephritis, plasma levels of these complement activation analytes were significantly elevated during active disease compared with remission.²⁰ Plasma levels of properdin, a positive regulator that stabilizes the C3 convertase of the alternative pathway, decreased during active disease. Moreover, plasma Bb levels correlated with disease severity scores such as the Birmingham Vasculitis Activity Score, erythrocyte sedimentation rate, and the proportion of total and cellular crescents observed in kidney biopsies.²¹ In the first examination of complement activation in patients with PR3–ANCA vasculitis, active disease was associated with increased levels of C3a, C5a, C4d, and sC5b-9 compared with healthy controls.²² Elevated levels of C4d in patients with PR3–ANCA vasculitis was recently confirmed.²³ When considering patients with MPO- and PR3–ANCA serotypes, cross-sectional analyses of complement activation during active disease versus remission vary depending on the cohort. Some studies did not show significant decreases of these analytes during remission.^22,24, 25, 26 Longitudinal studies revealed that levels of C5a, C3a, Bb²⁴, and sC5b-9²² decline during remission compared with active disease within the same patient. Interestingly, C5a may be indicative of long-term, sustained remission after discontinuation of therapy.²² A meta-analysis involving 220 patients further supported ongoing complement activation with reduced levels of C5a and sC5b-9 during remission.²⁴ Urinary markers such as Bb, C3a, C5a, and sC5b-9 are elevated in patients with active ANCA vasculitis compared with disease remission and healthy controls, reflecting complement activation.^21,27 Urinary Ba levels were increased during renal flare.²¹ In summary, there is ample evidence of the role of alternative complement pathway activation in both mice and humans with ANCA vasculitis and implicate their potential as sensitive biomarkers for disease activity.

How is Complement Activated in ANCA Vasculitis?

The answer to this critical question remains conjectural. Multiple in vitro studies demonstrate that ANCA-activated neutrophils degranulate and release reactive oxygen species and toxic granule products (Figure 1). These factors recruit additional neutrophils and monocytes that amplify the inflammatory response.²⁸ Importantly, neutrophils can be activated by a variety of cytokines, and by the anaphylatoxin, C5a. An interesting study showed that C3a- and C5a-conditioned sera increased primed neutrophils for ANCA-induced respiratory reactive oxygen species production, and this respiratory burst was inhibited when the C5a receptor blocker was present.¹⁴

Figure 1.

Complement Inhibition in ANCA vasculitis. The schematic represents the role of complement activation in ANCA vasculitis pathogenesis and potential therapeutic targets. ANCA, antineutrophil cytoplasmic autoantibody; TNF-α, tumor necrosis factor alpha; ROS, reactive oxygen species.

What is the Evidence That Avacopan is Useful in Patients With ANCA Vasculitis?

Initial evidence for the effectiveness and safety of avacopan comes from 2 phase 2 randomized controlled trials. The C5a Receptor Inhibitor Avacopan in ANCA-Associated Vasculitis (CLEAR) trial demonstrated that avacopan significantly reduced glucocorticoid exposure while maintaining adequate disease control.²⁹ The Adjunctive Treatment with Avacopan in Patients with ANCA–Associated Vasculitis (CLASSIC) trial further explored avacopan as an adjunct to standard therapy, establishing 30 mg twice daily as the optimal dose.³⁰

Pivotal evidence stems from the phase 3, randomized, placebo-controlled Avacopan for the Treatment of ANCA-Associated Vasculitis (ADVOCATE) trial, which enrolled 331 patients with ANCA vasculitis.³¹ The patients received either avacopan or prednisone, alongside induction therapy with cyclophosphamide or rituximab. In the avacopan group, prednisone was reduced to 20 mg/d before treatment initiation and tapered off within 4 weeks. Over 26 weeks, patients in the avacopan arm experienced a 71% reduction in cumulative oral prednisone. Importantly, avacopan was noninferior to prednisone for remission at 26 weeks (72.3% vs. 70.1%, respectively) and superior for sustained remission at 52 weeks (65.7% vs. 54.9%, respectively). In addition, patients treated with avacopan showed significant improvement in glucocorticoid-related toxicity, as measured by the glucocorticoid toxicity index.³¹

Based on these findings, clinical guidelines state that avacopan is an option for induction therapy for ANCA vasculitis.³² The 2024 Kidney Disease: Improving Global Outcomes guidelines include avacopan in its list of possible therapeutic strategies as an alternative to glucocorticoids, to be used with rituximab or cyclophosphamide during induction.³³ The rationale for incorporating avacopan is especially compelling when rapid glucocorticoid tapering is desired for patients who may be at greater risk for glucocorticoid-related toxicity. For such patients, some experts have reported on the safety and efficacy of another strategy combining cyclophosphamide with rituximab and no more than 2 weeks of glucocorticoids.³⁴

There are important limitations to the broader benefits and widespread use of avacopan that warrant consideration. Although avacopan is primarily marketed and used as an alternative to glucocorticoids, it does not entirely eliminate their use. For instance, in the ADVOCATE trial, the primary end point (remission Birmingham Vasculitis Activity Score = 0 with no use of glucocorticoids in the 4 weeks prior) was achieved in 72.3% of patients treated with avacopan. This means that nearly 30% of patients did not achieve remission or continued to require glucocorticoids to achieve and sustain remission. In addition, in the avacopan group, there was a mean of 914 mg of oral prednisone used in the first 26 weeks (including prescreening prednisone and not including i.v. methylprednisolone pulses).³¹ Although this amounted to 3123.5 mg of oral prednisone for the prednisone-treated group, patients with avacopan still received a substantial amount of glucocorticoid. Many patients require glucocorticoids for adequate disease control, and the potent antiinflammatory effects from up-front glucocorticoid use should not be underestimated in an often highly inflammatory condition such as ANCA vasculitis. Although glucocorticoid-sparing, avacopan may not be entirely glucocorticoid-avoiding.

Beyond Glucocorticoid-Sparing: Exploring Additional Therapeutic Benefits of Avacopan

Avacopan was approved by the US Food and Drug Administration on the basis of its glucocorticoid-sparing properties. As a practicing physician faced with a patient with ANCA vasculitis, when should one use avacopan? If, as a practice, the use of glucocorticoids is reduced to perhaps only 2 weeks,³⁴ or in our practice where it is removed entirely by 12 to 16 weeks, what would be the evidence for avacopan providing greater benefit as a glucocorticoid-sparing agent? This is especially of concern to patients and the practicing physician because the cost of the drug is substantial and access may be restricted. The question becomes whether there is substantial evidence that avacopan has a role other than as a glucocorticoid-sparing agent?

Avacopan may have a beneficial effect on the recovery of kidney function. In the phase 2 CLASSIC trial, which included 42 patients with systemic vasculitis (27 of whom had kidney involvement), patients receiving prednisone with 30 mg avacopan demonstrated notable improvements in kidney function. Specifically, at 12 weeks, the mean estimated glomerular filtration rate (eGFR) increased by +2.0, +1.3, and +6.2 ml/min per 1.73 m² in the control, avacopan 10 mg, and avacopan 30 mg groups, respectively. Moreover, renal response—defined as an increase in eGFR accompanied by reductions in hematuria and proteinuria—was achieved in 63% of patients receiving avacopan 30 mg, versus only 17% in the control group.³⁰

In the phase 3 ADVOCATE trial, patients treated with avacopan exhibited marginal improvement in eGFR from baseline to 26 and 52 weeks compared with those on prednisone. The difference in change in eGFR from baseline to 52 weeks between avacopan and prednisone was +3.2 ml/min per 1.73 m² (0.3–6.1).³¹ In a subanalysis of patients from the ADVOCATE trial with a baseline eGFR < 30 ml/min per 1.73 m², the difference in change in eGFR was +5.6 ml/min per 1.73 m² (1.7–9.5), and for those with eGFR < 20 ml/min per 1.73 m², it was +8.4 ml/min per 1.73 m² (2.9–13.8), compared with placebo.³⁵ These findings suggest that patients with a lower eGFR may derive some benefit from avacopan in terms of recovery of kidney function.

Although these results are promising, it is important to note that the primary end point of change in kidney function was not the focus of these studies. Individuals with eGFR < 15 ml/min per 1.73 m² on presentation were excluded in the ADVOCATE trial; therefore, subgroup analyses involved relatively small patient numbers without adjustments for multiple comparisons. Nonetheless, they provide at least a positive signal that warrants further dedicated investigation into the role of avacopan in promoting renal recovery, particularly in those with the most perturbed kidney function because they may have the most to benefit.

What is the Evidence That Avacopan Works in Patients With Respiratory Tract Disease?

Preclinical studies offer intriguing, albeit preliminary, insights into the potential effect of avacopan on pulmonary pathology. In a mouse model, deficiency of factor B—an integral component of the alternative complement pathway—did not attenuate lung lesions at all, suggesting that the pathogenic mechanisms involving complement activation in pulmonary lesions may differ from those in kidney lesions.³⁶ Although these findings are from animal models, they highlight the potential variability in complement inhibitor efficacy depending on the underlying disease mechanism and tissue architecture.

Clinical data regarding the impact of avacopan on severe pulmonary manifestations are limited. Individuals with pulmonary hemorrhage requiring mechanical ventilation were excluded from the ADVOCATE trial. A post hoc analysis of 12 patients in ADVOCATE who had diffuse alveolar hemorrhage at baseline (5 in avacopan group, 7 in prednisone group) found remission rates of 80.0% versus 71.4% for avacopan versus prednisone, respectively, at weeks 4 and 26, and of 80.0% and 57.1% at 52 weeks.³⁷ Emerging case reports hint at possible benefits for more severe cases. For instance, a recent series describes 8 patients with hypoxic pulmonary hemorrhage requiring oxygen therapy or mechanical ventilation, all of whom experienced complete resolution with a median of 10 days, along with survival and sustained remission.³⁸ These patients likely had aggressive pulmonary capillaritis, a process pathophysiologically akin to necrotizing glomerulonephritis, suggesting that avacopan may have therapeutic potential in such severe pulmonary conditions. Importantly, the availability of avacopan in intensive care unit settings could enable prompt intervention in critically ill patients. Dedicated studies examining the use of avacopan in severe pulmonary hemorrhage would be helpful to clarify its potential role.

Furthermore, a substudy of the ADVOCATE trial in patients with ear, nose, and throat involvement demonstrated remission rates at 26 weeks that were comparable between avacopan and prednisone taper groups (72% and 71%, respectively), with a trend toward higher remission in the avacopan group at 52 weeks (62.7% vs. 53.6%). Similarly, among patients with pulmonary manifestations, remission rates at 26 weeks were 73.2% with avacopan versus 66.2% with prednisone taper, and at 52 weeks, rates were 67.6% versus 53.5%, respectively.³⁹ Although encouraging, these results warrant more granular analysis to determine whether these benefits are attributable to certain types of lung disease. Specifically, how well does avacopan work in patients with granulomatosis with polyangiitis?

How Long Should Therapy Continue With Avacopan?

A critical consideration in the use of avacopan is determining its optimal treatment duration. In the ADVOCATE trial, avacopan was administered over a 52-week period, and to date, there is limited robust evidence supporting its safety and efficacy beyond this timeframe. The demonstrated superiority of avacopan over prednisone for sustained remission at 52 weeks in the ADVOCATE trial has spurred interest in avacopan as a potential maintenance therapy for ANCA vasculitis.³¹ It must be noted, though, that in the ADVOCATE trial, participants who received rituximab induction did not receive any further rituximab beyond the initial 4-week induction phase, which is not consistent with current standard of care. Meanwhile, participants who received cyclophosphamide induction were transitioned to azathioprine for maintenance. In a subgroup analysis, rates of remission at 52 weeks were comparable between the avacopan and prednisone groups among those who received cyclophosphamide induction (55.9% vs. 52.6%, respectively), whereas there was a signal favoring avacopan in those who received rituximab induction (71.0% vs. 56.1%).³¹ Therefore, it is unclear whether avacopan would provide additional benefit for maintenance remission over established maintenance therapies. An ongoing randomized, double-blind, placebo-controlled phase 4 trial (NCT06072482) will compare 1 year and 5 years of avacopan therapy with placebo to determine longer-term safety and efficacy.⁴⁰ The 2022 European Alliance of Associations for Rheumatology guidelines recommend discontinuing avacopan after 6 to 12 months, reflecting the limited data on long-term safety and efficacy.⁴¹ Conceptually, because complement inhibition primarily targets innate immune processes involved in disease pathogenesis, maintaining therapy once remission is achieved may offer only diminishing returns. Some centers have adopted a practice of discontinuing avacopan at 6 months in patients who have achieved remission, although this approach remains to be validated by larger, long-term studies.

What are the Safety Profile Considerations With Avacopan?

Despite its generally favorable safety profile, avacopan can cause adverse effects such as infections, hypersensitivity reactions,⁴² and liver abnormalities.⁴³ Glucocorticoids are often felt to be responsible for much of the infection risk in ANCA vasculitis, and infections are major contributors to morbidity and mortality.44, 45, 46 Despite providing significant reduction in glucocorticoid use, the impact of avacopan on infection rates seems modest at best. In the ADVOCATE trial, infections occurred in 68.1% versus 75.6%, and serious infections in 13.2% versus 15.1% for avacopan versus prednisone, respectively.³¹ Looking at the glucocorticoid reductions and subsequent infection reduction achieved in ANCA vasculitis trials that specifically studied reduced-glucocorticoid dosing regimens (such as the Plasma Exchange and Glucocorticoids in Severe ANCA-Associated Vasculitis trial, and the Effect of Reduced-Dose vs High-Dose Glucocorticoids Added to Rituximab on Remission Induction in ANCA-Associated Vasculitis trial) avacopan would be expected to provide a much greater reduction in infections than what was seen despite a 71% reduction in prednisone use (Table 1).^47,48 This suggests that long-term use of avacopan could have immune-suppressing effects and predispose to infection. In addition, in the phase 2 CLASSIC trial, avacopan 30 mg + glucocorticoids had numerically (though not statistically significant) higher rates of infection at 12 weeks than prednisone only (24% vs. 15%, respectively).³⁰ This highlights a potential trade-off of using a long-term medication, which reduces glucocorticoid exposure but may not improve infection risks, an important determinant of outcomes in ANCA vasculitis.

Table 1.

Cumulative glucocorticoid dosing and infection rates in ANCA vasculitis trials

Study	Cumulative oral GC-use (prednisone)	GC reduction	Infection rates (intervention vs. control)	Infection risk reduction
PEXIVAS (2020)47	Received GC (median) Intervention: 2310 mg Control: 3990 mg	42%	Serious: 27.2% vs. 33.0%	IRR 0.69 → 31%
LOVAS (2021)48	Received GC (median; 6 mo) Intervention: 1318 mg Control: 4151 mg	68%	Serious: 7.2% vs. 20.0% Any: 15.9% vs. 44.6%	RR 0.36 → 64% RR 0.36 → 64%
ADVOCATE (2021)31	Received GC (mean; 6 mo) Intervention: 914 mg Control: 3124 mg	71%	Serious: 13.3% vs. 15.2% Any: 68.1% vs. 75.6%	RR 0.88 → 12% RR 0.90 → 10%

ADVOCATE, Avacopan for the Treatment of ANCA-Associated Vasculitis trial; GC, glucocorticoid; IRR, incidence rate ratio; LOVAS, Effect of Reduced-Dose vs High-Dose Glucocorticoids Added to Rituximab on Remission Induction in ANCA-Associated Vasculitis; PEXIVAS, Plasma Exchange and Glucocorticoids in Severe ANCA-Associated Vasculitis trial; RR, relative risk.

In the ADVOCATE trial, there was no major signal for adverse safety profile compared with prednisone. However, concerns have been raised regarding possible liver toxicity in clinical practice. In the ADVOCATE trial, abnormalities of liver function testing occurred in 5.4% compared with 3.7% in prednisone.³¹ Retrospective studies examining the use of avacopan in clinical practice setting from the United States and from France showed low rates of liver function abnormality leading to discontinuation (4.3% and 3.2%, respectively).^49,50 However, reports have emerged, mostly from Japan, of significant liver toxicity possibly due to avacopan.⁵¹ This includes chronic liver damage even after withdrawal of avacopan,⁵² vanishing bile duct syndrome,⁵³ and drug-induced liver injury in a child.⁵⁴ Rates of liver enzyme abnormality in clinical practice setting in Japanese patients have varied between 17% and 44%.^43,55,56 A subanalysis from ADVOCATE trial of the 21 patients from Japan found similar rates of hepatic enzyme increase in the avacopan and placebo groups (27% vs. 30%, respectively). Interestingly, these rates are much higher than those in the full ADVOCATE cohort.³¹ There may be genetic predispositions to liver injury which have yet to be elucidated, highlighting the need to closely monitor liver function when using avacopan.

Although avacopan shows promise as an alternative to prolonged high-dose glucocorticoids for ANCA vasculitis, glucocorticoids remain a cornerstone of therapy, especially for initial treatment when the disease is most active. Its greatest promise could lie in the possibility of improving kidney function, but this requires further study. Ongoing prospective observational real-world studies assessing the postauthorization safety of avacopan will help clarify the potential risks, in particular liver toxicity (NCT05897684).⁵⁷ Finally, the cost of avacopan is a significant barrier to its widespread use. It may be necessary to show more than glucocorticoid-sparing ability for the cost-benefit trade-off to favor its use and be adopted more broadly by insurers. Ultimately, clinicians must carefully balance the biological benefits of complement inhibition against considerations of safety, cost, and the current evidence base. Providing robust evidence of benefit for outcomes such as recovery of kidney function and preventing end-stage kidney disease could tilt the scale toward more widespread use.

Other Complement Inhibition in ANCA Vasculitis Treatment

The expanding landscape of complement-targeted therapies offers promising new avenues for the treatment of ANCA vasculitis, with ongoing research poised to clarify their roles in clinical practice. Insights from mouse models of anti-MPO Ig-induced disease have further clarified the role of complement pathways. Dissection of these pathways indicates that the alternative complement pathway plays a critical role. Notably, mice deficient in classical pathway complement components, such as C4, did not show protection against ANCA glomerulonephritis, suggesting that the classical pathway is less involved.¹² Conversely, mice lacking factor B, an essential component of the alternative pathway, were protected from developing necrotizing glomerulonephritis, highlighting the importance of this pathway in disease pathogenesis.¹² This experimental evidence suggests that targeting the alternative pathway—specifically factor B—may be a promising therapeutic strategy. In addition, other components of the alternative pathway, such as factor D, which activates factor B to form C3 convertase, represent potential therapeutic targets. Inhibiting factor D could suppress complement activation upstream, offering another promising approach.⁵⁸

Regulation of the alternative complement pathway presents intriguing therapeutic possibilities. Factor H, a key regulator that accelerates the decay of C3 convertase (BbC3b) by competing for factor B binding to C3b, appears to be involved in disease activity. Studies have shown that during active ANCA vasculitis, factor H levels are significantly reduced compared with remission phases.⁵⁹ Moreover, qualitative differences in factor H have been observed in patients with active disease; purified factor H from these patients exhibits diminished capacity to promote decay of C3 convertase and to serve as a cofactor for complement factor I.⁶⁰ Interestingly, MPO can interact with factor H, impairing its regulatory function, which may exacerbate complement activation.⁶¹ These findings suggest that enhancing factor H activity or preventing its inhibition could be a novel therapeutic avenue—and is, theoretically, the most interesting possibility for therapy.

The growing understanding of complement’s role in the pathogenesis of ANCA vasculitis has spurred interest in additional pathway inhibitors.^62,63 Therapeutic agents targeting various points in the complement cascade are under development. Pegcetacoplan, which binds to C3 and inhibits its cleavage; and iptacopan, which inhibits factor B, are 2 such examples (Figure 1). Iptacopan acts upstream of avacopan, suppressing the formation of C3 convertase and thereby modulating the alternative pathway. Iptacopan is currently being studied as an add-on to standard-of-care therapy for induction and maintenance of remission (NCT06388941).⁶⁴ Vilobelimab, a monoclonal antibody against C5a, blocks the interaction of C5a with its receptors 1 and 2 (Figure 1). A phase 2 trial of vilobelimab demonstrated that it could serve as a glucocorticoid-sparing agent, achieving similar remission rates with significantly reduced steroid exposure compared with standard therapy.^65,66 Further studies are needed to define its precise role in disease management. Eculizumab, an anti-C5 monoclonal antibody, has been used in case reports, but its efficacy remains to be validated through rigorous randomized controlled trials.^67,68

Are There Additional Risks Associated With Disrupting the Alternative Complement Pathway?

As mentioned previously, avacopan may have an immune-suppressing effect predisposing to infection, given its limited impact on reducing infection despite its significant reduction in glucocorticoid use. Furthermore, inhibiting the alternative complement pathway carries a warning regarding serious infections caused by encapsulated bacteria, such as Neisseria meningitidis, Hemophilus influenzae, and Streptococcus pneumoniae.⁶⁹ In the ADVOCATE trial, there was no signal for increased risk for such infections with avacopan.³¹ In contrast, eculizumab binds with high affinity to C5 and prevents formation of the membrane attack complex, which is associated with an increased susceptibility to meningococcal infections. As a result, eculizumab carries a black box warning. Life-threatening and fatal meningococcal infections have been reported in patients treated with eculizumab.⁷⁰ Patients must receive appropriate vaccinations against these pathogens at least 2 weeks before initiating therapy with eculizumab or as early as possible afterward. This requirement is especially pertinent for patients currently receiving B cell–depleting therapies, such as rituximab, which can impair vaccine efficacy.^71,72 Therefore, clinicians must weigh the benefits of the alternative pathway of complement inhibition against the potential risk of infections in immunocompromised individuals.

What are Glomerular Disease and Vasculitis Experts Doing Now?

A nonsystematic survey of several experts who regularly treat ANCA vasculitis and glomerulonephritis revealed a prevailing uncertainty about the best approach to employing avacopan. For patients experiencing issues with glucocorticoid toxicity or intolerance, avacopan serves as a useful adjunctive therapy to rapidly reduce glucocorticoid dosing. In cases where a more rapid taper of glucocorticoids is warranted—particularly in protocols involving higher glucocorticoid doses—avacopan can help clinicians feel more comfortable reducing glucocorticoid doses safely. The optimal timing and circumstances for using avacopan remain subjects of an ongoing debate. A general consensus is that if avacopan is to be used for either rapidly progressive glomerulonephritis or pulmonary hemorrhage, it should be administered as early as possible—ideally immediately after diagnosis. Unfortunately, many inpatient pharmacies do not have this drug on their formularies, which is counterproductive because timely administration is crucial. Moreover, there is caution among providers regarding the use of avacopan for sole maintenance therapy to prevent relapse, given the lack of substantial evidence supporting its efficacy or safety in this role.

Conclusion

Targeting innate immunity remains a promising approach to preserving kidney and lung function in ANCA vasculitis. New approaches are rapidly being developed, including gene therapy, to target complement dysregulation, with the potential for more specific and effective complement inhibitors with fewer side effects.73, 74, 75 Complement system inhibition is likely to be one of several strategies under investigation, with other agents such as BTK inhibitors showing potential.⁷⁶ Future research will determine which complement inhibitors are most effective and safe, ultimately guiding personalized treatment approaches in vasculitis management. These treatment strategies will be based on the specific type of vasculitis, specific organ involvement, and specific patient characteristics such as genetic variations and biomarkers that can help predict disease activity, response to treatment, and risk of relapse.

Disclosure

JCJ has received royalties from Wolters Kluwer and consulting fees from Sangamo Therapeutics. RJF has received consulting fees from Vertex. All the other authors declared no competing interests.