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Anti-neutrophil cytoplasmic antibody associated vasculitis (AAV) is a multi-system autoimmune illness that can lead to grave consequences like kidney failure and pulmonary hemorrhage. Urgent treatment with glucocorticoids and immunosuppressive drugs like cyclophosphamide or rituximab helps to quell the ongoing inflammation and comprise the current standard induction therapy. AAV includes three diseases- Granulomatosis with polyangiitis (GPA), Microscopic polyangiitis (MPA), and Eosinophilic GPA (EGPA). Relapses are common and frequently seen in patients with GPA, which recurs in more than 50% of patients within 5 years.
The problem with steroids
Glucocorticoids (GC) serve as a double-edged sword in the treatment of ANCA associated vasculitis (AAV). As part of standard induction therapy, they tend to reduce organ inflammation, but with longer courses and prolonged tapers, they are associated with several side effects, which include weight gain, insomnia, cushingoid features, osteoporosis, sodium retention, skin atrophy, hyperglycemia, muscle atrophy, avascular necrosis and increased susceptibility to infections (Figure 1). Several studies have shown that infections, due to immunosuppressive therapy, were the most common cause of death in the first year of treatment. The need for steroid-sparing therapies remains.
Figure 1: Common side effects of Steroids
Pathogenesis of ANCA Vasculitis
Though the exact pathogenesis of ANCA vasculitis remains unknown, humoral, cell-mediated immunity and complement system have been implicated. Neutrophils are the primary mediators of vascular inflammation. “Priming” of neutrophils, wherein the ANCA antigens MPO and PR3 move to the cell surface of the neutrophils, is one of the main events in the pathogenesis. After priming, the ANCA binds to surface antigens leading to the activation and release of proteolytic enzymes causing tissue damage (Figure 2). The activated neutrophils bind to the vascular endothelium and cause small vessel injury by the release of reactive oxygen species. A special form of cell death called NETosis ensues wherein neutrophil extracellular traps (NET) entrapped with the complement proteins cause further damage to the vessels.
Figure 2: Pathogenesis of ANCA vasculitis.
Image created with source from Core curriculum AJKD 2020.
Role of Complement
Complement activity has been found to be one of the main pathogenic mechanisms involved in ANCA vasculitis (Figure 3). C5a is an anaphylatoxin that is formed from the cleavage of C5. Binding with its receptor C5aR (CD 88) induces neutrophil chemoattraction and activation. Evidence of attenuation of necrotizing and crescentic glomerulonephritis in a mouse model by Xiao Hong et al gave the initial support for the use of C5a receptor blockade in AAV. Subsequent studies by David Jayne, et al. further consolidated the importance of C5a receptor blockade in the treatment of AAV.
Figure 3: Complement cascade
Image created with source from Bekker et al. PLoS One. 2016
The discovery of complement inhibitors heralded the era of newer effective therapies for diseases previously deemed “untreatable” like atypical HUS and paroxysmal nocturnal hemoglobinuria. Thereafter, a myriad of complement inhibitors emerged for the treatment of glomerular disorders with many more still in the pipeline (Fig. 4).
Figure 4: Complement Inhibitors
Avacopan
Avacopan (formerly CCX168) is a new oral C5a receptor antagonist that received FDA approval in October 2021 as an adjunctive treatment of adult patients with severe active ANCA-associated vasculitis in adults in addition to standard induction treatment. It is a cyclopeptide with a molecular weight 581.6 g/mol. The unique chemical structure of avacopan allows it to bind to the C5a receptor causing allosteric hindrance to C5a thereby antagonizing C5a. The hindrance of C5a binding with C5aR (CD 88) impairs neutrophil chemoattraction and activation that is pathogenic in AAV. Moreover, a unique aspect of C5a receptor is that its blockade by an antagonist does not prevent the formation of the membrane attack complex (MAC), which is essential for defense against encapsulated bacteria, viruses, and parasites. The standard dose of avacopan is 30 mg twice daily, and it is to be taken with food.
Promising data was obtained from the phase 2 CLEAR and phase 3 ADVOCATE trials which showed the efficacy and non-inferiority of avacopan to glucocorticoids for the treatment of ANCA vasculitis. It is now undergoing trials for the treatment of C3 glomerulopathy.
A few words on the ADVOCATE trial
Published in NEJM in 2021, the ADVOCATE trial was a global randomized placebo controlled, phase 3 clinical trial conducted from 2017-2019. Patients were stratified prior to randomization based on induction treatment regimens (IV Rituximab, IV cyclophosphamide OR oral cyclophosphamide followed by oral azathioprine), diagnostic test (positive test for proteinase-3 or myeloperoxidase) and disease activity (newly diagnosed or relapsing ANCA). After stratification, patients were randomized in a 1:1 ratio to one of two treatment groups: 30 mg of Avacopan or oral prednisone on a tapering schedule.
Image source: https://www.nephjc.com/news/advocate
Important findings included:
Remission at week 26 was seen in 72% of patients receiving avacopan and 70% in the prednisone group. Avacopan noninferiority was met at week 26 and 52 (p< 0.001) and superiority was met at week 52 only (p=0.007).
Sustained remission at week 52 was observed in 66% receiving avacopan and in 55% receiving prednisone.
Serious adverse events (excluding worsening vasculitis) occurred in 37% of the patients receiving avacopan and in 39% of those receiving prednisone.
Avacopan patients reported better health related quality of life in several measures (physical health, health perception, emotional health and vitality) over 52 weeks.
The mean total prednisone dose was 4 mg per day in the avacopan group and 12 mg per day in the prednisone group.
It is a well accepted fact that glucocorticoids are effective in AAV at the time of diagnosis and relapse. However, duration of steroid use is associated with long-term damage as assessed by Vasculitis Damage Index, which is a predictor of mortality. It was the PEXIVAS trial that brought in a ray of hope that a quick steroid taper is non-inferior to a full steroid dose. Subsequently, avacopan highlighted exciting possibilities of steroid-free or steroid-sparing disease remission.
Among the positive points, the ADVOCATE trial had its own skeptics, part of the nephrology community asking for more compelling evidence. This can be attributed to the following limitations
The non-inferiority margin of 20% at week 26
The main treatment was chosen at physician discretion (oral/intravenous cyclophosphamide, rituximab)
The avacopan arm was not entirely steroid free (worsening vasculitis 10%, infections 68%)
The quick steroid taper in the prednisone group; much quicker than in PEXIVAS even (this might have caused less sustained remission in prednisone arm of the trial)
Heterogenous trial population (both newly diagnosed cases and relapses)
Last but not the least, the cost of avacopan (Avacopan, 10 mg: $34.24 per capsule; annual cost estimated as $75,051)
Moreover, FDA delayed avacopan’s approval as steroid-free therapy in AAV, due to methodological concerns. FDA had raised concerns that a non-inferiority comparison at week 26 would not suffice enough to validate that avacopan can replace glucocorticoids, as it would be difficult to establish whether avacopan is effective or whether rituximab/cyclophosphamide was the primary driver of the efficacy in both treatment arms.
So, are the statistical percentages in ADVOCATE trial a providence of methodological technicalities? Would avacopan really fare well in the real world? This was addressed in a recent Kidney International Reports article – a real world experience of using avacopan for AAV by R. Zonozi et al.
Visual abstract by Priya John
Study Design Multicenter retrospective analysis of 92 patients with active AAV who received treatment with avacopan at 12 academic medical centers across the United States from Oct 2021 to May 2023
Inclusion Criteria:
Patients ≥ 18 years
Newly diagnosed or relapsing AAV
Received 2 weeks of avacopan
Exclusion criteria
Patients with Anti GBM antibody disease
Patients with missing data of - values of clinical remission, eGFR, GC dosing, and other study outcomes
Treatment Regimen
Avacopan was given 30 mg orally twice daily with intention to treat for one year duration along with standard induction therapy followed by maintenance therapy. Induction therapy used included rituximab, cyclophosphamide, or both combined. Plasma exchange (PLEX) was used at the discretion of the treating physician. Maintenance therapy consisted of either azathioprine, methotrexate or rituximab.
Outcomes
Primary outcomes:
Proportion of patients in clinical remission at week 26 and
Sustained clinical remission at week 52
Secondary outcomes:
Dose of prednisone at week 12 and 52
Cumulative dose of glucocorticoid
Liberation from kidney replacement therapy
Change in the eGFR at week 26 and 52
Clinical remission at week 26 and 52 was defined as having no signs or symptoms of vasculitis activity and a prednisone dose ≤ 5 mg/day. Disease relapse was defined as AAV disease requiring dose escalation of immunosuppression during treatment.
Results
Study population
The study included 92 patients with newly diagnosed or relapsing AAV as outlined in Table 1. Most of the patients were in their 6th decade of life, females outnumbered males (64%).
Important points to note-
👉 Most of the patients had MPO ANCA disease (72 %),
👉 Only 77% of the patients had kidney involvement, and more than half had pulmonary involvement. Other organs involved included ENT, skin eyes, and heart
👉 Kidney replacement therapy was required in 10 % of patients
Treatment regimens
Most patients received either rituximab alone or in combination with low-dose cyclophosphamide for induction therapy. PLEX was used in 14 %. The cumulative methylprednisolone dose was 1340 mg. The time taken to initiate avacopan was 3.6 weeks, and to stop prednisone was 5.6 weeks. For maintenance therapy, most of the patients received periodic rituximab.
As shown in Table 3 from the study, 90 % (61 of 68 patients) and 84 % (32 of 38 patients) of the patients achieved remission at weeks 26 and 52 respectively. The mean (SD) eGFR change from baseline to weeks 26 and 52 was +12.2 (25.4) and +19.8 (23.1) ml/min/1.73 m2 respectively. There was no significant difference in the eGFR change at weeks 26 and 52.
The mean (SD) proteinuria at weeks 26 and 52 was 454 mg/g and 290 mg/g respectively and the time taken to reach nadir proteinuria was 15.4 weeks.
In patients with entry eGFR <15 ml/min/1.73 m2, there was a tendency for more frequent PLEX use (43 %, P <0.01), delayed use of avacopan at a median 47 days (compared to a median of 21 days in those with an eGFR >15 ml/min/1.73 m2) and higher risk of ESKD (30 %) compared to those with entry eGFR > 15 ml/min/1.73 m2. The mean (SD) rise in the eGFR from baseline to week 26 was 19.4 (22.7) ml/min/1.73 m2 in the patients with initial eGFR < 15 ml/min/1.73 m2. This box plot shows the eGFR change during follow-up.
Most of the patients were initiated on avacopan within 30 days (60 %, n= 55), and they were less likely to receive PLEX at entry. The mean (SD) eGFR was higher (but not statistically significant) from the entry eGFR at weeks 26 and 52 for those who received avacopan within 30 days as compared to those who received after.
Safety
Avacopan was discontinued in approximately 1/3rd of the patients in view of adverse events — the most common of which was transaminitis (4.3 %) followed by gastrointestinal side effects, worsening of kidney functions, proteinuria, and breathlessness etc.
Discussion
This was a large retrospective multicenter post-marketing study that confirmed the findings of earlier trials that avacopan may help sustain remission and possibly have a role as a steroid-sparing agent and/or steroid-reducing therapies in AAV. Majority of the patients in this study had MPO ANCA disease, which is usually associated with glomerulosclerosis, chronicity and fibrosis on kidney biopsy as compared to that seen in patients with PR3 ANCA disease.
There were certain subtle differences between the present study and the ADVOCATE trial. The present study defined remission as an absence of any vasculitis activity as determined by individual investigator- a subjective criteria, as opposed to the more stringent objective remission criteria of the ADVOCATE trial - BVAS of 0 and no receipt of glucocorticoids for four weeks before week 26, and sustained remission being remission at weeks 26 and 52 with no use of glucocorticoids for four weeks before week 52. An interesting feature of the present study was the inclusion of patients with eGFR < 15 ml/min/1.73 m2, patients on kidney replacement therapy and those who received PLEX- populations that were excluded in the ADVOCATE trial. A higher cumulative dose of oral steroids was noted in the present study (2212 mg) at week 52 as compared to the cumulative steroid dose in the ADVOCATE trial (1676 mg) at week 52.
AcademicCME (www.academiccme.com) is accrediting this educational activity for CE and CME for clinician learners. Please go to https://academiccme.com/kicr_blogposts/ to claim credit for participation.
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