By Martina McGrath, MD
December 6, 2017
In recent years, there is a growing body of work describing the role of activation of the alternative complement cascade in the pathogenesis of ANCA vasculitis.
Neutrophils, primed by infection or exposure to pro-inflammatory cytokines, release properdin, which activates the alternative complement cascade, leading to the breakdown of C5 into C5a and C5b (please see figure below). C5b combines with C6-9 to form the membrane attack complex; while C5a binds C5a receptors, expressed on the surface of neutrophils, as well as other cells. Interestingly, the neutrophil expresses two distinct C5a receptors. C5L2 is an inhibitory receptor, and binding of C5a leads to down-regulation of neutrophil activation; in contrast, CD88 is an activating neutrophil receptor.1 When C5a binds CD88, an amplification loop is set up, with increased activation of the alternative complement cascade by neutrophil-released properdin, leading to more C5a generation and ever more neutrophil activation.1,2 Neutrophil activation also leads to expression of MPO and PR3 on the surface of the neutrophil, allowing for increased binding of anti-MPO and anti-PR3 ANCA, driving the disease process forward.
With this new understanding, there is increasing interest in targeting the complement pathway as a mechanism to achieve rapid disease control.
An interesting clinical study led by David Jayne and colleagues from Cambridge, UK, was published in JASN earlier this year, examining the effect of a small molecule inhibitor of the C5a receptor, avacopan, on ANCA vasculitis.3 They assessed the efficacy and safety of using avacopan as a means to decrease steroid exposure in patients with newly diagnosed or relapsing ANCA vasculitis.
Following induction therapy with rituximab or cyclophosphamide, patients were randomized to one of three study arms: standard dose steroids (prednisone 60mg qd) alone, or avacopan 30mg bid with prednisone 20mg qd, or avacopan 30mg bid alone.
This was a non-inferiority design, and was of short duration, with 12-weeks treatment and a 12-week follow-up period. Sixty-seven patients were enrolled in total, 23 in the high-dose steroid group and 22 in each of the avacopan treated arms. Seventy-five percent were newly diagnosed while the remaining patients had relapsing disease. These were patients with considerable disease burden: greater than 95% had renal involvement, with mean eGFR ~50mls/min and roughly one-third had pulmonary involvement. The primary outcome was the proportion of patients achieving >50% reduction in Birmingham Vasculitis Activity Score (BVAS) at 12 weeks.
Clinical response was similar across the three study arms, seen in 70% of high-dose steroid patients, 86.4% of the avacopan + steroid patients, and 81% of avacopan alone patients.3 However, the avacopan-treated patients had a more uniform fall in BVAS, and also experienced greater decreases in albuminuria than those treated with steroids alone. Rates of flare, adverse events, and achieving a negative ANCA titer were similar across the three groups. Interestingly, those in the avacopan-treated arms also scored more highly on quality of life measurements than high-dose steroid-treated patients.3 Given the significant burden of treatment-associated morbidity in ANCA vasculitis patients, this is an important finding.
In the era of effective induction therapies, treatment-related complications and infections are now a much more common cause of death in patients with vasculitis than the primary disease itself. Therefore, the ability to employ a more targeted therapy and reduce steroid dosing in patients with ANCA vasculitis is very appealing. Avacopan does appear to decrease the amplification of neutrophil activation described in the figure, but longer term follow-up in a larger cohort will be needed to assess if a short course is sufficient to prevent relapses, particularly if lower doses of immunosuppressing steroids are utilized. Indeed, these promising data have formed the basis of a larger, 300-patient clinical trial, which is currently recruiting (ClinicalTrials,gov NCT: 02994927),4 so more data will be available in the coming years.
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1. Kettritz R. Vasculitis: A CLEAR argument for targeting complement in ANCA vasculitis. Nature reviews Nephrology 2017;13:448-50.
2. Schreiber A, Xiao H, Jennette JC, Schneider W, Luft FC, Kettritz R. C5a receptor mediates neutrophil activation and ANCA-induced glomerulonephritis. Journal of the American Society of Nephrology : JASN 2009;20:289-98.
3. Jayne DRW, Bruchfeld AN, Harper L, et al. Randomized Trial of C5a Receptor Inhibitor Avacopan in ANCA-Associated Vasculitis. Journal of the American Society of Nephrology : JASN 2017;28:2756-67.
4. Phase 3 Clinical Trial of CCX168 (Avacopan) in Patients With ANCA-Associated Vasculitis (ADVOCATE). 2017. (Accessed 12/06/17, at clinicaltrials.gov.)
Dr. Martina McGrath is an Instructor in Medicine at Harvard Medical School, and a member of the Renal Division, Department of Medicine, at Brigham and Women’s Hospital, both in Boston. Dr. McGrath is the Medical Editor for the Trends in Medicine blog.