Hypocomplementemia is associated with worse renal survival in ANCA-positive granulomatosis with polyangiitis and microscopic polyangiitis

Abstract

Recent data suggest the existence of a complement alternative pathway activation in the pathogenesis of antineutrophilic cytoplasmic antibody (ANCA)-associated vasculitis (AAV), a condition that remains poorly understood. This study aims to assess the clinical characteristics and outcomes of granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA) patients with regard to their plasma complement levels at diagnosis. A retrospective monocentric study carried out at Caen University Hospital led to the identification of proteinase-3- or myeloperoxidase-ANCA-positive GPA and MPA patients from January 2000 to June 2016 and from September 2011 to June 2016, respectively. All patients with available C3 and C4 levels at diagnosis were included. Patients were categorized in the hypocomplementemia group if their C3 and/or C4 levels at diagnosis were below the lower limit of the normal range. Among the 76 AAV patients (43 GPA, 33 MPA), 4 (5%) had hypocomplementemia, and the 72 remaining patients exhibited normal plasma complement levels. All 4 hypocomplementemia patients had renal involvement. Hypocomplementemia was followed in 1 patient whose post-treatment complement level normalized within 1 month. Among all clinical and ANCA specificity, including relapse-free survival (p = 0.093), only overall and renal survival rates were significantly lower in the hypocomplementemia group (p = 0.0011 and p<0.001, respectively). Hypocomplementemia with low C3 and/or C4 levels at GPA or MPA diagnosis may be responsible for worse survival and renal prognosis. These results argue for larger and prospective studies to better determine the epidemiology of the disease and to assess complement-targeting therapy in these patients.

Granulomatosis with polyangiitis (GPA) or ANCA associated vasculitis (AAV): a case report

“…In 25% of the patients with GPA, involvement of the airways can be the only manifestation (15). Levels of C3 and C4 were normal, hypocomplementemia with low C3 and/or C4 levels at GPA or MPA diagnosis may be responsible for worse survival and renal prognosis (16). Platelet to lymphocyte ratio (PLR) as a useful index to estimate the current activity of vasculitis in AAV patients, in our patient was 115, the value >160 is associated with poor prognosis (17).…”

ANCA associated vasculitis: The journey to complement-targeted therapies

“…(28)(29) Moreover, a study confirmed the presence of hypocomplementaemia in a small group of patients with worst overall and renal prognosis. (30) Finally, a proteomic analysis of renal tissues from AAV patients with ANCA-negative GN showed larger amounts of C3 and C9 deposition compared with ANCA-positive patients suggesting that ANCA-negative AAV was as a separate disease phenotype, promoted by a specific alteration in the activation of the alternative complement pathway. (31) Since some years, the role of neutrophils in complement activation (both classical and alternative pathways) by expelling neutrophil extracellular traps (NETs) was well characterised.…”

“…In 2015, Manenti et al reported, in a study that included 46 patients with AAV, that 35% of these individuals had decreased levels of C3 in serum, and this finding was associated with decreased renal survival and the presence of renal thrombotic microangiopathy in the biopsy (39). Recently, a study in 76 AVV patients reported that only 5% had hypocomplementaemia, however, this finding implied worst prognosis with lower overall and renal survival in this subset of individuals (30).…”

Vasculitis Pathogenesis: Can We Talk About Precision Medicine?

“…Recent studies have highlighted the role of complement alternative pathway activation in AAV pathogenesis ( 107 ). In a recent randomized trial, Jayne et al have demonstrated that avacopan, an orally administered selective C5a receptor inhibitor was effective in replacing high-dose corticosteroid treatment in AAV ( 108 ).…”