AB0496 AUTOANTIBODIES TARGETING COMPLEMENT RECEPTORS 3A AND 5A1 ARE DECREASED IN ANCA-ASSOCIATED VASCULITIS AND CORRELATE WITH HIGHER RELAPSE RATE.

Abstract

Background: Activation of the alternative and final common pathways have been shown in ANCA-associated vasculitis (AAV) (1). Circulating titers of C5a are elevated and correlate with disease activity in AAV. Binding to the corre- sponding G protein-coupled receptor (GPCR) C5aR1 enhances the influx of neutrophils, leading to ROS generation and severe necrotizing of vascular walls (2). Moreover, subsequent interaction of C5a with C5aR1 may represent a proinflammatory amplification loop (3). Blocking of the receptor is protective in a murine model in AAV (4). In humans, avacopan, a C5aR1-inhibitor showed promising results as glucocorticoid-sparing agent in two randomized phase II and one ongoing phase III clinicals trials in AAV (NCT02994927). Notably, disease-specific anti-GPCR autoantibody (aab) signatures have been found in different autoimmune diseases (5). Objectives: The aim of the present study was to examine whether (patho)phys- iological anti-C3aR and anti-C5aR1 aabs correlate with clinical findings in AAV, and whether this is linked to the clinical outcome. Methods: Sera and plasma of AAV patients [granulomatosis with polyangiitis (GPA), n=64; microscopic polyangiitis (MPA), n=26; eosinophilic granuloma- tosis with polyangiitis (EGPA), n=11] were measured by Elisa for circulating autoantibodies against complement receptors C3a (anti-C3aR aab) and C5a (anti-C5aR1 aab) and plasma levels of C3a and C5a. Expression of C3aR and C5aR1 on T-cells was determined using flow cytometry. Clinical data were assessed at the time of serum sampling and during follow-up for 48 months Results: GPA displayed low titers of anti-C3aR aab (GPA:5.33±2.54 vs. HD:6.47±2.61, P=0.0031). Anti-C5aR1 aab were decreased in AAV, especially in GPA (GPA:1.02±1.07 vs. HD:6.63±2.91, P=<0.0001). Plasma levels of C5a and anti-C5aR aab yielded an inverse correlation in AAV (r=-0.6813, P=0.0127). C5aR1 expression was increased on T-cells in GPA (CD4+C5aR1+T-cells: GPA:10.76±2.55% vs. HD:3.44±0.68%, P=0.0021; CD8+C5aR1+T-cells GPA:9.74±2.10% vs. HD:4.11±0.92%, P=0.0198). Reduced titers of anti-C5aR1 aab <0.45U/ml displayed an increased relapse risk for major organ involvement in GPA (HR 12.85, P=0.0014). Conclusion: As potential diagnostic marker, anti-C5aR1 aab titer may addition- ally be useful to monitor disease activity in AAV.