100. Longitudinal Pattern of Circulating Complement Activation in ANCA Vasculitis

Background: There is accumulating evidence that alternative complement pathway activation is important in ANCA vasculitis pathogenesis. Our group was the first to show that complement activation occurs in both MPO-ANCA and PR3-ANCA vasculitis.¹ Objectives for this study were to investigate complement system activation in a longitudinal cohort of MPO-ANCA and PR3-ANCA vasculitis and evaluate for potential relationships between complement activation measures and clinical characteristics.

Methods: Subjects included 39 patients with ANCA vasculitis (18 MPO-ANCA, 21 PR3-ANCA) and 10 healthy controls. 20 patients had paired samples obtained during disease activity and remission, and 16 had samples obtained during long-term remission off therapy for ³2 years (LTROT). Plasma was obtained from blood collected in EDTA tubes including 100 µg/mL futhan per prior report.¹ Levels of Bb, C3a, C5a, sC5b-9, properdin, and C4d were measured by ELISA and median values reported. Group comparisons were made using Wilcoxon two-sample test. Paired data were analyzed with paired signed-rank test. A p-value of <0.05 was considered statistically significant. Bonferroni correction was applied for multiple comparisons when applicable.

Results: Of the 39 ANCA vasculitis patients, 25 were male and median age was 59 years. Compared to healthy controls, patients with active ANCA vasculitis had higher levels of C3a (128.30 vs. 34.00 ng/mL, p<0.0001), sC5b-9 (217.60 vs. 149.04 ng/mL, p=0.01), and C4d (2.39 vs. 1.02 µg/mL, p=0.004). Compared to patients in remission, patients with active ANCA vasculitis had higher levels of Bb (0.79 vs. 0.65 µg/mL, p=0.003), C3a (128.30 vs. 53.67 ng/mL, p<0.0001), and sC5b-9 (217.60 vs. 135.20 ng/mL, p<0.0001) and lower levels of properdin (14.30 vs. 18.04 µg/mL, p=0.009). Compared to patients with active ANCA vasculitis, those with LTROT status had lower levels of Bb (0.79 vs. 0.63 µg/mL, p=0.003), C3a (128.30 vs. 53.31 ng/mL, p<0.0001), and sC5b-9 (217.60 vs. 144.81 ng/mL, p<0.002). Among the patients with paired active-remission samples, levels of Bb (0.79 vs. 0.66 µg/mL, p=0.03), C3a (128.25 vs. 63.22 ng/mL, p=0.01), C5a (7.94 vs. 5.32 ng/mL, p=0.0001), and sC5b-9 (218.98 vs. 130.48 ng/mL, p<0.0001) were higher and properdin (14.58 vs. 17.89 µg/mL, p=0.04) lower during active disease compared to remission. Evaluating disease manifestations among patients with paired active-remission samples, levels of C5a (8.96 vs. 5.51 ng/mL, p=0.0006) and sC5b-9 (218.77 vs. 132.44 ng/mL, p=0.0001) were higher and properdin lower (14.10 vs. 16.08 µg/mL, p=0.04) among the 15 patients with renal involvement during active disease. In contrast, no difference was observed in any analyte in the 5 patients with paired active-remission samples and without renal involvement during active disease.

Conclusions: Complement activation occurs in both MPO-ANCA and PR3-ANCA vasculitis, and the activation profile differs by disease activity with higher Bb, C3a, C5a, and sC5b-9 levels and lower properdin levels during active disease compared to remission in our longitudinal cohort. More study is needed to determine if complement activation measures correlate with specific disease manifestations, in particular renal involvement, or can reliably predict those patients who can safely discontinue therapy.

Disclosures: Elizabeth McInnis has investments in Chemocentryx, otherwise none