FC075: Role of Factor H and its Related Proteins (FHR-1, FHR-2 FHR-5) in ANCA-Associated Vasculitis: A Genetic and Longitudinal Serological Study

Abstract

Abstract BACKGROUND AND AIMS The complement system was not initially thought to be associated with the development of ANCA-associated vasculitis (AAV). Convincing evidence from animal models and clinical observations indicates, however, that activation of the complement system, the alternative pathway (ACP) in particular, is pivotal for the development of AAV. Recently, a phase 3 clinical trial has shown that C5a receptor inhibition with avacopan was effective in replacing high dose glucocorticoids in AAV patients treated with rituximab or cyclophosphamide during induction treatment. We hypothesized that in AAV, a disorder in regulatory factors of ACP or in its related proteins (FHR-1, FHR-2, FHR-5) could be present, similar to other diseases in which its dysregulation have been shown. Method We measured longitudinal levels of alternative complements factors (FH, FB, properdin, FHR-1, FHR-2, FHR-5) and performed a genetic study for these factors in three cohorts: active renal ANCA vasculitis (active AAV, n = 54), inactive ANCA vasculitis (remission, n = 48) and in a control cohort of healthy individuals (n = 99). RESULTS ANCA serology was positive in all patients; 83.3% showed activity against MPO, whereas activity against PR3 was identified in 16.7% of patients. Median BVAS at the onset was 15 (IQR 14–19). Extrarenal involvement was present in 46.3% of participants. Haplotype CFH-H6 and the allele CFB32R are significantly associated with increased risk to develop AAV [OR 3.32; 95% confidence interval (95% CI) 1.39–7.89; P = 0.008 and OR 1.71, 95% CI 1.11–2.54; P = 0.008, respectively]. The allele frequency of ΔCFHR3/1 was significantly decreased in patients with severe AAV (T3, BVAS > 16) compared with patients with a lower BVAS score (T1-T2 ≤ 15). Circulating levels of regulatory factors (FH, FB, properdin) were significantly lower in patients with active disease compared to samples in remission, and FHR1 (FH competitor) levels were higher. C3 levels increased over time, while sC5b-9 decreased after initiating the immunosuppressive treatment, with the biggest change observed after the first month of treatment. After 12 months of follow-up, FHR-1 levels decreased in responder patients and did not decrease in nonresponders. CONCLUSION This is the first study to associate the presence of certain alleles of regulatory factors of the alternative complement pathway (Factor H and Factor B) with an increased risk of developing ANCA-associated vasculitis. Likewise, the absence of the ΔCHR3-CFHR1 deletion was associated with more severe forms of the disease. We could conclude that ACP is not a simple additional factor in the inflammatory loop in AAV and, like in other glomerular diseases related to ACP, dysregulation of FH and its regulatory proteins play an essential role in its development.