The Complement System in ANCA‐Associated Vasculitis: Mechanistic Insights, Therapeutic Horizons, and Unmet Clinical Needs

ABSTRACT Background ANCA‐associated vasculitides (AAV) are autoimmune small‐vessel vasculitides characterized by necrotizing inflammation with few immune deposits (“pauci‐immune” lesions). Historically, complement was thought to play a minor role in AAV due to scant complement deposition on biopsy. However, growing evidence from animal models and patient studies indicate that complement activation, particularly the alternative pathway, is a critical amplifier of inflammation in AAV. Methods We searched PubMed, Embase, and Web of Science (January 2000–October 2024) for peer‐reviewed studies on complement in AAV prioritizing preclinical, clinical, and therapeutic research. Findings Complement activation bridges innate and adaptive immunity in AAV: ANCA‐activated neutrophils release factors that trigger the alternative complement pathway, generating C5a, which further recruits and primes neutrophils, creating a self‐amplifying loop of inflammation. Complement components (C3a, C5a, C5b‐9) are detectable in active AAV patients' plasma/urine and in affected tissues, correlating with disease activity and severity. Therapeutically, the C5a‐receptor antagonist, avacopan has demonstrated clinical efficacy, achieving remission with reduced corticosteroid exposure. Conclusion Complement dysregulation is a pivotal mechanism in AAV pathogenesis, opening a new era of complement‐targeted therapies. Avacopan's success illustrates the potential to improve outcomes and safety by modulating complement. Yet, major unmet clinical needs remain. Up to 50% of patients relapse within 5 years. There are no validated biomarkers to predict relapse. Long‐term steroid dependence and cumulative toxicity from rituximab and cyclophosphamide compromise patient safety. Better tools are needed to detect early disease, stratify relapse risk, and personalize therapy. Future directions must prioritize biomarker development, novel complement inhibitors, and deliver durable remission with fewer side effects.