{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T13:27:44Z","timestamp":1789133264081,"version":"build-2803163510"},"reference-count":57,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2026,2,12]],"date-time":"2026-02-12T00:00:00Z","timestamp":1770854400000},"content-version":"vor","delay-in-days":11,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,2,1]],"date-time":"2026-02-01T00:00:00Z","timestamp":1769904000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Immunity Inflam &amp;amp; Disease"],"published-print":{"date-parts":[[2026,2]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>ANCA\u2010associated vasculitides (AAV) are autoimmune small\u2010vessel vasculitides characterized by necrotizing inflammation with few immune deposits (\u201cpauci\u2010immune\u201d 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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We searched PubMed, Embase, and Web of Science (January 2000\u2013October 2024) for peer\u2010reviewed studies on complement in AAV prioritizing preclinical, clinical, and therapeutic research.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Findings<\/jats:title>\n                    <jats:p>Complement activation bridges innate and adaptive immunity in AAV: ANCA\u2010activated neutrophils release factors that trigger the alternative complement pathway, generating C5a, which further recruits and primes neutrophils, creating a self\u2010amplifying loop of inflammation. Complement components (C3a, C5a, C5b\u20109) are detectable in active AAV patients' plasma\/urine and in affected tissues, correlating with disease activity and severity. Therapeutically, the C5a\u2010receptor antagonist, avacopan has demonstrated clinical efficacy, achieving remission with reduced corticosteroid exposure.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Complement dysregulation is a pivotal mechanism in AAV pathogenesis, opening a new era of complement\u2010targeted 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\u2010term 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.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/iid3.70338","type":"journal-article","created":{"date-parts":[[2026,2,13]],"date-time":"2026-02-13T06:47:40Z","timestamp":1770965260000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["The Complement System in ANCA\u2010Associated Vasculitis: Mechanistic Insights, Therapeutic Horizons, and Unmet Clinical Needs"],"prefix":"10.1002","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4824-1340","authenticated-orcid":false,"given":"Kehinde","family":"Sunmboye","sequence":"first","affiliation":[{"name":"Rheumatology University Hospitals of Leicester NHS Trust, Leicester, GBR Leicester England UK"},{"name":"College of life sciences, University of Leicester Leicester England 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