{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T00:51:12Z","timestamp":1792457472951,"version":"4.5.0"},"reference-count":43,"publisher":"MDPI AG","issue":"22","license":[{"start":{"date-parts":[[2025,11,18]],"date-time":"2025-11-18T00:00:00Z","timestamp":1763424000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Eosinophilic granulomatosis with polyangiitis (EGPA) is a rare systemic vasculitis characterized by asthma, eosinophilia, and necrotizing inflammation of small- to medium-sized vessels. Accumulating evidence indicates that EGPA is a polygenic and heterogeneous disorder comprising distinct antineutrophil cytoplasmic antibody (ANCA)\u2013defined endotypes with divergent genetic backgrounds, immune pathways, and clinical phenotypes. Its pathogenesis reflects the convergence of epithelial\u2013alarmin signaling, type 2 inflammation, eosinophil effector mechanisms, and B-cell\/autoantibody responses, with myeloperoxidase (MPO)-ANCA serving as a hallmark of the vasculitic subset. Recent advances in genomics, immunology, and multi-omics profiling have uncovered biomarkers and molecular circuits sustaining disease activity and guiding therapeutic stratification. The identification of the interleukin (IL)-5\u2013eosinophil axis, epithelial-derived alarmins, and B-cell\/IgG4 networks as central pathogenic nodes has enabled the development of targeted biologic therapies that are redefining treatment paradigms. Benralizumab (anti-IL-5R\u03b1) has recently been approved for EGPA following the phase 3 head-to-head MANDARA trial, which demonstrated non-inferiority to mepolizumab in achieving remission (BVAS = 0 with \u22644 mg\/day prednisone equivalent) at weeks 36 and 48. These results, together with the established efficacy of mepolizumab, inform practical selection between IL-5 and IL-5R\u03b1 blockade and support glucocorticoid-sparing approaches. A structured literature search (2015\u20132025) was conducted in PubMed, Scopus, and Web of Science to identify recent advances in epidemiology, genetics, biomarkers, and targeted therapies for EGPA. This updated review integrates molecular insights, clinical endotypes, and therapeutic innovations to outline current evidence and future precision-medicine strategies aimed at improving long-term patient outcomes.<\/jats:p>","DOI":"10.3390\/ijms262211141","type":"journal-article","created":{"date-parts":[[2025,11,18]],"date-time":"2025-11-18T11:05:31Z","timestamp":1763463931000},"page":"11141","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Molecular Pathogenesis and Targeted Therapies in Eosinophilic Granulomatosis with Polyangiitis: An Updated Review"],"prefix":"10.3390","volume":"26","author":[{"given":"Mar\u00eda","family":"L\u00f3pez Paraja","sequence":"first","affiliation":[{"name":"Systemic Autoinmmune Diseases Unit, Department of Internal Medicine, Hospital Universitario Ram\u00f3n y Cajal, Instituto Ram\u00f3n y Cajal de Investigaci\u00f3n Sanitaria (IRYCIS), 28034 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0666-3035","authenticated-orcid":false,"given":"Grisell","family":"Starita Fajardo","sequence":"additional","affiliation":[{"name":"Systemic Autoinmmune Diseases Unit, Department of Internal Medicine, Hospital Universitario Ram\u00f3n y Cajal, Instituto Ram\u00f3n y Cajal de Investigaci\u00f3n Sanitaria (IRYCIS), 28034 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ignacio","family":"Donate Velasco","sequence":"additional","affiliation":[{"name":"Systemic Autoinmmune Diseases Unit, Department of Internal Medicine, Hospital Universitario Ram\u00f3n y Cajal, Instituto Ram\u00f3n y Cajal de Investigaci\u00f3n Sanitaria (IRYCIS), 28034 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Lucena L\u00f3pez","sequence":"additional","affiliation":[{"name":"Systemic Autoinmmune Diseases Unit, Department of Internal Medicine, Hospital Universitario Ram\u00f3n y Cajal, Instituto Ram\u00f3n y Cajal de Investigaci\u00f3n Sanitaria (IRYCIS), 28034 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4488-8713","authenticated-orcid":false,"given":"Mar\u00eda Pilar","family":"Iranzo Alcolea","sequence":"additional","affiliation":[{"name":"Systemic Autoinmmune Diseases Unit, Department of Internal Medicine, Hospital Universitario Ram\u00f3n y Cajal, Instituto Ram\u00f3n y Cajal de Investigaci\u00f3n Sanitaria (IRYCIS), 28034 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-2379-9778","authenticated-orcid":false,"given":"Francisco Jos\u00e9","family":"Lirola S\u00e1nchez","sequence":"additional","affiliation":[{"name":"Systemic Autoinmmune Diseases Unit, Department of Internal Medicine, Hospital Universitario Ram\u00f3n y Cajal, Instituto Ram\u00f3n y Cajal de Investigaci\u00f3n Sanitaria (IRYCIS), 28034 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-3542-6863","authenticated-orcid":false,"given":"Mercedes","family":"Pe\u00f1a Rodriguez","sequence":"additional","affiliation":[{"name":"Systemic Autoinmmune Diseases Unit, Department of Internal Medicine, Hospital Universitario Ram\u00f3n y Cajal, Instituto Ram\u00f3n y Cajal de Investigaci\u00f3n Sanitaria (IRYCIS), 28034 Madrid, Spain"},{"name":"Faculty of Medicina and Health Sciences, Universidad de Alcal\u00e1 (UAH), 28801 Alcal\u00e1 de Henares, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7367-9523","authenticated-orcid":false,"given":"Andr\u00e9s","family":"Gonz\u00e1lez Garc\u00eda","sequence":"additional","affiliation":[{"name":"Systemic Autoinmmune Diseases Unit, Department of Internal Medicine, Hospital Universitario Ram\u00f3n y Cajal, Instituto Ram\u00f3n y Cajal de Investigaci\u00f3n Sanitaria (IRYCIS), 28034 Madrid, Spain"},{"name":"Faculty of Medicina and Health Sciences, Universidad de Alcal\u00e1 (UAH), 28801 Alcal\u00e1 de Henares, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0472-1820","authenticated-orcid":false,"given":"Luis","family":"Manzano Espinosa","sequence":"additional","affiliation":[{"name":"Systemic Autoinmmune Diseases Unit, Department of Internal Medicine, Hospital Universitario Ram\u00f3n y Cajal, Instituto Ram\u00f3n y Cajal de Investigaci\u00f3n Sanitaria (IRYCIS), 28034 Madrid, Spain"},{"name":"Faculty of Medicina and Health Sciences, Universidad de Alcal\u00e1 (UAH), 28801 Alcal\u00e1 de Henares, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,11,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1111\/all.12088","article-title":"Eosinophilic granulomatosis with polyangiitis (Churg\u2013Strauss): State of the art","volume":"68","author":"Vaglio","year":"2013","journal-title":"Allergy"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Gioffredi, A., Maritati, F., Oliva, E., and Buzio, C. (2014). Eosinophilic granulomatosis with polyangiitis: An overview. Front. Immunol., 5.","DOI":"10.3389\/fimmu.2014.00549"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1366","DOI":"10.1002\/art.41773","article-title":"2021 American College of Rheumatology\/Vasculitis Foundation guideline for the management of antineutrophil cytoplasmic antibody\u2013associated vasculitis","volume":"73","author":"Chung","year":"2021","journal-title":"Arthritis Rheumatol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"00430-2023","DOI":"10.1183\/23120541.00430-2023","article-title":"Prevalence, incidence and healthcare burden of eosinophilic granulomatosis with polyangiitis","volume":"10","author":"Hwee","year":"2024","journal-title":"ERJ Open Res."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1429","DOI":"10.1183\/13993003.00097-2016","article-title":"Respiratory manifestations of eosinophilic granulomatosis with polyangiitis (Churg\u2013Strauss)","volume":"48","author":"Cottin","year":"2016","journal-title":"Eur. Respir. J."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"270","DOI":"10.1002\/art.37721","article-title":"Clinical characteristics and long-term follow-up of 383 patients","volume":"65","author":"Comarmond","year":"2013","journal-title":"Arthritis Rheum."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"168","DOI":"10.4168\/aair.2024.16.2.168","article-title":"Incidence, prevalence and mortality in Korea","volume":"16","author":"Lee","year":"2024","journal-title":"Allergy Asthma Immunol. Res."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"e002949","DOI":"10.1136\/rmdopen-2022-002949","article-title":"Stable incidence but increased prevalence","volume":"9","author":"Rathmann","year":"2023","journal-title":"RMD Open"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"374","DOI":"10.1002\/acr.22686","article-title":"Long-term follow-up of 101 patients","volume":"68","author":"Durel","year":"2016","journal-title":"Arthritis Care Res."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1136\/annrheumdis-2021-221795","article-title":"2022 ACR\/EULAR classification criteria for GPA","volume":"81","author":"Robson","year":"2022","journal-title":"Ann. Rheum. Dis."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"5120","DOI":"10.1038\/s41467-019-12515-9","article-title":"Genome-wide association study of EGPA","volume":"10","author":"Lyons","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"7516","DOI":"10.3390\/cimb46070446","article-title":"Genetic and non-genetic contributions to EGPA","volume":"46","author":"Treccani","year":"2024","journal-title":"Curr. Issues Mol. Biol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"i92","DOI":"10.1093\/rheumatology\/keae608","article-title":"Highlights from the plenary session: EGPA and HES","volume":"64","author":"Holle","year":"2025","journal-title":"Rheumatology"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Watanabe, R., and Hashimoto, M. (2023). Latest findings and updated treatment recommendations. J. Clin. Med., 12.","DOI":"10.3390\/jcm12185996"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"103219","DOI":"10.1016\/j.autrev.2022.103219","article-title":"Eosinophilic granulomatosis with polyangiitis: A review","volume":"22","author":"White","year":"2023","journal-title":"Autoimmun. Rev."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"iii84","DOI":"10.1093\/rheumatology\/kez570","article-title":"Understanding the disease and its management","volume":"59","author":"Trivioli","year":"2020","journal-title":"Rheumatology"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Fijo\u0142ek, J., and Radzikowska, E. (2023). Eosinophilic granulomatosis with polyangiitis\u2014Advances in pathogenesis, diagnosis and treatment. Front. Med., 10.","DOI":"10.3389\/fmed.2023.1145257"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Paroli, M., Gioia, C., and Accapezzato, D. (2023). New insights into pathogenesis and treatment of ANCA-associated vasculitis: Autoantibodies and beyond. Antibodies, 12.","DOI":"10.3390\/antib12010025"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"551","DOI":"10.1111\/1346-8138.16656","article-title":"Eosinophil extracellular trap cell death","volume":"50","author":"Kawakami","year":"2023","journal-title":"J. Dermatol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1683","DOI":"10.1002\/art.41727","article-title":"Galectin-10 release in EGPA","volume":"73","author":"Fukuchi","year":"2021","journal-title":"Arthritis Rheumatol."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Dejaco, C., Oppl, B., Monach, P., Cuthbertson, D., Carette, S., Hoffman, G., Khalidi, N., Koening, C., Langford, C., and McKinnon-Maksimowicz, K. (2015). Serum biomarkers in patients with relapsing eosinophilic granulomatosis with polyangiitis (Churg\u2013Strauss). PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0121737"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Xiao, J., Lu, S., Wang, X., Liang, M., Dong, C., Zhang, X., Qiu, M., Ou, C., Zeng, X., and Lan, Y. (2022). Serum proteomic analysis identifies SAA1, FGA, SAP, and CETP as new biomarkers for eosinophilic granulomatosis with polyangiitis. Front. Immunol., 13.","DOI":"10.3389\/fimmu.2022.866035"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"378","DOI":"10.1038\/s41584-023-00958-w","article-title":"Evidence-based guideline for EGPA","volume":"19","author":"Emmi","year":"2023","journal-title":"Nat. Rev. Rheumatol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1016\/j.ejim.2020.12.008","article-title":"Cardiac involvement in EGPA","volume":"85","author":"Zampieri","year":"2021","journal-title":"Eur. J. Intern. Med."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2926","DOI":"10.1002\/art.21250","article-title":"ANCA in Churg\u2013Strauss","volume":"52","author":"Sinico","year":"2005","journal-title":"Arthritis Rheum."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"632","DOI":"10.7326\/0003-4819-143-9-200511010-00006","article-title":"ANCA and Churg\u2013Strauss syndrome","volume":"143","author":"Cohen","year":"2005","journal-title":"Ann. Intern. Med."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1921","DOI":"10.1056\/NEJMoa1702079","article-title":"Mepolizumab or placebo for EGPA","volume":"376","author":"Wechsler","year":"2017","journal-title":"N. Engl. J. Med."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"911","DOI":"10.1056\/NEJMoa2311155","article-title":"Benralizumab vs mepolizumab for EGPA (MANDARA)","volume":"390","author":"Wechsler","year":"2024","journal-title":"N. Engl. J. Med."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"545","DOI":"10.1016\/j.ejim.2015.04.022","article-title":"EGPA Consensus Task Force recommendations","volume":"26","author":"Groh","year":"2015","journal-title":"Eur. J. Intern. Med."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"696","DOI":"10.1016\/j.anai.2021.01.035","article-title":"Reslizumab in EGPA","volume":"126","author":"Manka","year":"2021","journal-title":"Ann. Allergy Asthma Immunol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"2475","DOI":"10.1056\/NEJMoa1804093","article-title":"Dupilumab in glucocorticoid-dependent asthma","volume":"378","author":"Rabe","year":"2018","journal-title":"N. Engl. J. Med."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1800","DOI":"10.1056\/NEJMoa2034975","article-title":"Tezepelumab in severe asthma","volume":"384","author":"Corren","year":"2021","journal-title":"N. Engl. J. Med."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"e000905","DOI":"10.1136\/rmdopen-2019-000905","article-title":"Rituximab in EGPA","volume":"5","author":"Teixeira","year":"2019","journal-title":"RMD Open"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1580","DOI":"10.1136\/ard-2023-224624","article-title":"Benralizumab for EGPA","volume":"82","author":"Cottu","year":"2023","journal-title":"Ann. Rheum Dis."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1186\/2045-7022-4-38","article-title":"High-dose IVIG therapy for EGPA","volume":"4","author":"Tsurikisawa","year":"2014","journal-title":"Clin. Transl. Allergy"},{"key":"ref_36","unstructured":"U.S. Food and Drug Administration (2025, November 07). Fasenra (Benralizumab) Prescribing Information: EGPA Indication Update, Available online: https:\/\/www.accessdata.fda.gov\/drugsatfda_docs\/label\/2024\/761070s021lbl.pdf."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"e126219","DOI":"10.1172\/jci.insight.126219","article-title":"Siglec-8 antibody reduces eosinophils and mast cells","volume":"4","author":"Youngblood","year":"2019","journal-title":"JCI Insight"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"814","DOI":"10.1016\/j.jaci.2020.10.022","article-title":"Janus kinase inhibitors in autoimmune diseases","volume":"147","author":"Damsky","year":"2021","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1694","DOI":"10.1002\/art.41722","article-title":"Occupational exposures and smoking","volume":"73","author":"Maritati","year":"2021","journal-title":"Arthritis Rheumatol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1097\/MD.0b013e318205a4c6","article-title":"The Five-Factor Score revisited","volume":"90","author":"Guillevin","year":"2011","journal-title":"Medicine"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1859","DOI":"10.1182\/blood.2019000518","article-title":"Eosinophil\u2013platelet interactions promote atherosclerosis and stabilize thrombosis with eosinophil extracellular traps","volume":"134","author":"Marx","year":"2019","journal-title":"Blood"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"102660","DOI":"10.1016\/j.autrev.2020.102660","article-title":"Environmental risk factors","volume":"19","author":"Scott","year":"2020","journal-title":"Autoimmun. Rev."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"599","DOI":"10.1056\/NEJMoa2023386","article-title":"Avacopan for ANCA-associated vasculitis","volume":"384","author":"Jayne","year":"2021","journal-title":"N. Engl. J. Med."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/22\/11141\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,11,18]],"date-time":"2025-11-18T11:06:41Z","timestamp":1763464001000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/22\/11141"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,18]]},"references-count":43,"journal-issue":{"issue":"22","published-online":{"date-parts":[[2025,11]]}},"alternative-id":["ijms262211141"],"URL":"https:\/\/doi.org\/10.3390\/ijms262211141","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,11,18]]}}}