{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,10]],"date-time":"2026-03-10T06:36:36Z","timestamp":1773124596130,"version":"3.50.1"},"reference-count":53,"publisher":"Public Library of Science (PLoS)","issue":"3","license":[{"start":{"date-parts":[[2026,3,9]],"date-time":"2026-03-09T00:00:00Z","timestamp":1773014400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS One"],"abstract":"\n Objective<\/jats:title>\n The relationship between leukotriene receptor antagonists (LTRAs) usage and the subsequent occurrence of eosinophilic granulomatosis with polyangiitis (EGPA) remained highly polarizing and controversial in previous studies. We aimed to investigate the risk of EGPA caused by LTRAs and the potential toxicological mechanisms of LTRAs-related EGPA.<\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n In this real-world pharmacovigilance study, we collected adverse event (AE) reports of EGPA associated with LTRAs use from the U.S. FDA Adverse Event Reporting System (FAERS), Japanese Adverse Drug Event Reporting (JADER), and Canadian Vigilance Adverse Reaction (CVAR) databases. The reporting odds ratio (ROR), proportional reporting ratio (PRR), information component (IC), and empirical Bayesian geometric mean (EBGM) were calculated to quantify the strength of the association between LTRAs and EGPA. The Weibull shape parameter (WSP) test was applied to analyze time-to-onset profiles of EGPA toxicity. Network pharmacology analysis was subsequently performed to identify the central genes to determine the potential mechanisms underlying LTRAs-induced EGPA.<\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n LTRAs, including montelukast, zafirlukast, and pranlukast, exhibited a strong association with EGPA in three databases (the lower limit of 95% confidence interval (CI) for ROR\u2009>\u20091, PRR\u2009>\u20092 with \u03c7\n 2<\/jats:sup>\n values \u22654, EBGM05\u2009>\u20092, and IC025\u2009>\u20090). After excluding corticosteroids as concomitant medication, montelukast remained significantly associated with EGPA in the FAERS database. The median time-to-onset of EGPA associated with LTRAs was 233 (range: 76\u2013660) days, and the WSP test indicated LTRAs had early failure-type profiles. We isolated 81 interactive target genes linking LTRAs to EGPA. Several central genes, including SRC, PTGS2, EDN1, HMOX1, KDR, and OCLN, were revealed via protein-protein interactions analysis and molecular complex detection (MCODE) algorithm.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusion<\/jats:title>\n Our study revealed LTRAs could increase the risk of EGPA, and initially explored potential genes and mechanisms of LTRAs-induced EGPA. It is helpful for clinicians to be alerted to the risk of EGPA during LTRAs administration.<\/jats:p>\n <\/jats:sec>","DOI":"10.1371\/journal.pone.0343084","type":"journal-article","created":{"date-parts":[[2026,3,9]],"date-time":"2026-03-09T17:36:32Z","timestamp":1773077792000},"page":"e0343084","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["Leukotriene receptor antagonists and eosinophilic granulomatosis with polyangiitis: a disproportionality analysis from FAERS, JADER, CVAR databases integrated with network pharmacology"],"prefix":"10.1371","volume":"21","author":[{"given":"Cuilv","family":"Liang","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pingping","family":"Zhuo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-4936-663X","authenticated-orcid":true,"given":"Yin","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2026,3,9]]},"reference":[{"issue":"1","key":"pone.0343084.ref001","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":"J White","year":"2023","journal-title":"Autoimmun Rev"},{"key":"pone.0343084.ref002","doi-asserted-by":"crossref","DOI":"10.1093\/rheumatology\/kez570","article-title":"Eosinophilic granulomatosis with polyangiitis: understanding the disease and its management","volume":"59","author":"G Trivioli","year":"2020","journal-title":"Rheumatology (Oxford)"},{"issue":"12","key":"pone.0343084.ref003","doi-asserted-by":"crossref","first-page":"4829","DOI":"10.1007\/s10067-021-05783-8","article-title":"Burden of illness associated with eosinophilic granulomatosis with polyangiitis: a systematic literature review and meta-analysis","volume":"40","author":"RW Jakes","year":"2021","journal-title":"Clin Rheumatol"},{"issue":"1","key":"pone.0343084.ref004","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1007\/s11926-020-0881-2","article-title":"Eosinophilic vasculitis","volume":"22","author":"KL Vega Villanueva","year":"2020","journal-title":"Curr Rheumatol Rep"},{"issue":"2","key":"pone.0343084.ref005","doi-asserted-by":"crossref","first-page":"380","DOI":"10.1093\/mr\/roab007","article-title":"The prevalence, burden of disease, and healthcare utilization of patients with eosinophilic granulomatosis with polyangiitis in Japan: a retrospective, descriptive cohort claims database study","volume":"32","author":"K-E Sada","year":"2022","journal-title":"Mod Rheumatol"},{"issue":"1","key":"pone.0343084.ref006","doi-asserted-by":"crossref","first-page":"5120","DOI":"10.1038\/s41467-019-12515-9","article-title":"Genome-wide association study of eosinophilic granulomatosis with polyangiitis reveals genomic loci stratified by ANCA status","volume":"10","author":"PA Lyons","year":"2019","journal-title":"Nat Commun"},{"issue":"6","key":"pone.0343084.ref007","doi-asserted-by":"crossref","first-page":"1839","DOI":"10.1002\/art.23496","article-title":"Functionally relevant variations of the interleukin-10 gene associated with antineutrophil cytoplasmic antibody-negative Churg-Strauss syndrome, but not with Wegener\u2019s granulomatosis","volume":"58","author":"S Wieczorek","year":"2008","journal-title":"Arthritis Rheum"},{"issue":"3","key":"pone.0343084.ref008","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1111\/all.12088","article-title":"Eosinophilic granulomatosis with polyangiitis (Churg-Strauss): state of the art","volume":"68","author":"A Vaglio","year":"2013","journal-title":"Allergy"},{"issue":"12","key":"pone.0343084.ref009","doi-asserted-by":"crossref","first-page":"1129","DOI":"10.1016\/j.autrev.2013.06.016","article-title":"The association between silica exposure and development of ANCA-associated vasculitis: systematic review and meta-analysis","volume":"12","author":"JA G\u00f3mez-Puerta","year":"2013","journal-title":"Autoimmun Rev"},{"issue":"1","key":"pone.0343084.ref010","first-page":"45","article-title":"Eosinophilic granulomatosis with polyangiitis induced by montelukast","volume":"63","author":"P Grama","year":"2024","journal-title":"Acta Clin Croat"},{"issue":"9","key":"pone.0343084.ref011","doi-asserted-by":"crossref","first-page":"1119","DOI":"10.1111\/ped.14540","article-title":"A case of omalizumab-associated eosinophilic granulomatosis with polyangiitis","volume":"63","author":"Y Yamaki","year":"2021","journal-title":"Pediatr Int"},{"issue":"7","key":"pone.0343084.ref012","doi-asserted-by":"crossref","first-page":"474","DOI":"10.1016\/j.ejim.2004.07.008","article-title":"Macrolide-induced churg-strauss syndrome","volume":"15","author":"M Roux","year":"2004","journal-title":"Eur J Intern Med"},{"key":"pone.0343084.ref013","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1016\/j.jaut.2014.01.018","article-title":"Diagnosis and classification of eosinophilic granulomatosis with polyangiitis (formerly named Churg-Strauss syndrome)","author":"L Mouthon","year":"2014","journal-title":"J Autoimmun"},{"issue":"3","key":"pone.0343084.ref014","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1056\/NEJM199901213400306","article-title":"Treatment of asthma with drugs modifying the leukotriene pathway","volume":"340","author":"JM Drazen","year":"1999","journal-title":"N Engl J Med"},{"issue":"1","key":"pone.0343084.ref015","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1186\/s13195-021-00892-7","article-title":"Leukotriene receptor antagonist use and cognitive decline in normal cognition, mild cognitive impairment, and Alzheimer\u2019s dementia","volume":"13","author":"LY Xiong","year":"2021","journal-title":"Alzheimers Res Ther"},{"issue":"8","key":"pone.0343084.ref016","article-title":"Is leukotriene receptor antagonist the direct cause of churg-strauss syndrome in asthmatic patients?","volume":"14","author":"S Paul","year":"2022","journal-title":"Cureus"},{"issue":"6","key":"pone.0343084.ref017","doi-asserted-by":"crossref","first-page":"620","DOI":"10.1002\/pds.1353","article-title":"Asthma drug use and the development of Churg-Strauss syndrome (CSS)","volume":"16","author":"LR Harrold","year":"2007","journal-title":"Pharmacoepidemiol Drug Saf"},{"issue":"3","key":"pone.0343084.ref018","doi-asserted-by":"crossref","first-page":"708","DOI":"10.1378\/chest.117.3.708","article-title":"Churg-Strauss syndrome in patients receiving montelukast as treatment for asthma","volume":"117","author":"ME Wechsler","year":"2000","journal-title":"Chest"},{"issue":"10","key":"pone.0343084.ref019","doi-asserted-by":"crossref","first-page":"1769","DOI":"10.1007\/s10067-006-0510-0","article-title":"Churg-Strauss syndrome associated with leukotriene receptor antagonists (LTRA)","volume":"26","author":"R Cuchacovich","year":"2007","journal-title":"Clin Rheumatol"},{"issue":"6","key":"pone.0343084.ref020","doi-asserted-by":"crossref","first-page":"1381","DOI":"10.1007\/s11096-024-01778-y","article-title":"Identification of novel signal of proton pump inhibitor-associated drug reaction with eosinophilia and systemic symptoms: a disproportionality analysis","volume":"46","author":"W Li","year":"2024","journal-title":"Int J Clin Pharm"},{"key":"pone.0343084.ref021","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1080\/14740338.2025.2517232","article-title":"Analysis of the relationship between histamine H1 receptor antagonists and broad dementia events using the FAERS, JADER, and CVAR databases","author":"J Kan","year":"2025","journal-title":"Expert Opin Drug Saf"},{"issue":"6","key":"pone.0343084.ref022","doi-asserted-by":"crossref","first-page":"585","DOI":"10.1007\/s40264-024-01423-7","article-title":"The reporting of A disproportionality analysis for drug safety signal detection using individual case safety reports in pharmaco vigilance (READUS-PV): explanation and elaboration","volume":"47","author":"M Fusaroli","year":"2024","journal-title":"Drug Saf"},{"issue":"7","key":"pone.0343084.ref023","doi-asserted-by":"crossref","first-page":"1092","DOI":"10.1016\/S0149-2918(04)90181-6","article-title":"Association of asthma therapy and Churg-Strauss syndrome: an analysis of postmarketing surveillance data","volume":"26","author":"W DuMouchel","year":"2004","journal-title":"Clin Ther"},{"issue":"3","key":"pone.0343084.ref024","first-page":"161","article-title":"Eosinophilic granulomatosis with polyangiitis in a 4-year-old child: is montelukast and\/or clarithromycin a trigger?","volume":"22","author":"E Altinel Acoglu","year":"2019","journal-title":"Arch Iran Med"},{"key":"pone.0343084.ref025","doi-asserted-by":"crossref","first-page":"1485190","DOI":"10.3389\/fphar.2024.1485190","article-title":"A real-world pharmacovigilance analysis of adverse events associated with irbesartan using the FAERS and JADER databases","volume":"15","author":"Q Liu","year":"2024","journal-title":"Front Pharmacol"},{"issue":"1","key":"pone.0343084.ref026","doi-asserted-by":"crossref","first-page":"1231","DOI":"10.1186\/s12913-021-07260-z","article-title":"Pragmatic pharmacoeconomic analyses by using post-market adverse drug reaction reports: an illustration using infliximab, adalimumab, and the Canada vigilance adverse reaction database","volume":"21","author":"T Maity","year":"2021","journal-title":"BMC Health Serv Res"},{"key":"pone.0343084.ref027","doi-asserted-by":"crossref","DOI":"10.1093\/nar\/gkad976","article-title":"DrugBank 6.0: the DrugBank knowledgebase for 2024","volume":"52","author":"C Knox","year":"2024","journal-title":"Nucleic Acids Res"},{"issue":"7","key":"pone.0343084.ref028","doi-asserted-by":"crossref","first-page":"804","DOI":"10.1089\/thy.2023.0030","article-title":"A Disproportionality analysis of the adverse effect profiles of methimazole and propylthiouracil in patients with hyperthyroidism using the Japanese adverse drug event report database","volume":"33","author":"M Arai","year":"2023","journal-title":"Thyroid"},{"key":"pone.0343084.ref029","doi-asserted-by":"crossref","first-page":"1516449","DOI":"10.3389\/fphar.2025.1516449","article-title":"Safety evaluation of irinotecan: a real-world disproportionality analysis using FAERS and JADER databases during the time period 2004-2024","volume":"16","author":"S Lou","year":"2025","journal-title":"Front Pharmacol"},{"issue":"1","key":"pone.0343084.ref030","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1111\/jcpt.13024","article-title":"Time-to-onset analysis of amiodarone-associated thyroid dysfunction","volume":"45","author":"S Kinoshita","year":"2020","journal-title":"J Clin Pharm Ther"},{"issue":"9","key":"pone.0343084.ref031","doi-asserted-by":"crossref","first-page":"1281","DOI":"10.1080\/14712598.2021.1948529","article-title":"The impact of anti-TNF\u03b1 agents on weight-related changes: new insights from a real-world pharmacovigilance study using the FDA adverse event reporting system (FAERS) database","volume":"21","author":"F Mazhar","year":"2021","journal-title":"Expert Opin Biol Ther"},{"issue":"1","key":"pone.0343084.ref032","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1186\/s10020-024-01033-0","article-title":"Elucidating the role of gut microbiota metabolites in diabetes by employing network pharmacology","volume":"30","author":"W Yao","year":"2024","journal-title":"Mol Med"},{"issue":"2","key":"pone.0343084.ref033","doi-asserted-by":"crossref","first-page":"794","DOI":"10.3390\/ijms23020794","article-title":"Identification of core genes and pathways in melanoma metastasis via bioinformatics analysis","volume":"23","author":"R Xie","year":"2022","journal-title":"Int J Mol Sci"},{"issue":"5","key":"pone.0343084.ref034","doi-asserted-by":"crossref","first-page":"284","DOI":"10.1089\/omi.2011.0118","article-title":"clusterProfiler: an R package for comparing biological themes among gene clusters","volume":"16","author":"G Yu","year":"2012","journal-title":"OMICS"},{"issue":"10","key":"pone.0343084.ref035","doi-asserted-by":"crossref","first-page":"883","DOI":"10.1136\/thx.2007.093955","article-title":"Churg-Strauss syndrome and leukotriene antagonist use: a respiratory perspective","volume":"63","author":"N Nathani","year":"2008","journal-title":"Thorax"},{"issue":"8","key":"pone.0343084.ref036","doi-asserted-by":"crossref","first-page":"677","DOI":"10.1136\/thx.2007.087825","article-title":"The leucotriene receptor antagonist montelukast and the risk of Churg-Strauss syndrome: a case-crossover study","volume":"63","author":"T Hauser","year":"2008","journal-title":"Thorax"},{"issue":"2","key":"pone.0343084.ref037","doi-asserted-by":"crossref","first-page":"186","DOI":"10.1159\/000331901","article-title":"A case of Churg-Strauss syndrome treated with montelukast","volume":"21","author":"C Anar","year":"2012","journal-title":"Med Princ Pract"},{"key":"pone.0343084.ref038","doi-asserted-by":"crossref","first-page":"412524","DOI":"10.1155\/2011\/412524","article-title":"A case of montelukast-induced churg-strauss syndrome associated with liver dysfunction","volume":"2011","author":"K Matsui","year":"2011","journal-title":"Case Reports Hepatol"},{"issue":"6","key":"pone.0343084.ref039","first-page":"201","article-title":"Neuropathy in eosinophilic granulomatosis with polyangiitis: a comparison study of 24 cases with or without prior leukotriene antagonist exposure","volume":"46","author":"L Giusti Del Giardino","year":"2014","journal-title":"Eur Ann Allergy Clin Immunol"},{"issue":"6","key":"pone.0343084.ref040","doi-asserted-by":"crossref","first-page":"661","DOI":"10.1007\/s10067-004-1035-z","article-title":"Churg-Strauss syndrome and the leukotriene receptor antagonist pranlukast","volume":"24","author":"J Shimbo","year":"2005","journal-title":"Clin Rheumatol"},{"issue":"1","key":"pone.0343084.ref041","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1159\/000500544","article-title":"Anti-neutrophil cytoplasmic antibodies positivity and anti-leukotrienes in eosinophilic granulomatosis with polyangiitis: a retrospective monocentric study on 134 Italian patients","volume":"180","author":"JW Schroeder","year":"2019","journal-title":"Int Arch Allergy Immunol"},{"issue":"6","key":"pone.0343084.ref042","doi-asserted-by":"crossref","first-page":"2153","DOI":"10.1007\/s10067-024-07000-8","article-title":"Eosinophilic granulomatosis with polyangiitis and its association with montelukast: a case-based review","volume":"43","author":"G Alexander","year":"2024","journal-title":"Clin Rheumatol"},{"key":"pone.0343084.ref043","doi-asserted-by":"crossref","first-page":"106875","DOI":"10.1016\/j.prostaglandins.2024.106875","article-title":"PGE2 synthesis and signaling in the liver physiology and pathophysiology: an update","volume":"174","author":"E Qiang","year":"2024","journal-title":"Prostaglandins Other Lipid Mediat"},{"key":"pone.0343084.ref044","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1186\/1471-2407-12-19","article-title":"DNA methylation regulates expression of VEGF-R2 (KDR) and VEGF-R3 (FLT4)","volume":"12","author":"H Quentmeier","year":"2012","journal-title":"BMC Cancer"},{"key":"pone.0343084.ref045","doi-asserted-by":"crossref","first-page":"512926","DOI":"10.1155\/2012\/512926","article-title":"The role of Src kinase in macrophage-mediated inflammatory responses","volume":"2012","author":"SE Byeon","year":"2012","journal-title":"Mediators Inflamm"},{"issue":"5","key":"pone.0343084.ref046","doi-asserted-by":"crossref","first-page":"562","DOI":"10.1016\/j.chom.2014.10.009","article-title":"The impact of hepatitis C virus entry on viral tropism","volume":"16","author":"Q Ding","year":"2014","journal-title":"Cell Host Microbe"},{"issue":"5","key":"pone.0343084.ref047","doi-asserted-by":"crossref","first-page":"610","DOI":"10.1161\/ATVBAHA.122.317539","article-title":"Causal gene confusion: the complicated EDN1\/PHACTR1 locus for coronary artery disease","volume":"42","author":"RM Gupta","year":"2022","journal-title":"Arterioscler Thromb Vasc Biol"},{"issue":"4","key":"pone.0343084.ref048","doi-asserted-by":"crossref","first-page":"1449","DOI":"10.1152\/physrev.00003.2016","article-title":"Heme oxygenases in cardiovascular health and disease","volume":"96","author":"A Ayer","year":"2016","journal-title":"Physiol Rev"},{"issue":"14","key":"pone.0343084.ref049","doi-asserted-by":"crossref","first-page":"3580","DOI":"10.3390\/ijms20143580","article-title":"The role of leukotrienes as potential therapeutic targets in allergic disorders","volume":"20","author":"A Jo-Watanabe","year":"2019","journal-title":"Int J Mol Sci"},{"issue":"1","key":"pone.0343084.ref050","article-title":"Leukotriene D4 paradoxically limits LTC4-driven platelet activation and lung immunopathology","volume":"148","author":"T Liu","year":"2021","journal-title":"J Allergy Clin Immunol"},{"issue":"4","key":"pone.0343084.ref051","doi-asserted-by":"crossref","first-page":"329","DOI":"10.5551\/jat.20123","article-title":"Expression analysis of leukotriene-inflammatory gene interaction network in patients with coronary artery disease","volume":"21","author":"J Nair","year":"2014","journal-title":"J Atheroscler Thromb"},{"issue":"9","key":"pone.0343084.ref052","doi-asserted-by":"crossref","first-page":"981","DOI":"10.1007\/s00011-021-01492-9","article-title":"Montelukast potentiates the antiinflammatory effect of NSAIDs in the rat paw formalin model and simultaneously minimizes the risk of gastric damage","volume":"70","author":"SA Abdelhady","year":"2021","journal-title":"Inflamm Res"},{"issue":"2","key":"pone.0343084.ref053","doi-asserted-by":"crossref","first-page":"204","DOI":"10.1111\/j.1365-2222.2010.03653.x","article-title":"Cysteinyl-leukotrienes induce vascular endothelial growth factor production in human monocytes and bronchial smooth muscle cells","volume":"41","author":"S Poulin","year":"2011","journal-title":"Clin Exp Allergy"}],"container-title":["PLOS One"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0343084","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,9]],"date-time":"2026-03-09T17:36:41Z","timestamp":1773077801000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0343084"}},"subtitle":[],"editor":[{"given":"Vipula Rasanga","family":"Bataduwaarachchi","sequence":"first","affiliation":[],"role":[{"role":"editor","vocabulary":"crossref"}]}],"short-title":[],"issued":{"date-parts":[[2026,3,9]]},"references-count":53,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2026,3,9]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0343084","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,3,9]]}}}