{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T16:17:20Z","timestamp":1792513040685,"version":"4.5.0"},"reference-count":57,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,10,20]],"date-time":"2022-10-20T00:00:00Z","timestamp":1666224000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Neurol."],"abstract":"<jats:sec><jats:title>Background and purpose<\/jats:title><jats:p>Previous studies reported conflicting results about the risk of ischemic stroke associated with the use of non-steroidal anti-inflammatory drugs (NSAIDs) in patients with rheumatoid arthritis (RA). We aimed to investigate two specific COX-2 inhibitors, Celecoxib and Etoricoxib, and their corresponding effects on the risk of ischemic stroke in patients with RA.<\/jats:p><\/jats:sec><jats:sec><jats:title>Patients and methods<\/jats:title><jats:p>10,857 patients newly diagnosed with RA were identified and sampled from the Taiwanese National Health Insurance Research Database during the period from 2001 to 2009. The identification of RA was based on the criteria of ICD-9-CM diagnosis code 714.0. Patients diagnosed with cerebrovascular disease and those receiving RA treatment prior to the first diagnosis of RA were excluded. Study endpoint was ischemic stroke, defined by ICD-9-CM code. Cox proportional hazard models and Kaplan Meier curves were used to reveal covariates and differences by drugs in the risk of ischemic stroke. Dosages for Celecoxib were defined as \u2264 200 and &amp;gt;200 mg\/day; those for Etoricoxib were 0 and &amp;gt;0 mg\/day.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Among 7,904 RA patients, 6,669 did not take Celecoxib and 564 (8.46%) of them experienced an ischemic stroke event. Of the 597 individuals who took \u2264 200 mg\/day of Celecoxib, 58 (9.72%) had strokes. Of the 638 patients who took &amp;gt;200 mg\/day of Celecoxib, 38 (5.96%) eventually experienced a stroke. Among the 7,681 patients who did not take Etoricoxib, 654 (8.51%) experienced an ischemic stroke, while 6 (2.69%) in 223 patients who consumed Etoricoxib had a stroke event. Consuming more than 200 mg of Celecoxib per day for &amp;lt;3.5 years lowered the incidence rate for strokes [hazard ratio (HR) 0.67, 95% Confidence Interval (CI) 0.48\u20130.93 for dosage and HR 0.22, 95% CI 0.10\u20130.46 for duration, both <jats:italic>p<\/jats:italic> &amp;lt; 0.001], while consuming any dosage of Etoricoxib significantly decreases the possibility (HR 0.35, 95% CI 0.16\u20130.80, <jats:italic>p<\/jats:italic> &amp;lt; 0.001). On the other hand, consuming Etoricoxib for 8 years might have a neutral or even a potentially protective effect compared to at 3.8 years.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>This population-based retrospective cohort study has shown that Celecoxib and Etoricoxib reduce the risk of ischemic stroke in patients with RA in a dose- and time-dependent manner.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fneur.2022.1018521","type":"journal-article","created":{"date-parts":[[2022,10,20]],"date-time":"2022-10-20T05:33:05Z","timestamp":1666243985000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":5,"title":["Celecoxib and Etoricoxib may reduce risk of ischemic stroke in patients with rheumatoid arthritis: A nationwide retrospective cohort study"],"prefix":"10.3389","volume":"13","author":[{"given":"Acer I-Hung","family":"Chen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yung-Heng","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wuu-Tsun","family":"Perng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeng-Yuan","family":"Chiou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu-Hsun","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lichi","family":"Lin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James Cheng-Chung","family":"Wei","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hsi-Kai","family":"Tsou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,10,20]]},"reference":[{"key":"B1","unstructured":"Stroke Facts2022"},{"key":"B2","doi-asserted-by":"publisher","first-page":"2429","DOI":"10.1056\/NEJMoa1804492","article-title":"Global, regional, and country-specific lifetime risks of stroke, 1990 and 2016","volume":"379","author":"Collaborators","year":"2018","journal-title":"N Engl J Med."},{"key":"B3","doi-asserted-by":"publisher","first-page":"e67","DOI":"10.1161\/CIR.0000000000000573","article-title":"Heart disease and stroke statistics-2018 update: a report from the American Heart Association","volume":"137","author":"Benjamin","year":"2018","journal-title":"Circulation."},{"key":"B4","doi-asserted-by":"publisher","first-page":"1092","DOI":"10.1056\/NEJMoa050493","article-title":"Cardiovascular events associated with rofecoxib in a colorectal adenoma chemoprevention trial","volume":"352","author":"Bresalier","year":"2005","journal-title":"N Engl J Med."},{"key":"B5","doi-asserted-by":"publisher","first-page":"114147","DOI":"10.1016\/j.bcp.2020.114147","article-title":"Non-steroidal anti-inflammatory drugs (NSAIDs) and organ damage: a current perspective","volume":"180","author":"Bindu","year":"2020","journal-title":"Biochem Pharmacol."},{"key":"B6","doi-asserted-by":"publisher","first-page":"812631","DOI":"10.3389\/fcvm.2021.812631","article-title":"Effect of anti-rheumatic drugs on cardiovascular disease events in rheumatoid arthritis","volume":"8","author":"Baoqi","year":"2021","journal-title":"Front Cardiovasc Med."},{"key":"B7","doi-asserted-by":"publisher","first-page":"25","DOI":"10.1007\/s40266-019-00664-x","article-title":"Safety of cyclooxygenase-2 inhibitors in osteoarthritis: outcomes of a systematic review and meta-analysis","volume":"36","author":"Curtis","year":"2019","journal-title":"Drugs Aging."},{"key":"B8","doi-asserted-by":"publisher","first-page":"1071","DOI":"10.1056\/NEJMoa050405","article-title":"Cardiovascular risk associated with Celecoxib in a clinical trial for colorectal adenoma prevention","volume":"352","author":"Solomon","year":"2005","journal-title":"N Engl J Med."},{"key":"B9","doi-asserted-by":"publisher","first-page":"301","DOI":"10.1007\/s40264-019-00900-8","article-title":"Coronary risks associated with diclofenac and other NSAIDs: an update","volume":"43","author":"Moore","year":"2020","journal-title":"Drug Safety."},{"key":"B10","doi-asserted-by":"publisher","first-page":"e0203362","DOI":"10.1371\/journal.pone.0203362","article-title":"Risk of ischemic stroke and the use of individual non-steroidal anti-inflammatory drugs: a multi-country European database study within the SOS Project","volume":"13","author":"Schink","year":"2018","journal-title":"PLoS ONE."},{"key":"B11","doi-asserted-by":"publisher","first-page":"525","DOI":"10.5694\/mja11.10055","article-title":"Stroke risk and NSAIDs: an Australian population-based study","volume":"195","author":"Caughey","year":"2011","journal-title":"Med J Austral."},{"key":"B12","doi-asserted-by":"publisher","first-page":"c7086","DOI":"10.1136\/bmj.c7086","article-title":"Cardiovascular safety of non-steroidal anti-inflammatory drugs: network meta-analysis","volume":"342","author":"Trelle","year":"2011","journal-title":"BMJ."},{"key":"B13","doi-asserted-by":"publisher","first-page":"e0204746","DOI":"10.1371\/journal.pone.0204746","article-title":"Risk of acute myocardial infarction during use of individual NSAIDs: a nested case-control study from the SOS project","volume":"13","author":"Masclee","year":"2018","journal-title":"PLoS ONE."},{"key":"B14","doi-asserted-by":"publisher","first-page":"173","DOI":"10.1177\/2042098617690485","article-title":"Cardiovascular and cerebrovascular risk with nonsteroidal anti-inflammatory drugs and cyclooxygenase 2 inhibitors: latest evidence and clinical implications","volume":"8","author":"Fanelli","year":"2017","journal-title":"Therapeutic Adv Drug Safety."},{"key":"B15","doi-asserted-by":"publisher","first-page":"885","DOI":"10.1056\/NEJMoa061652","article-title":"Celecoxib for the prevention of colorectal adenomatous polyps","volume":"355","author":"Arber","year":"2006","journal-title":"N Engl J Med."},{"key":"B16","doi-asserted-by":"publisher","first-page":"3940","DOI":"10.3390\/molecules26133940","article-title":"Toward multitasking pharmacological COX-targeting agents: non-steroidal anti-inflammatory prodrugs with antiproliferative effects","volume":"26","author":"Grande","year":"2021","journal-title":"Molecules"},{"key":"B17","doi-asserted-by":"publisher","first-page":"619","DOI":"10.1007\/s00228-010-0789-2","article-title":"Rofecoxib, but not Celecoxib, increases the risk of thromboembolic cardiovascular events in young adults-a nationwide registry-based study","volume":"66","author":"Gudbjornsson","year":"2010","journal-title":"Euro J Clin Pharmacol."},{"key":"B18","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1111\/jcpt.12484","article-title":"Non-steroidal anti-inflammatory drug-induced cardiovascular adverse events: a meta-analysis","volume":"42","author":"Gunter","year":"2017","journal-title":"J Clin Pharm Therap."},{"key":"B19","doi-asserted-by":"publisher","first-page":"818877","DOI":"10.3389\/fphar.2022.818877","article-title":"NSAID-associated small intestinal injury: an overview from animal model development to pathogenesis, treatment, and prevention","volume":"13","author":"Zhang","year":"2022","journal-title":"Front Pharmacol."},{"key":"B20","doi-asserted-by":"publisher","first-page":"4262","DOI":"10.3390\/ijms20174262","article-title":"Cyclo-oxygenase (COX) inhibitors and cardiovascular risk: are non-steroidal anti-inflammatory drugs really anti-inflammatory?","volume":"20","author":"Khan","year":"2019","journal-title":"Int J Mol Sci."},{"key":"B21","doi-asserted-by":"publisher","first-page":"91","DOI":"10.1016\/j.amjcard.2006.07.069","article-title":"Risk of cardiovascular events in patients receiving Celecoxib: a meta-analysis of randomized clinical trials","volume":"99","author":"White","year":"2007","journal-title":"Am J Cardiol."},{"key":"B22","doi-asserted-by":"publisher","first-page":"3225","DOI":"10.2174\/0929867325666180514112124","article-title":"Cyclooxygenase-2 inhibitors as a therapeutic target in inflammatory diseases","volume":"26","author":"Ferrer","year":"2019","journal-title":"Curr Med Chem."},{"key":"B23","doi-asserted-by":"publisher","first-page":"589","DOI":"10.2174\/1381612043453108","article-title":"Clinical pharmacology of novel selective COX-2 inhibitors","volume":"10","author":"Tacconelli","year":"2004","journal-title":"Curr Pharm Design."},{"key":"B24","doi-asserted-by":"publisher","first-page":"e0179081","DOI":"10.1371\/journal.pone.0179081","article-title":"The effect of anti-rheumatic medications for coronary artery diseases risk in patients with rheumatoid arthritis might be changed over time: a nationwide population-based cohort study","volume":"12","author":"Hung","year":"2017","journal-title":"PLoS ONE."},{"key":"B25","doi-asserted-by":"publisher","first-page":"1591","DOI":"10.1111\/1756-185X.13267","article-title":"Methotrexate might reduce ischemic stroke in patients with rheumatoid arthritis: a population-based retrospective cohort study","volume":"21","author":"Tam","year":"2018","journal-title":"Int J Rheum Dis."},{"key":"B26","doi-asserted-by":"publisher","first-page":"1734","DOI":"10.1136\/annrheumdis-2019-215931","article-title":"Association of human papillomavirus infection with risk for rheumatoid arthritis: a population-based cohort study","volume":"78","author":"Liu","year":"2019","journal-title":"Ann Rheum Dis."},{"key":"B27","doi-asserted-by":"publisher","first-page":"1194","DOI":"10.3390\/ijerph15061194","article-title":"Analysis of socioeconomic status in the patients with rheumatoid arthritis","volume":"15","author":"Yang","year":"2018","journal-title":"Int J Environ Res Public Health."},{"key":"B28","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1002\/pst.2051","article-title":"To use or not to use propensity score matching?","volume":"20","author":"Wang","year":"2021","journal-title":"Pharm Stat."},{"key":"B29","doi-asserted-by":"publisher","first-page":"250","DOI":"10.1037\/a0018719","article-title":"The importance of covariate selection in controlling for selection bias in observational studies","volume":"15","author":"Steiner","year":"2010","journal-title":"Psychol Methods."},{"key":"B30","doi-asserted-by":"publisher","first-page":"2347","DOI":"10.1002\/sim.7274","article-title":"Combining biomarkers for classification with covariate adjustment","volume":"36","author":"Kim","year":"2017","journal-title":"Stat Med."},{"key":"B31","doi-asserted-by":"publisher","first-page":"699","DOI":"10.1111\/1756-185X.14328","article-title":"Comorbidities in Black South Africans with established rheumatoid arthritis","volume":"25","author":"Lala","year":"2022","journal-title":"Int J Rheum Dis."},{"key":"B32","doi-asserted-by":"crossref","DOI":"10.1007\/978-1-4757-3294-8","volume-title":"Modeling Survival Data: Extending the Cox Model","author":"Therneau","year":"2000"},{"key":"B33","unstructured":"GraingerR\n          Best Practice Advocacy Centre New ZealandCelecoxib: Now Fully Subsidised in New Zealand2018"},{"key":"B34","unstructured":"ClinicM\n          Celecoxib (Oral Route). Mayo Clinic2022"},{"key":"B35","doi-asserted-by":"publisher","first-page":"246","DOI":"10.1186\/1471-2474-11-246","article-title":"Comparing Etoricoxib and Celecoxib for preemptive analgesia for acute postoperative pain in patients undergoing arthroscopic anterior cruciate ligament reconstruction: a randomized controlled trial","volume":"11","author":"Boonriong","year":"2010","journal-title":"BMC Musculoskeletal Disord."},{"key":"B36","doi-asserted-by":"publisher","first-page":"6","DOI":"10.2174\/1874312901206010006","article-title":"Efficacy of Etoricoxib, Celecoxib, Lumiracoxib, non-selective NSAIDs, and acetaminophen in osteoarthritis: a mixed treatment comparison","volume":"6","author":"Stam","year":"2012","journal-title":"Open Rheumatol J."},{"key":"B37","doi-asserted-by":"publisher","first-page":"669","DOI":"10.1111\/1756-185X.14323","article-title":"Sex differences in circulating proteins of patients with rheumatoid arthritis: a cohort study","volume":"25","author":"Ferreira","year":"2022","journal-title":"Int J Rheum Dis."},{"key":"B38","unstructured":"RA Pathophysiology2021"},{"key":"B39","doi-asserted-by":"publisher","first-page":"253","DOI":"10.1161\/01.HYP.20.2.253","article-title":"Hypertension, the endothelial cell, and the vascular complications of diabetes mellitus","volume":"20","author":"Hsueh","year":"1992","journal-title":"Hypertension."},{"key":"B40","doi-asserted-by":"publisher","first-page":"25","DOI":"10.2147\/VHRM.S54159","article-title":"Risk of stroke associated with nonsteroidal anti-inflammatory drugs","volume":"10","author":"Park","year":"2014","journal-title":"Vasc Health Risk Manage."},{"key":"B41","doi-asserted-by":"publisher","first-page":"S2","DOI":"10.1186\/ar4174","article-title":"Use of NSAIDs in treating patients with arthritis","volume":"15","author":"Crofford","year":"2013","journal-title":"Arthritis Res Ther."},{"key":"B42","doi-asserted-by":"publisher","first-page":"7129","DOI":"10.1039\/D1RA00328C","article-title":"Application of nanomaterials in the treatment of rheumatoid arthritis","volume":"11","author":"Zheng","year":"2021","journal-title":"RSC Adv"},{"key":"B43","doi-asserted-by":"publisher","first-page":"926","DOI":"10.1016\/j.jfma.2020.08.026","article-title":"Recommendations for psoriatic arthritis management: a joint position paper of the Taiwan Rheumatology Association and the Taiwanese Association for Psoriasis and Skin Immunology","volume":"120","author":"Tsai","year":"2021","journal-title":"J Formosan Med Assoc."},{"key":"B44","doi-asserted-by":"publisher","first-page":"827","DOI":"10.1111\/1756-185X.14356","article-title":"A comprehensive insight into effects of resveratrol on molecular mechanism in rheumatoid arthritis: a literature systematic review","volume":"25","author":"Karimi","year":"2022","journal-title":"Int J Rheum Dis"},{"key":"B45","doi-asserted-by":"publisher","first-page":"986","DOI":"10.1161\/ATVBAHA.110.207449","article-title":"Prostaglandins and inflammation","volume":"31","author":"Ricciotti","year":"2011","journal-title":"Arterioscl Thromb Vasc Biol."},{"key":"B46","doi-asserted-by":"publisher","first-page":"589","DOI":"10.1111\/fcp.12463","article-title":"Cyclo-oxygenase selectivity and chemical groups of nonsteroidal anti-inflammatory drugs and the frequency of reporting hypersensitivity reactions: a case\/noncase study in VigiBase","volume":"33","author":"Bakhriansyah","year":"2019","journal-title":"Fundamental Clin Pharmacol."},{"key":"B47","doi-asserted-by":"publisher","first-page":"1725","DOI":"10.1161\/01.STR.0000226642.55207.94","article-title":"Cyclooxygenase-2 selective nonsteroidal anti-inflammatory drugs and the risk of ischemic stroke: a nested case-control study","volume":"37","author":"Andersohn","year":"2006","journal-title":"Stroke."},{"key":"B48","doi-asserted-by":"publisher","first-page":"739506","DOI":"10.3389\/fncel.2021.739506","article-title":"Inflammation and oxidative stress: potential targets for improving prognosis after subarachnoid hemorrhage","volume":"15","author":"Wu","year":"2021","journal-title":"Front Cell Neurosci."},{"key":"B49","doi-asserted-by":"publisher","first-page":"450","DOI":"10.4103\/1673-5374.245468","article-title":"Combining anti-inflammatory and unfolding protein responses to fight stroke","volume":"14","author":"Anuncibay-Soto","year":"2019","journal-title":"Neural Regener Res."},{"key":"B50","doi-asserted-by":"publisher","first-page":"1410","DOI":"10.1111\/1756-185X.13588","article-title":"Body mass index and glucocorticoid dose contribute to subclinical atherosclerosis in Korean patients with systemic lupus erythematosus: a prospective 4 year follow-up study","volume":"22","author":"Jung","year":"2019","journal-title":"Int J Rheum Dis."},{"key":"B51","doi-asserted-by":"publisher","first-page":"267","DOI":"10.1136\/ewjm.175.4.267","article-title":"Are cyclooxygenase 2 inhibitors free of gastrointestinal side effects?","volume":"175","author":"Bjarnason","year":"2001","journal-title":"Western J Med."},{"key":"B52","doi-asserted-by":"publisher","first-page":"13","DOI":"10.1097\/EDE.0b013e3181c1ea43","article-title":"The hazards of hazard ratios","volume":"21","author":"Hern\u00e1n","year":"2010","journal-title":"Epidemiology."},{"key":"B53","doi-asserted-by":"publisher","first-page":"310","DOI":"10.1097\/FPC.0b013e32834f94cb","article-title":"Celecoxib pathways: pharmacokinetics and pharmacodynamics","volume":"22","author":"Gong","year":"2012","journal-title":"Pharmacogenet Genom."},{"key":"B54","doi-asserted-by":"publisher","first-page":"313","DOI":"10.1080\/03007995.2018.1492910","article-title":"Combination effect of anti-rheumatic medications for coronary artery diseases risk in rheumatoid arthritis: a nationwide population-based cohort study","volume":"35","author":"Hung","year":"2019","journal-title":"Curr Med Res Opinion."},{"key":"B55","doi-asserted-by":"publisher","first-page":"140","DOI":"10.1161\/01.HYP.0000136134.31846.83","article-title":"Relationship between COX-2 specific inhibitors and hypertension","volume":"44","author":"Solomon","year":"2004","journal-title":"Hypertension."},{"key":"B56","doi-asserted-by":"publisher","first-page":"1804","DOI":"10.1016\/j.biopha.2018.10.047","article-title":"The effect of Celecoxib on blood pressure and plasma oxidant\/antioxidant status in co-administration with glucocorticoid in rat","volume":"108","author":"Safaeian","year":"2018","journal-title":"Biomed Pharmacother."},{"key":"B57","doi-asserted-by":"publisher","first-page":"24","DOI":"10.1111\/1756-185X.12043","article-title":"How safe is Celecoxib for Asian-Indian patients with rheumatic diseases?","volume":"16","author":"Danda","year":"2013","journal-title":"Int J Rheum Dis."}],"container-title":["Frontiers in Neurology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fneur.2022.1018521\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,10,20]],"date-time":"2022-10-20T05:33:09Z","timestamp":1666243989000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fneur.2022.1018521\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,10,20]]},"references-count":57,"alternative-id":["10.3389\/fneur.2022.1018521"],"URL":"https:\/\/doi.org\/10.3389\/fneur.2022.1018521","relation":{},"ISSN":["1664-2295"],"issn-type":[{"value":"1664-2295","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,10,20]]},"article-number":"1018521"}}