{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,9]],"date-time":"2026-04-09T04:49:31Z","timestamp":1775710171225,"version":"3.50.1"},"reference-count":28,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,4,9]],"date-time":"2026-04-09T00:00:00Z","timestamp":1775692800000},"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>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>This study aimed to assess the risk of sudden sensorineural hearing loss in patients with ankylosing spondylitis receiving adalimumab in combination with methotrexate, as well as to elucidate the mechanisms underlying drug synergy and ototoxicity.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>A retrospective analysis was performed on data from 2,564 ankylosing spondylitis patients who were admitted to the department of rheumatology and immunology at Henan Provincial People\u2019s Hospital between 2015 and 2024. Fifty-five patients with sudden deafness were designated as the case group, while 110 matched patients without sudden deafness served as the control group. Relevant risk factors were analyzed. Drug exposure was quantified by calculating the defined daily dose (ddd), hearing classification was conducted in accordance with the latest guidelines, and confounding factors were controlled using the inverse probability weighting method (iptw).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Result<\/jats:title>\n                    <jats:p>\n                      The case group exhibited a longer duration of ankylosing spondylitis, with an elevated disease activity index, a higher dosage of medications administered, and an extended treatment duration (\n                      <jats:italic>p<\/jats:italic>\n                      \u202f&amp;lt;\u202f0.05). The incidence of prior otologic conditions and tinnitus was also significantly higher compared to the control group (\n                      <jats:italic>p<\/jats:italic>\n                      \u202f&amp;lt;\u202f0.05). Among the various subtypes of hearing loss, the cumulative drug exposure in patients with total deafness was significantly greater than that in other subtypes (\n                      <jats:italic>p<\/jats:italic>\n                      \u202f&amp;lt;\u202f0.05), while patients exhibiting low-frequency decline were more prone to experience tinnitus symptoms. Adalimumab may disrupt the tight junction proteins of the blood-labyrinth barrier, and methotrexate may inhibit mitochondrial folate metabolism in hair cells, thereby synergistically contributing to disturbances in the inner ear microenvironment.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>The occurrence of sudden deafness in patients treated with the combination of adalimumab and methotrexate for ankylosing spondylitis is associated with drug dosage, treatment duration, and the patient\u2019s individual condition. Patients receiving high-dose, long-term therapy and those with a history of otologic conditions are exposed to an increased risk. This study elucidated the synergistic ototoxicity of combination therapy and identified risk factors for sudden deafness in patients with ankylosing spondylitis undergoing treatment with adalimumab and methotrexate, thereby providing a reference for clinical monitoring.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fneur.2026.1752449","type":"journal-article","created":{"date-parts":[[2026,4,9]],"date-time":"2026-04-09T04:11:24Z","timestamp":1775707884000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["The synergistic ototoxicity of adalimumab combined with methotrexate in the treatment of ankylosing spondylitis"],"prefix":"10.3389","volume":"17","author":[{"given":"Hui","family":"Wei","sequence":"first","affiliation":[{"name":"Department of Otorhinolaryngology, Head and Neck Surgery, Henan Provincial People's Hospital","place":["Zhengzhou, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chunyan","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Otorhinolaryngology, Head and Neck Surgery, Henan Provincial People's Hospital","place":["Zhengzhou, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2026,4,9]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"2273","DOI":"10.1007\/s00405-022-07750-8","article-title":"Evaluation of middle ear and hearing status of ankylosing spondylitis patients with wideband tympanometry and pure tone audiometry tests","volume":"280","author":"Do\u011fan","year":"2023","journal-title":"Eur Arch Otorrinolaringol"},{"key":"ref2","doi-asserted-by":"publisher","first-page":"1103","DOI":"10.1007\/s10067-012-1984-6","article-title":"Hearing and cochlear function of patients with ankylosing spondylitis","volume":"31","author":"Kahveci","year":"2012","journal-title":"Clin Rheumatol"},{"key":"ref3","doi-asserted-by":"publisher","first-page":"1142459","DOI":"10.3389\/fneur.2023.1142459","article-title":"Comorbidities and laboratory changes of sudden sensorineural hearing loss: a review","volume":"14","author":"Xie","year":"2023","journal-title":"Front Neurol"},{"key":"ref4","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1155\/2017\/1824794","article-title":"The nonradiographic axial Spondyloarthritis, the radiographic axial Spondyloarthritis, and ankylosing spondylitis: the tangled skein of rheumatology","volume":"2017","author":"Malaviya","year":"2017","journal-title":"Int J Rheumatol"},{"key":"ref5","doi-asserted-by":"publisher","first-page":"259","DOI":"10.1007\/s10067-008-1027-5","article-title":"The relationship between enthesitis indices and disease activity parameters in patients with ankylosing spondylitis. Comparative study [j]","volume":"28","author":"Sivas","year":"2009","journal-title":"Clin Rheumatol"},{"key":"ref6","doi-asserted-by":"publisher","first-page":"363","DOI":"10.1111\/1756-185X.12986","article-title":"Sulfasalazine might reduce risk of cardiovascular diseases in patients with ankylosing spondylitis: a nationwide population-based retrospective cohort study","volume":"20","author":"Tam","year":"2017","journal-title":"Int J Rheum Dis"},{"key":"ref7","doi-asserted-by":"publisher","first-page":"111395","DOI":"10.1016\/j.ijporl.2022.111395","article-title":"Clinical decision making in paediatric otitis media: a pilot quality improvement study","volume":"164","author":"Cleere","year":"2023","journal-title":"Int J Pediatr Otorhinolaryngol"},{"key":"ref8","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1080\/10543406.2025.2604126","article-title":"Demystifying stabilization in inverse probability of treatment weighting","volume":"31","author":"Ma","year":"2025","journal-title":"J Biopharm Stat"},{"key":"ref9","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1007\/978-981-13-6123-4_2","article-title":"Protection of hair cells from ototoxic drug-induced hearing loss [j]","volume":"1130","author":"Guo","year":"2019","journal-title":"Adv Exp Med Biol"},{"key":"ref10","doi-asserted-by":"publisher","first-page":"3293","DOI":"10.1002\/lary.31276","article-title":"Relevant research of inflammatory cytokines spectrum in peripheral blood of sudden hearing loss","volume":"134","author":"Tan","year":"2024","journal-title":"Laryngoscope"},{"key":"ref11","doi-asserted-by":"publisher","first-page":"109262","DOI":"10.1016\/j.heares.2025.109262","article-title":"Drug-induced hearing loss: a real-world pharmacovigilance study using the FDA adverse event reporting system database","volume":"461","author":"Wu","year":"2025","journal-title":"Hear Res"},{"key":"ref12","doi-asserted-by":"publisher","first-page":"G7594","DOI":"10.1136\/bmj.g7594","article-title":"Transparent reporting of a multivariable prediction model for individual prognosis or diagnosis (tripod): the tripod statement [j]","volume":"350","author":"Collins","year":"2015","journal-title":"BMJ"},{"key":"ref13","doi-asserted-by":"publisher","first-page":"56","DOI":"10.1016\/j.toxlet.2021.10.015","article-title":"The disruption and hyperpermeability of blood-labyrinth barrier mediates cisplatin-induced ototoxicity","volume":"354","author":"Gu","year":"2022","journal-title":"Toxicol Lett"},{"key":"ref14","doi-asserted-by":"publisher","first-page":"G989","DOI":"10.1152\/ajpgi.00183.2012","article-title":"Adalimumab prevents barrier dysfunction and antagonizes distinct effects of tnf-\u03b1 on tight junction proteins and signaling pathways in intestinal epithelial cells [j]","volume":"304","author":"Fischer","year":"2012","journal-title":"Am J Physiol Gastrointest Liver Physiol"},{"key":"ref15","doi-asserted-by":"publisher","first-page":"330","DOI":"10.1590\/S0100-879X2010007500020","article-title":"Tumor necrosis factor alpha increases epithelial barrier permeability by disrupting tight junctions in caco-2 cells","volume":"43","author":"Cui","year":"2010","journal-title":"Braz J Med Biol Res"},{"key":"ref16","doi-asserted-by":"publisher","first-page":"233","DOI":"10.1080\/1744666X.2021.1879640","article-title":"The pathogenesis of secondary forms of autoimmune inner ear disease (AIED): advancing beyond the audiogram data","volume":"17","author":"Corazzi","year":"2021","journal-title":"Expert Rev Clin Immunol"},{"key":"ref17","doi-asserted-by":"publisher","first-page":"1012","DOI":"10.1080\/00016480600606723","article-title":"Immune-mediated inner ear disease","volume":"126","author":"Bovo","year":"2006","journal-title":"Acta Otolaryngol"},{"key":"ref18","doi-asserted-by":"publisher","first-page":"G367","DOI":"10.1152\/ajpgi.00173.2003","article-title":"Tnf-\u03b1-induced increase in intestinal epithelial tight junction permeability requires nf-\u03bab activation [j]","volume":"286","author":"Ma","year":"2004","journal-title":"Am J Physiol Gastrointest Liver Physiol"},{"key":"ref19","doi-asserted-by":"publisher","first-page":"357","DOI":"10.1159\/000095897","article-title":"Local perfusion of the tumor necrosis factor \u03b1 blocker infliximab to the inner ear improves autoimmune neurosensory hearing loss [j]","volume":"11","author":"Van Wijk","year":"2006","journal-title":"Audiol neurotol"},{"key":"ref20","doi-asserted-by":"publisher","first-page":"447","DOI":"10.3760\/cma.j.cn115330-20241120-00644","article-title":"Effect of TNF-\u03b1 on cisplatin-induced permeability change of blood labyrinth barrier in cochlea of C57BL\/6J mice [j]","volume":"60","author":"Yu","year":"2025","journal-title":"Zhonghua Er Bi Yan Hou Tou Jing Wai Ke Za Zhi"},{"key":"ref21","doi-asserted-by":"publisher","first-page":"1243370","DOI":"10.3389\/fnmol.2023.1243370","article-title":"Human blood-labyrinth barrier model to study the effects of cytokines and inflammation","volume":"16","author":"Sekulic","year":"2023","journal-title":"Front Mol Neurosci"},{"key":"ref22","doi-asserted-by":"publisher","first-page":"40","DOI":"10.3899\/jrheum.200276","article-title":"Hearing loss in patients with ankylosing spondylitis: a systematic review and meta-analysis [j]","volume":"48","author":"Yan","year":"2021","journal-title":"J Rheumatol"},{"key":"ref23","doi-asserted-by":"publisher","first-page":"657","DOI":"10.1044\/2023_aja-22-00157","article-title":"Is methotrexate ototoxic? Investigating the ototoxic late effects of pediatric cancer treatment [j]","volume":"32","author":"Moore","year":"2023","journal-title":"Am J Audiol"},{"key":"ref24","doi-asserted-by":"publisher","first-page":"81","DOI":"10.1097\/01.rhu.0000158542.43099.35","article-title":"Audiovestibular disorders in patients with ankylosing spondylitis [j]","volume":"11","author":"Casellini","year":"2005","journal-title":"JCR: J Clinical Rheumatol"},{"key":"ref25","doi-asserted-by":"publisher","first-page":"1215","DOI":"10.1093\/rheumatology\/keq031","article-title":"Transmembrane TNF-alpha: structure, function and interaction with anti-TNF agents [j]","volume":"49","author":"Horiuchi","year":"2010","journal-title":"Rheumatology (Oxford)"},{"key":"ref26","doi-asserted-by":"publisher","first-page":"qiag002","DOI":"10.1093\/jleuko\/qiag002","article-title":"TNFR2-targeting biologics: molecular mode of action, possible applications, and future developments","volume":"118","author":"Zaitseva","year":"2026","journal-title":"J Leukoc Biol"},{"key":"ref27","doi-asserted-by":"publisher","first-page":"1890","DOI":"10.1007\/s12264-024-01326-8","article-title":"Conditional Tnfaip6-knockout in inner ear hair cells does not Alter auditory function [j]","volume":"40","author":"Qiu","year":"2024","journal-title":"Neurosci Bull"},{"key":"ref28","doi-asserted-by":"publisher","first-page":"99","DOI":"10.1097\/md.0b013e3182079866","article-title":"Audiovestibular manifestations in patients with ankylosing spondylitis [j]","volume":"90","author":"Amor-dorado","year":"2011","journal-title":"Medicine"}],"container-title":["Frontiers in Neurology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fneur.2026.1752449\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,9]],"date-time":"2026-04-09T04:11:27Z","timestamp":1775707887000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fneur.2026.1752449\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4,9]]},"references-count":28,"alternative-id":["10.3389\/fneur.2026.1752449"],"URL":"https:\/\/doi.org\/10.3389\/fneur.2026.1752449","relation":{},"ISSN":["1664-2295"],"issn-type":[{"value":"1664-2295","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,4,9]]},"article-number":"1752449"}}