{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T00:44:30Z","timestamp":1790729070242,"version":"4.1.0"},"reference-count":36,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2024,1,9]],"date-time":"2024-01-09T00:00:00Z","timestamp":1704758400000},"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. Pharmacol."],"abstract":"<jats:p><jats:bold>Background:<\/jats:bold> Given that the fight against coronavirus disease 2019 (COVID-19) is not over, we aimed to explore the occurrence of agranulocytosis and infectious complications in patients with and without COVID-19 following immunoregulatory therapy based on real-world data.<\/jats:p><jats:p><jats:bold>Methods:<\/jats:bold> This was a retrospective disproportionality analysis based on the US Food and Drug Administration Adverse Event Reporting System (FAERS). All cases reported between the first quarter of 2004 and the fourth quarter of 2022 about Janus kinase inhibitors (baricitinib, tofacitinib, ruxolitinib) and interleukin-6 receptor blockers (tocilizumab, sarilumab) were collected. Disproportionality analyses were conducted by reporting odds ratio (ROR) and information component (IC).<\/jats:p><jats:p><jats:bold>Results:<\/jats:bold> A total of 211,363 cases were recognized from the FDA Adverse Event Reporting System database. Data analysis showed that tocilizumab (reporting odds ratio: 3.18, 95% CI: 3.18\u20133.29; information component: 1.37, 95% CI: 1.31\u20131.42), sarilumab (ROR: 1.64, 95% CI: 1.55\u20131.73; IC: 0.61, 95% CI: 0.43\u20130.79), baricitinib (ROR: 3.42, 95% CI: 3.19\u20133.67; IC: 1.43, 95% CI: 1.21\u20131.65), tofacitinib (ROR: 2.53, 95% CI: 2.49\u20132.57; IC: 1.11, 95% CI: 1.05\u20131.16), and ruxolitinib (ROR: 1.87, 95% CI: 1.83\u20131.91; IC: 0.77, 95% CI: 0.70\u20130.84) were all associated with secondary infection. The association in the combination group was higher than that in the monotherapy group (ROR: 4.69, 95% CI: 4.53\u20134.86; IC: 1.73, 95% CI: 1.62\u20131.84). As for agranulocytosis, tocilizumab (ROR: 1.61, 95% CI: 1.53\u20131.69; IC: 0.67, 95% CI: 0.50\u20130.84) and ruxolitinib (ROR: 2.32, 95% CI: 2.21\u20132.43; IC: 1.18, 95% CI: 1.02\u20131.33) showed the significant signals. The association was higher in the combination group than in the monotherapy group (ROR: 2.36, 95% CI: 2.15\u20132.58; IC: 1.20, 95% CI: 0.90\u20131.51). Secondary infection after treatment with tofacitinib (ROR: 1.37, 95% CI: 1.02\u20131.84), tocilizumab (ROR: 1.46, 95% CI: 1.01\u20132.09), and sarilumab (ROR: 2.46, 95% CI: 1.10\u20135.50) was reported more frequently in COVID-19 than in non\u2013COVID-19 patients.<\/jats:p><jats:p><jats:bold>Conclusion:<\/jats:bold> Both Janus kinase inhibitors and interleukin-6 receptor blockers are significantly associated with secondary infection and agranulocytosis, and the combined treatment further increases the association. The correlation with secondary infection in patients treated with tofacitinib, tocilizumab, and sarilumab is higher in COVID-19 than in non\u2013COVID-19 patients.<\/jats:p>","DOI":"10.3389\/fphar.2023.1323240","type":"journal-article","created":{"date-parts":[[2024,1,9]],"date-time":"2024-01-09T04:11:45Z","timestamp":1704773505000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":4,"title":["Agranulocytosis and secondary infection related to JAK inhibitors and IL-6 receptor blockers: a disproportionality analysis using the US Food and drug administration adverse event reporting system"],"prefix":"10.3389","volume":"14","author":[{"given":"Chunyan","family":"Wei","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wanhong","family":"Yin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tingting","family":"Hu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingyi","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huifang","family":"Dan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bin","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2024,1,9]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"313","DOI":"10.4014\/jmb.2003.03011","article-title":"Current status of epidemiology, diagnosis, therapeutics, and vaccines for novel coronavirus disease 2019 (Covid-19)","volume":"30","author":"Ahn","year":"2020","journal-title":"J. Microbiol. Biotechnol."},{"key":"B2","doi-asserted-by":"publisher","first-page":"99","DOI":"10.1046\/j.1365-2257.2002.00437.x","article-title":"Nonchemotherapy drug-induced agranulocytosis: experience of the strasbourg teaching hospital (1985-2000) and review of the literature","volume":"24","author":"Andr\u00e8s","year":"2002","journal-title":"Clin. Lab. Haematol."},{"key":"B3","doi-asserted-by":"publisher","first-page":"655","DOI":"10.1016\/s2213-2600(21)00139-9","article-title":"Interleukin-6 receptor blockade in patients with Covid-19: placing clinical trials into context","volume":"9","author":"Angriman","year":"2021","journal-title":"Lancet Respir. Med."},{"key":"B4","doi-asserted-by":"publisher","first-page":"493","DOI":"10.1080\/15321819.2021.1904414","article-title":"An overview of Covid-19 pandemic: immunology and Pharmacology","volume":"42","author":"Arif","year":"2021","journal-title":"J. Immunoass. Immunochem."},{"key":"B5","doi-asserted-by":"publisher","first-page":"1885","DOI":"10.1007\/s13760-022-02125-6","article-title":"Immune responses following Covid-19 infection in multiple sclerosis patients using immunomodulatory therapy","volume":"123","author":"Bilge","year":"2023","journal-title":"Acta Neurol. Belg"},{"key":"B6","doi-asserted-by":"publisher","first-page":"591","DOI":"10.1007\/s15010-021-01602-z","article-title":"State-of-the-Art review of secondary pulmonary infections in patients with Covid-19 pneumonia","volume":"49","author":"Chong","year":"2021","journal-title":"Infection"},{"key":"B7","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1002\/rmv.2141","article-title":"Interleukin-6 in Covid-19: a systematic review and meta-analysis","volume":"30","author":"Coomes","year":"2020","journal-title":"Rev. Med. Virol."},{"key":"B8","doi-asserted-by":"publisher","first-page":"2351","DOI":"10.1016\/s0140-6736(22)00484-6","article-title":"Estimating global, regional, and national daily and cumulative infections with sars-cov-2 through nov 14, 2021: a statistical analysis","volume":"399","year":"2022","journal-title":"Lancet"},{"key":"B9","doi-asserted-by":"publisher","first-page":"1513","DOI":"10.1016\/s0140-6736(21)02796-3","article-title":"Estimating excess mortality due to the Covid-19 pandemic: a systematic analysis of Covid-19-related mortality, 2020-21","volume":"399","year":"2022","journal-title":"Lancet"},{"key":"B10","doi-asserted-by":"publisher","first-page":"53100719","DOI":"10.1016\/j.drup.2020.100719","article-title":"Fda approved drugs with pharmacotherapeutic potential for sars-cov-2 (Covid-19) therapy","volume":"53","author":"Dro\u017cd\u017cal","year":"2020","journal-title":"Drug Resist Updat"},{"key":"B11","doi-asserted-by":"publisher","first-page":"59100794","DOI":"10.1016\/j.drup.2021.100794","article-title":"An update on drugs with therapeutic potential for sars-cov-2 (Covid-19) treatment","volume":"59","author":"Dro\u017cd\u017cal","year":"2021","journal-title":"Drug Resist Updat"},{"key":"B12","doi-asserted-by":"publisher","first-page":"105108536","DOI":"10.1016\/j.intimp.2022.108536","article-title":"An updated overview of recent advances, challenges, and clinical considerations of il-6 signaling blockade in severe coronavirus disease 2019 (Covid-19)","volume":"105","author":"Elahi","year":"2022","journal-title":"Int. Immunopharmacol."},{"key":"B13","doi-asserted-by":"publisher","first-page":"1541","DOI":"10.1016\/s0140-6736(13)60250-0","article-title":"Tocilizumab monotherapy versus adalimumab monotherapy for treatment of rheumatoid arthritis (adacta): a randomised, double-blind, controlled phase 4 trial","volume":"381","author":"Gabay","year":"2013","journal-title":"Lancet"},{"key":"B14","doi-asserted-by":"publisher","first-page":"406","DOI":"10.1056\/NEJMoa2101643","article-title":"Tofacitinib in patients hospitalized with Covid-19 pneumonia","volume":"385","author":"Guimar\u00e3es","year":"2021","journal-title":"N. Engl. J. Med."},{"key":"B15","doi-asserted-by":"publisher","first-page":"141135145","DOI":"10.3389\/fphar.2023.1135145","article-title":"Therapeutic implications of current Janus kinase inhibitors as anti-Covid agents: a review","volume":"14","author":"Jain","year":"2023","journal-title":"Front. Pharmacol."},{"key":"B16","doi-asserted-by":"publisher","first-page":"674","DOI":"10.1164\/rccm.202103-0714OC","article-title":"Long-term safety and efficacy of tocilizumab in early systemic sclerosis-interstitial lung disease: open-label extension of a phase 3 randomized controlled trial","volume":"205","author":"Khanna","year":"2022","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"B17","doi-asserted-by":"publisher","first-page":"e002236","DOI":"10.1136\/rmdopen-2022-002236","article-title":"Waiting for jak inhibitor safety data","volume":"8","author":"Kragstrup","year":"2022","journal-title":"RMD Open"},{"key":"B18","doi-asserted-by":"publisher","first-page":"m3379","DOI":"10.1136\/bmj.m3379","article-title":"A living who guideline on drugs for Covid-19","volume":"370","author":"Lamontagne","year":"2020","journal-title":"Bmj"},{"key":"B19","doi-asserted-by":"publisher","first-page":"e002838","DOI":"10.1136\/jitc-2021-002838","article-title":"Jak inhibitors and Covid-19","volume":"10","author":"Levy","year":"2022","journal-title":"J. Immunother. Cancer"},{"key":"B20","doi-asserted-by":"publisher","first-page":"593","DOI":"10.1002\/pds.1601","article-title":"A comparison of measures of disproportionality for signal detection on adverse drug reaction spontaneous reporting database of guangdong province in China","volume":"17","author":"Li","year":"2008","journal-title":"Pharmacoepidemiol Drug Saf."},{"key":"B21","doi-asserted-by":"publisher","first-page":"13","DOI":"10.23736\/s2784-8671.20.06772-3","article-title":"Tocilizumab and its usage for skin diseases","volume":"157","author":"Mastorino","year":"2022","journal-title":"Ital. J. Dermatol Venerol."},{"key":"B22","doi-asserted-by":"publisher","first-page":"1576","DOI":"10.1002\/art.27425","article-title":"Is the incidence of rheumatoid arthritis rising? results from olmsted county, Minnesota, 1955-2007","volume":"62","author":"Myasoedova","year":"2010","journal-title":"Arthritis Rheum."},{"key":"B23","doi-asserted-by":"publisher","first-page":"337","DOI":"10.1097\/ccm.0000000000005756","article-title":"Outcomes and adverse effects of baricitinib versus tocilizumab in the management of severe Covid-19","volume":"51","author":"Peterson","year":"2023","journal-title":"Crit. Care Med."},{"key":"B24","doi-asserted-by":"publisher","first-page":"601","DOI":"10.1080\/1744666x.2021.1919086","article-title":"The role of il-6 and il-6 blockade in Covid-19","volume":"17","author":"Potere","year":"2021","journal-title":"Expert Rev. Clin. Immunol."},{"key":"B25","doi-asserted-by":"publisher","first-page":"359","DOI":"10.1016\/s0140-6736(22)01109-6","article-title":"Baricitinib in patients admitted to hospital with Covid-19 (recovery): a randomised, controlled, open-label, platform trial and updated meta-analysis","volume":"400","author":"Abbas","year":"2022","journal-title":"Lancet"},{"key":"B26","doi-asserted-by":"publisher","first-page":"729","DOI":"10.1007\/s13555-023-00892-5","article-title":"A review on the safety of using jak inhibitors in dermatology: clinical and laboratory monitoring","volume":"13","author":"Samuel","year":"2023","journal-title":"Dermatol Ther. (Heidelb)"},{"key":"B27","doi-asserted-by":"publisher","first-page":"745","DOI":"10.1016\/j.jaad.2016.12.004","article-title":"Janus kinase inhibitors in dermatology: a systematic review","volume":"76","author":"Shreberk-Hassidim","year":"2017","journal-title":"J. Am. Acad. Dermatol"},{"key":"B28","doi-asserted-by":"publisher","first-page":"e445","DOI":"10.1093\/cid\/ciaa954","article-title":"Tocilizumab for treatment of mechanically ventilated patients with Covid-19","volume":"73","author":"Somers","year":"2021","journal-title":"Clin. Infect. Dis."},{"key":"B29","doi-asserted-by":"publisher","first-page":"317","DOI":"10.1056\/NEJMoa1613849","article-title":"Trial of tocilizumab in giant-cell arteritis","volume":"377","author":"Stone","year":"2017","journal-title":"N. Engl. J. Med."},{"key":"B30","doi-asserted-by":"publisher","first-page":"652","DOI":"10.1056\/NEJMoa1608345","article-title":"Baricitinib versus placebo or adalimumab in rheumatoid arthritis","volume":"376","author":"Taylor","year":"2017","journal-title":"N. Engl. J. Med."},{"key":"B31","doi-asserted-by":"publisher","first-page":"335","DOI":"10.1136\/annrheumdis-2021-221276","article-title":"Safety of baricitinib for the treatment of rheumatoid arthritis over a median of 4.6 and up to 9.3 Years of treatment: final results from long-term extension study and integrated database","volume":"81","author":"Taylor","year":"2022","journal-title":"Ann. Rheum. Dis."},{"key":"B32","doi-asserted-by":"publisher","first-page":"3548","DOI":"10.3390\/jcm12103548","article-title":"Reporting of drug-induced myopathies associated with the combination of statins and daptomycin: a disproportionality analysis using the us Food and drug administration adverse event reporting system","volume":"12","author":"Wei","year":"2023","journal-title":"J. Clin. Med."},{"key":"B33","doi-asserted-by":"publisher","first-page":"10709","DOI":"10.1038\/s41598-021-90108-7","article-title":"A pharmacovigilance study of association between proton pump inhibitor and dementia event based on fda adverse event reporting system data","volume":"11","author":"Wu","year":"2021","journal-title":"Sci. Rep."},{"key":"B34","doi-asserted-by":"publisher","first-page":"13692828","DOI":"10.3389\/fphar.2022.692828","article-title":"Acute kidney injury associated with remdesivir: a comprehensive pharmacovigilance analysis of Covid-19 reports in faers","volume":"13","author":"Wu","year":"2022","journal-title":"Front. Pharmacol."},{"key":"B35","doi-asserted-by":"publisher","first-page":"97","DOI":"10.1186\/s12859-019-2628-5","article-title":"Study of serious adverse drug reactions using fda-approved drug labeling and meddra","volume":"20","author":"Wu","year":"2019","journal-title":"BMC Bioinforma."},{"key":"B36","doi-asserted-by":"publisher","first-page":"141125246","DOI":"10.3389\/fimmu.2023.1125246","article-title":"The development of Covid-19 treatment","volume":"14","author":"Yuan","year":"2023","journal-title":"Front. Immunol."}],"container-title":["Frontiers in Pharmacology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2023.1323240\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,1,9]],"date-time":"2024-01-09T04:11:47Z","timestamp":1704773507000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2023.1323240\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,1,9]]},"references-count":36,"alternative-id":["10.3389\/fphar.2023.1323240"],"URL":"https:\/\/doi.org\/10.3389\/fphar.2023.1323240","relation":{},"ISSN":["1663-9812"],"issn-type":[{"value":"1663-9812","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,1,9]]},"article-number":"1323240"}}