{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,4]],"date-time":"2026-06-04T17:39:56Z","timestamp":1780594796091,"version":"3.54.1"},"reference-count":32,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2021,1,13]],"date-time":"2021-01-13T00:00:00Z","timestamp":1610496000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2021,1,13]],"date-time":"2021-01-13T00:00:00Z","timestamp":1610496000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100004587","name":"Instituto de Salud Carlos III","doi-asserted-by":"publisher","award":["PI15\/01578"],"award-info":[{"award-number":["PI15\/01578"]}],"id":[{"id":"10.13039\/501100004587","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>The anti-inflammatory effect of OnabotulinumtoxinA (OnabotA) has been a matter of discussion for many years. In chronic migraine, however, increased pro-inflammatory state is associated with good response to OnabotA. We aimed to investigate whether a mild systemic inflammatory state elicited by a common oral infection (periodontitis) could enhance treatment response to OnabotA. In this study, we included 61 chronic migraineurs otherwise healthy treated with OnabotA of which 7 were poor responders and 54 good responders. Before receiving OnabotA therapy, all participants underwent a full-mouth periodontal examination and blood samples were collected to determine serum levels of calcitonin gene-related peptide (CGRP), interleukin 6 (IL-6), IL-10 and high sensitivity C-reactive protein (hs-CRP). Periodontitis was present in 70.4% of responders and 28.6% of non-responders (P\u2009=\u20090.042). Responders showed greater levels of inflammation than non-responders (IL-6: 15.3\u2009\u00b1\u20098.7 vs. 9.2\u2009\u00b1\u20094.7\u00a0ng\/mL, P\u2009=\u20090.016; CGRP: 18.8\u2009\u00b1\u20097.6 vs. 13.0\u2009\u00b1\u20093.1\u00a0pg\/mL, P\u2009=\u20090.002; and hs-CRP: 3.9\u2009\u00b1\u20096.6 vs. 0.9\u2009\u00b1\u20090.8\u00a0mg\/L, P\u2009=\u20090.003). A linear positive correlation was found between the amount of periodontal tissue inflamed in the oral cavity and markers of inflammation (IL-6: r\u2009=\u20090.270, P\u2009=\u20090.035; CGRP: r\u2009=\u20090.325, P\u2009=\u20090.011; and hs-CRP: r\u2009=\u20090.370, P\u2009=\u20090.003). This report shows that in presence of elevated systemic inflammatory markers related to periodontitis, OnabotA seems to reduce migraine attacks. The changes of scheduled inflammatory parameters after treatment and subsequent assessment during an adequate period still need to be done.<\/jats:p>","DOI":"10.1038\/s41598-020-80283-4","type":"journal-article","created":{"date-parts":[[2021,1,13]],"date-time":"2021-01-13T11:26:43Z","timestamp":1610537203000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Mild systemic inflammation enhances response to OnabotulinumtoxinA in chronic migraineurs"],"prefix":"10.1038","volume":"11","author":[{"given":"Yago","family":"Leira","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Clara","family":"Dom\u00ednguez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pablo","family":"Ameijeira","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Esteban","family":"L\u00f3pez-Arias","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paulo","family":"\u00c1vila-G\u00f3mez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mar\u00eda","family":"P\u00e9rez-Mato","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tom\u00e1s","family":"Sobrino","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francisco","family":"Campos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan","family":"Blanco","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rogelio","family":"Leira","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,1,13]]},"reference":[{"key":"80283_CR1","doi-asserted-by":"publisher","first-page":"30","DOI":"10.1038\/nri3785","volume":"15","author":"G Hajishengallis","year":"2015","unstructured":"Hajishengallis, G. Periodontitis: From microbial immune subversion to systemic inflammation. Nat. Rev. Immunol. 15, 30\u201344 (2015).","journal-title":"Nat. Rev. Immunol."},{"key":"80283_CR2","doi-asserted-by":"publisher","first-page":"1528","DOI":"10.1902\/jop.2000.71.10.1528","volume":"71","author":"BG Loos","year":"2000","unstructured":"Loos, B. G., Craandijk, J., Hoek, F. J., van Dillen, P. M. W. & van der Velden, U. Elevation of systemic markers related to cardiovascular diseases in the peripheral blood of periodontitis patients. J. Periodontol. 71, 1528\u20131534 (2000).","journal-title":"J. Periodontol."},{"key":"80283_CR3","doi-asserted-by":"publisher","first-page":"1088","DOI":"10.1002\/JPER.19-0051","volume":"90","author":"Y Leira","year":"2019","unstructured":"Leira, Y. et al. Periodontal inflammation is related to increased serum calcitonin gene-related peptide (CGRP) levels in patients with chronic migraine. J. Periodontol. 90, 1088\u20131095 (2019).","journal-title":"J. Periodontol."},{"key":"80283_CR4","doi-asserted-by":"publisher","first-page":"202","DOI":"10.1007\/s10266-019-00461-3","volume":"108","author":"Y Leira","year":"2020","unstructured":"Leira, Y. et al. Periodontitis and vascular inflammatory biomarkers: An experimental in vivo study in rats. Odontology 108, 202\u2013212 (2020).","journal-title":"Odontology"},{"key":"80283_CR5","doi-asserted-by":"publisher","first-page":"561","DOI":"10.1111\/jcpe.13267","volume":"47","author":"Y Leira","year":"2020","unstructured":"Leira, Y. et al. Periodontitis and systemic markers of neurodegeneration: A case\u2013control study. J. Clin. Periodontol. 47, 561\u2013571 (2020).","journal-title":"J. Clin. Periodontol."},{"key":"80283_CR6","doi-asserted-by":"publisher","first-page":"109","DOI":"10.1111\/head.12999","volume":"57","author":"SK Aurora","year":"2017","unstructured":"Aurora, S. K. & Brin, M. F. Chronic migraine: An update on physiology, imaging, and the mechanism of action of two available pharmacologic therapies. Headache. 57, 109\u2013125 (2017).","journal-title":"Headache."},{"key":"80283_CR7","doi-asserted-by":"publisher","first-page":"S9","DOI":"10.1046\/j.1526-4610.43.7s.3.x","volume":"43","author":"KR Aoki","year":"2003","unstructured":"Aoki, K. R. Evidence for antinociceptive activity of botulinum toxin type A in pain management. Headache. 43, S9-15 (2003).","journal-title":"Headache."},{"key":"80283_CR8","doi-asserted-by":"publisher","first-page":"503","DOI":"10.1111\/j.1472-8206.2008.00615.x","volume":"22","author":"L Bach-Rojecky","year":"2008","unstructured":"Bach-Rojecky, L., Dominis, M. & Lackovi\u0107, Z. Lack of anti-inflammatory effect of botulinum toxin type A in experimental models of inflammation. Fund. Clin. Pharmacol. 22, 503\u2013509 (2008).","journal-title":"Fund. Clin. Pharmacol."},{"key":"80283_CR9","doi-asserted-by":"publisher","first-page":"125","DOI":"10.1016\/j.pain.2003.10.008","volume":"107","author":"M Cui","year":"2004","unstructured":"Cui, M., Khanijou, S., Rubino, J. & Aoki, K. R. Subcutaneous administration of botulinum toxin A reduces formalin-induced pain. Pain 107, 125\u2013133 (2004).","journal-title":"Pain"},{"key":"80283_CR10","doi-asserted-by":"publisher","first-page":"1119","DOI":"10.1016\/j.eururo.2006.11.037","volume":"51","author":"YC Chuang","year":"2007","unstructured":"Chuang, Y. C. et al. Intraprostatic capsaicin injection as a novel model for nonbacterial prostatitis and effects of botulinum toxin A. Eur. Urol. 51, 1119\u20131127 (2007).","journal-title":"Eur. Urol."},{"key":"80283_CR11","doi-asserted-by":"publisher","first-page":"555","DOI":"10.1186\/s10194-015-0555-z","volume":"16","author":"J Edvinsson","year":"2015","unstructured":"Edvinsson, J., Warfvinge, K. & Edvinsson, L. Modulation of inflammatory mediators in the trigeminal ganglion by botulinum neurotoxin type A: An organ culture study. J. Headache Pain. 16, 555. https:\/\/doi.org\/10.1186\/s10194-015-0555-z (2015).","journal-title":"J. Headache Pain."},{"key":"80283_CR12","doi-asserted-by":"publisher","first-page":"820","DOI":"10.1097\/j.pain.0000000000000119","volume":"156","author":"E Cernuda-Moroll\u00f3n","year":"2015","unstructured":"Cernuda-Moroll\u00f3n, E. et al. OnabotulinumtoxinA decreases interictal CGRP plasma levels in patients with chronic migraine. Pain 156, 820\u2013824 (2015).","journal-title":"Pain"},{"key":"80283_CR13","doi-asserted-by":"publisher","first-page":"78","DOI":"10.1111\/head.13211","volume":"58","author":"C Dom\u00ednguez","year":"2018","unstructured":"Dom\u00ednguez, C. et al. CGRP and PTX3 as predictors of efficacy of Onabotulinumtoxin type A in chronic migraine: An observational study. Headache. 58, 78\u201387 (2018).","journal-title":"Headache."},{"key":"80283_CR14","doi-asserted-by":"publisher","first-page":"987","DOI":"10.1111\/head.12372","volume":"54","author":"E Cernuda-Moroll\u00f3n","year":"2014","unstructured":"Cernuda-Moroll\u00f3n, E. et al. CGRP and VIP levels as predictors of efficacy of Onabotulinumtoxin type A in chronic migraine. Headache. 54, 987\u2013995 (2014).","journal-title":"Headache."},{"key":"80283_CR15","doi-asserted-by":"publisher","first-page":"90","DOI":"10.1007\/s10266-018-0360-7","volume":"107","author":"P Ameijeira","year":"2019","unstructured":"Ameijeira, P., Leira, Y., Dom\u00ednguez, C., Leira, R. & Blanco, J. Association between periodontitis and chronic migraine: A case\u2013control study. Odontology. 107, 90\u201395 (2019).","journal-title":"Odontology."},{"key":"80283_CR16","doi-asserted-by":"publisher","first-page":"629","DOI":"10.1177\/0333102413485658","volume":"33","author":"Headache Classification Committee of the International Headache Society (IHS)","year":"2013","unstructured":"Headache Classification Committee of the International Headache Society (IHS). The International Classification of Headache Disorders, 3rd edition (beta version). Cephalalgia 33, 629\u2013808 (2013).","journal-title":"Cephalalgia"},{"key":"80283_CR17","doi-asserted-by":"publisher","first-page":"921","DOI":"10.1111\/j.1526-4610.2010.01678.x","volume":"50","author":"DW Dodick","year":"2010","unstructured":"Dodick, D. W. et al. OnabotulinumtoxinA for treatment of chronic migraine: Pooled results from the double-blind, randomized, placebo-controlled phases of the PREEMPT clinical program. Headache. 50, 921\u2013936 (2010).","journal-title":"Headache."},{"key":"80283_CR18","doi-asserted-by":"publisher","first-page":"344","DOI":"10.1016\/j.jclinepi.2007.11.008","volume":"61","author":"E Von Elm","year":"2008","unstructured":"Von Elm, E. et al. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: Guidelines for reporting observational studies. J. Clin. Epidemiol. 61, 344\u2013349 (2008).","journal-title":"J. Clin. Epidemiol."},{"key":"80283_CR19","first-page":"229","volume":"25","author":"J Ainamo","year":"1975","unstructured":"Ainamo, J. & Bay, I. Problems and proposals for recording gingivitis and plaque. Int. Dent. J. 25, 229\u2013235 (1975).","journal-title":"Int. Dent. J."},{"key":"80283_CR20","doi-asserted-by":"publisher","first-page":"1449","DOI":"10.1902\/jop.2012.110664","volume":"83","author":"PI Eke","year":"2012","unstructured":"Eke, P. I., Page, R. C., Wei, L., Thornton-Evans, G. & Genco, R. J. Update of the case definitions for population-based surveillance of periodontitis. J. Periodontol. 83, 1449\u20131454 (2012).","journal-title":"J. Periodontol."},{"key":"80283_CR21","doi-asserted-by":"publisher","first-page":"668","DOI":"10.1111\/j.1600-051X.2008.01249.x","volume":"35","author":"W Nesse","year":"2008","unstructured":"Nesse, W. et al. Periodontal inflamed surface area: Quantifying inflammatory burden. J. Clin. Periodontol. 35, 668\u2013673 (2008).","journal-title":"J. Clin. Periodontol."},{"key":"80283_CR22","doi-asserted-by":"publisher","first-page":"48","DOI":"10.1034\/j.1600-0765.2001.00011.x","volume":"36","author":"PP Hujoel","year":"2001","unstructured":"Hujoel, P. P., White, B. A., Garc\u00eda, R. I. & Listgarten, M. A. The dentogingival epithelial surface area revisited. J. Periodontal. Res. 36, 48\u201355 (2001).","journal-title":"J. Periodontal. Res."},{"key":"80283_CR23","doi-asserted-by":"publisher","first-page":"315","DOI":"10.1016\/j.ejphar.2004.07.035","volume":"500","author":"U Arulmani","year":"2004","unstructured":"Arulmani, U., Maassenvandenbrink, A., Villal\u00f3n, C. M. & Saxena, P. R. Calcitonin gene-related peptide and its role in migraine pathophysiology. Eur. J. Pharmacol. 500, 315\u2013330 (2004).","journal-title":"Eur. J. Pharmacol."},{"key":"80283_CR24","doi-asserted-by":"publisher","first-page":"54","DOI":"10.1046\/j.1468-2982.2002.00310.x","volume":"22","author":"LH Lassen","year":"2002","unstructured":"Lassen, L. H. et al. CGRP may play a causative role in migraine. Cephalalgia 22, 54\u201361 (2002).","journal-title":"Cephalalgia"},{"key":"80283_CR25","doi-asserted-by":"publisher","first-page":"281","DOI":"10.1097\/WCO.0000000000000440","volume":"30","author":"C Ram\u00f3n","year":"2017","unstructured":"Ram\u00f3n, C., Cernuda-Moroll\u00f3n, E. & Pascual, J. Calcitonin gene-related peptide in peripheral blood as a biomarker for migraine. Curr. Opin. Neurol. 30, 281\u2013286 (2017).","journal-title":"Curr. Opin. Neurol."},{"key":"80283_CR26","doi-asserted-by":"publisher","first-page":"1191","DOI":"10.1212\/WNL.0b013e3182a6cb72","volume":"81","author":"E Cernuda-Moroll\u00f3n","year":"2013","unstructured":"Cernuda-Moroll\u00f3n, E. et al. Interictal increase of CGRP levels in peripheral blood as a biomarker of chronic migraine. Neurology. 81, 1191\u20131196 (2013).","journal-title":"Neurology."},{"key":"80283_CR27","doi-asserted-by":"publisher","first-page":"1573","DOI":"10.1111\/j.1526-4610.2011.02022.x","volume":"51","author":"PL Durham","year":"2011","unstructured":"Durham, P. L. & Cady, R. Insights into the mechanism of OnabotulinumtoxinA in chronic migraine. Headache. 51, 1573\u20131577 (2011).","journal-title":"Headache."},{"key":"80283_CR28","doi-asserted-by":"publisher","first-page":"301","DOI":"10.1016\/S0197-0186(01)00094-8","volume":"40","author":"MC Cuesta","year":"2002","unstructured":"Cuesta, M. C., Quintero, L., Pons, H. & Suarez-Roca, H. Substance P and calcitonin gene-related peptide increase IL-1 beta, IL-6 and TNF alpha secretion from human peripheral blood mononuclear cells. Neurochem. Int. 40, 301\u2013306 (2002).","journal-title":"Neurochem. Int."},{"key":"80283_CR29","doi-asserted-by":"publisher","first-page":"207","DOI":"10.1016\/S0165-5728(97)00257-9","volume":"84","author":"Y Tang","year":"1998","unstructured":"Tang, Y., Feng, Y. & Wang, X. Calcitonin gene-related peptide potentiates LPS-induced IL-6 release form mouse peritoneal macrophages. J. Neuroimmunol. 84, 207\u2013212 (1998).","journal-title":"J. Neuroimmunol."},{"key":"80283_CR30","doi-asserted-by":"publisher","first-page":"390","DOI":"10.1111\/jcpe.12534","volume":"43","author":"P Monsarrat","year":"2016","unstructured":"Monsarrat, P. et al. Clinical research activity in periodontal medicine: A systematic mapping of trial registers. J. Clin. Periodontol. 43, 390\u2013400 (2016).","journal-title":"J. Clin. Periodontol."},{"key":"80283_CR31","doi-asserted-by":"publisher","first-page":"678159","DOI":"10.1155\/2013\/678159","volume":"2013","author":"H Rodr\u00edguez-Hern\u00e1ndez","year":"2013","unstructured":"Rodr\u00edguez-Hern\u00e1ndez, H., Simental-Mend\u00eda, L. E., Rodr\u00edguez-Ram\u00edrez, G. & Reyes-Romero, M. A. Obesity and inflammation: Epidemiology, risk factors, and markers of inflammation. Int. J. Endocrinol. 2013, 678159. https:\/\/doi.org\/10.1155\/2013\/678159 (2013).","journal-title":"Int. J. Endocrinol."},{"key":"80283_CR32","doi-asserted-by":"publisher","first-page":"61","DOI":"10.1111\/ane.12171","volume":"129","author":"SK Aurora","year":"2014","unstructured":"Aurora, S. K. et al. OnabotulinumtoxinA for chronic migraine: Efficacy, safety, and tolerability in patients who received all five treatment cycles in the PREEMPT clinical program. Acta. Neurol. Scand. 129, 61\u201370 (2014).","journal-title":"Acta. Neurol. Scand."}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-020-80283-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-020-80283-4","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-020-80283-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,3]],"date-time":"2022-12-03T01:50:24Z","timestamp":1670032224000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-020-80283-4"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,1,13]]},"references-count":32,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2021,12]]}},"alternative-id":["80283"],"URL":"https:\/\/doi.org\/10.1038\/s41598-020-80283-4","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,1,13]]},"assertion":[{"value":"7 May 2020","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"14 December 2020","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"13 January 2021","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"1092"}}