{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,10]],"date-time":"2026-03-10T15:00:45Z","timestamp":1773154845601,"version":"3.50.1"},"reference-count":77,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2022,9,8]],"date-time":"2022-09-08T00:00:00Z","timestamp":1662595200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JPM"],"abstract":"<jats:p>Background: Multiple Sclerosis treatment with B-cell targeted therapies may be associated with an increased incidence of headache. We aimed to find and compare the association of B-cell targeted therapies with the incidence of headache in patients with Multiple Sclerosis. Methods: In a systematic based approach, the following databases were searched from inception until the 6th of June 2020: Pubmed\/MEDLINE, ClinicalTrials.gov, EU Clinical Trials Register. Only randomized clinical trials (RCTs) enrolling patients with Multiple Sclerosis comparing B-cell targeted therapies (Rituximab, Ocrelizumab, Ofatumumab, Ublituximab or Cladribine) with placebo were selected for the systematic review and further meta-analysis. PRISMA guidelines were followed at all stages of the systematic review. The primary outcome was an all-cause headache of B-cell targeting therapy in patients with Multiple Sclerosis. Results: Nine RCTs were included. Compared with placebo, treatment with B-cell targeting therapies revealed a trend in headache risk, but it was not statistically significant (Relative Risk 1.12 [95% Confidence Interval 0.96\u20131.30]; p = 0.15; I2 = 9.32%). Surprisingly, in a sub-group analysis, Cladribine was statistically significant for an increase in headache risk (RR 1.20 [95% CI 1.006\u20131.42]; p = 0.042; I2 = 0%; 3 studies with 2107 participants). Conclusions: Even though a trend is shown, B-cell targeted therapies do not correlate with an increased incidence of headache as an adverse effect. Sub-analyses revealed a significant association between Cladribine alone and an increased incidence of headache. Whereas a purinergic signaling cascade is proposed as a mechanism of action, further research is needed to unravel the underlying pathogenetic mechanism of headache induction and establish headache prevention strategies.<\/jats:p>","DOI":"10.3390\/jpm12091474","type":"journal-article","created":{"date-parts":[[2022,9,8]],"date-time":"2022-09-08T09:51:09Z","timestamp":1662630669000},"page":"1474","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["B-Cell Targeted Therapies in Patients with Multiple Sclerosis and Incidence of Headache: A Systematic Review and Meta-Analysis"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5952-5106","authenticated-orcid":false,"given":"Theodoros","family":"Mavridis","sequence":"first","affiliation":[{"name":"1st Department of Neurology, Eginition Hospital, Medical School, National and Kapodistrian University of Athens, 72-74 V. Sofia\u2019s Avenue, 11528 Athens, Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8401-8472","authenticated-orcid":false,"given":"Nikolaos","family":"Papagiannakis","sequence":"additional","affiliation":[{"name":"1st Department of Neurology, Eginition Hospital, Medical School, National and Kapodistrian University of Athens, 72-74 V. Sofia\u2019s Avenue, 11528 Athens, Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marianthi","family":"Breza","sequence":"additional","affiliation":[{"name":"1st Department of Neurology, Eginition Hospital, Medical School, National and Kapodistrian University of Athens, 72-74 V. Sofia\u2019s Avenue, 11528 Athens, Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0413-4028","authenticated-orcid":false,"given":"Georgios D.","family":"Vavougios","sequence":"additional","affiliation":[{"name":"Neuroimmunology Laboratory, Department of Neurology, Athens Naval Hospital, 11521 Athens, Greece"},{"name":"Department of Respiratory Medicine, Faculty of Medicine, University of Thessaly, Biopolis, 41334 Larissa, Greece"},{"name":"Department of Computer Science and Telecommunications, University of Thessaly, Galaneika, 41334 Lamia, Greece"},{"name":"Department of Nursing, University of Thessaly, 41334 Larissa, Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kostas","family":"Patas","sequence":"additional","affiliation":[{"name":"1st Department of Neurology, Eginition Hospital, Medical School, National and Kapodistrian University of Athens, 72-74 V. Sofia\u2019s Avenue, 11528 Athens, Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6292-858X","authenticated-orcid":false,"given":"Ariadne","family":"Daponte","sequence":"additional","affiliation":[{"name":"1st Department of Neurology, Eginition Hospital, Medical School, National and Kapodistrian University of Athens, 72-74 V. Sofia\u2019s Avenue, 11528 Athens, Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2456-5781","authenticated-orcid":false,"given":"Achilleas","family":"Laskaratos","sequence":"additional","affiliation":[{"name":"Medical School of Athens, National and Kapodistrian University of Athens, 11527 Athens, Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6660-6916","authenticated-orcid":false,"given":"Paraschos","family":"Archontakis-Barakakis","sequence":"additional","affiliation":[{"name":"Northeast Internal Medicine Associates, LaGrange, IN 46761, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8846-519X","authenticated-orcid":false,"given":"Ioannis","family":"Pantazopoulos","sequence":"additional","affiliation":[{"name":"Department of Emergency Medicine, Faculty of Medicine, University of Thessaly, Biopolis, 41500 Larissa, Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dimos D.","family":"Mitsikostas","sequence":"additional","affiliation":[{"name":"1st Department of Neurology, Eginition Hospital, Medical School, National and Kapodistrian University of Athens, 72-74 V. Sofia\u2019s Avenue, 11528 Athens, Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,9,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1789","DOI":"10.1016\/S0140-6736(18)32279-7","article-title":"Global, Regional, and National Incidence, Prevalence, and Years Lived with Disability for 354 Diseases and Injuries for 195 Countries and Territories, 1990\u20132017: A Systematic Analysis for the Global Burden of Disease Study 2017","volume":"392","author":"James","year":"2018","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1186\/s10194-018-0899-2","article-title":"Aids to Management of Headache Disorders in Primary Care (2nd Edition): On Behalf of the European Headache Federation and Lifting the Burden: The Global Campaign against Headache","volume":"20","author":"Steiner","year":"2019","journal-title":"J. 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