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First and foremost, our analysis highlights the necessity of separate PML incidence assessments for the U.S. versus Europe, and indicates that the risk in John Cunningham virus (JCV) antibody\u2010negative patients may be higher than previously communicated. Additionally, we advocate introducing a low\u2010risk JCV index threshold of 0.45 for individuals with prior exposure to an immunosuppressant, and setting the low\u2010risk threshold at 0.6 instead of 0.9 for those without such pretherapies. On the other hand, the risk of PML on natalizumab, in general, appears to not only plateau but to actually decrease after about 5\u00a0years of continuous dosing.<\/jats:p>","DOI":"10.1002\/acn3.51130","type":"journal-article","created":{"date-parts":[[2021,2,8]],"date-time":"2021-02-08T01:18:07Z","timestamp":1612747087000},"page":"696-703","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Improving risk\u2010stratification of natalizumab\u2010associated PML"],"prefix":"10.1002","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9837-5884","authenticated-orcid":false,"given":"Bastian","family":"Tugemann","sequence":"first","affiliation":[{"name":"Munich Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph R.","family":"Berger","sequence":"additional","affiliation":[{"name":"Perelman School of Medicine University of Pennsylvania Philadelphia PA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2021,2,4]]},"reference":[{"key":"e_1_2_14_2_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.24286"},{"key":"e_1_2_14_3_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1107829"},{"issue":"3","key":"e_1_2_14_4_1","first-page":"659","article-title":"New algorithm to estimate risk of natalizumab\u2010associated progressive multifocal leukoencephalopathy (PML) in anti\u2010JCV antibody positive patients: analyses of clinical trial data to provide further temporal precision and inform clinical practice","volume":"22","author":"Koendgen H","year":"2016","journal-title":"Mult Scler"},{"key":"e_1_2_14_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(17)30282-X"},{"key":"e_1_2_14_6_1","first-page":"e1452","article-title":"Risk of natalizumab\u2010associated PML in patients with MS is reduced with extended interval dosing","volume":"93","author":"Zhovtis Ryerson L","year":"2019","journal-title":"Neurology"},{"key":"e_1_2_14_7_1","doi-asserted-by":"crossref","first-page":"S30.002","DOI":"10.1212\/WNL.80.7_supplement.S30.002","article-title":"Natalizumab related PML: an evolving risk stratification paradigm","volume":"80","author":"Foley J","year":"2013","journal-title":"Neurology"},{"key":"e_1_2_14_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.msard.2019.101863"},{"key":"e_1_2_14_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(19)30022-5"},{"key":"e_1_2_14_10_1","doi-asserted-by":"crossref","first-page":"S26.006","DOI":"10.1212\/WNL.92.15_supplement.S26.006","article-title":"Reduced risk of progressive multifocal leukoencephalopathy (PML) associated with natalizumab extended interval dosing (EID): updated analysis of the TOUCH prescribing program database","volume":"92","author":"Zhovtis Ryerson L","year":"2019","journal-title":"Neurology"},{"key":"e_1_2_14_11_1","volume-title":"Life tables","author":"Diener\u2010West M","year":"2008"},{"key":"e_1_2_14_12_1","doi-asserted-by":"crossref","first-page":"P4.031","DOI":"10.1212\/WNL.84.14_supplement.P4.031","article-title":"Anti\u2010JC virus (JCV) antibody index differentiates risk of progressive multifocal leukoencephalopathy (PML) in natalizumab\u2010treated multiple sclerosis (MS) patients with no prior immunosuppressant (IS) use: an updated analysis","volume":"84","author":"Kuesters G","year":"2015","journal-title":"Neurology"},{"key":"e_1_2_14_13_1","doi-asserted-by":"publisher","DOI":"10.1212\/NXI.0000000000000195"},{"key":"e_1_2_14_14_1","article-title":"Longitudinal analyses of anti\u2010JCV antibody index for risk assessment of progressive multifocal leukoencephalopathy","volume":"2","author":"Salmen A","year":"2016","journal-title":"Mult Scler J Exp Transl Clin"},{"key":"e_1_2_14_15_1","doi-asserted-by":"publisher","DOI":"10.1177\/1352458514567728"},{"key":"e_1_2_14_16_1","unstructured":"European Medicines Agency.Assessment report of the Pharmacovigilance Risk Assessment Committee (PRAC) \u2013 Procedure under article 20 of regulation (EC) no 726\/2004 resulting from pharmacovigilance data (invented name: Tysabri; 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