Progressive multifocal leukoencephalopathy risk stratification in multiple sclerosis patients treated with natalizumab Review article
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Published:
Jun 30, 2026
Keywords:
natalizumab, progressive multifocal leukoencephalopathy, JC virus
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Abstract
Progressive multifocal leukoencephalopathy (PML) is a rare but serious adverse effect of immunosuppressive and immunomodulatory treatment. Among multiple sclerosis treatments, natalizumab has been identified as a therapy most strongly linked to increased PML incidence. However, high efficacy in reducing relapses, new MRI lesions and overall disability progression demonstrated by natalizumab makes it a worthwhile option for multiple sclerosis treatment, including early high-efficacy therapy strategy. This creates a need for tools aimed at identifying and mitigating PML risk in multiple sclerosis patients treated with natalizumab. The aim of this paper is to characterize PML, and describe ways to limit its risk in multiple sclerosis population, as well as provide practical information for clinical use.
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References
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2. Markowitz RB, Thompson HC, Mueller JF et al. Incidence of BK virus and JC virus viruria in human immunodeficiency virus-infected and -uninfected subjects. J Infect Dis. 1993; 167(1): 13-20.
3. Astrom KE, Mancall EL, Richardson EP Jr. Progressive multifocal leuko-encephalopathy; a hitherto unrecognized complication of chronic lymphatic leukaemia and Hodgkin’s disease. Brain. 1958; 81(1): 93-111.
4. Grebenciucova E, Berger JR. Progressive Multifocal Leukoencephalopathy. Neurol Clin. 2018; 36(4): 739-50.
5. Bellizzi A, Anzivino E, Rodio DM et al. New insights on human polyomavirus JC and pathogenesis of progressive multifocal leukoencephalopathy. Clin Dev Immunol. 2013; 2013: 839719.
6. Berger JR, Aksamit AJ, Clifford DB et al. PML diagnostic criteria: consensus statement from the AAN Neuroinfectious Disease Section. Neurology. 2013; 80(15): 1430-8.
7. Brew B, Davies N, Cinque P et al. Progressive multifocal leukoencephalopathy and other forms of JC virus disease. Nat Rev Neurol. 2010; 6: 667-79.
8. Schweitzer F, Laurent S, Cortese I et al. Progressive Multifocal Leukoencephalopathy: Pathogenesis, Diagnostic Tools, and Potential Biomarkers of Response to Therapy. Neurology. 2023; 101(16): 700-13.
9. Sriwastava S, Kataria S, Srivastava S et al. Disease-modifying therapies and progressive multifocal leukoencephalopathy in multiple sclerosis: A systematic review and meta-analysis. J Neuroimmunol. 2021; 360: 577721.
10. Polman CH, O’Connor PW, Havrdova E et al.; AFFIRM Investigators. A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med. 2006; 354(9): 899-910.
11. Kappos L, O’Connor PW, Polman CH et al. Clinical effects of natalizumab on multiple sclerosis appear early in treatment course. J Neurol. 2013; 260(5): 1388-95.
12. Krysko KM, O’Connor PW. The Toronto observational study of natalizumab in multiple sclerosis. Can J Neurol Sci. 2011; 38(3): 422-8.
13. Outteryck O, Ongagna JC, Brochet B et al.; BIONAT Network; CFSEP. A prospective observational post-marketing study of natalizumab-treated multiple sclerosis patients: clinical, radiological and biological features and adverse events. The BIONAT cohort. Eur J Neurol. 2014; 21(1): 40-8.
14. Butzkueven H, Kappos L, Wiendl H et al.; Tysabri Observational Program (TOP) Investigators. Long-term safety and effectiveness of natalizumab treatment in clinical practice: 10 years of real-world data from the Tysabri Observational Program (TOP). J Neurol Neurosurg Psychiatry. 2020; 91(6): 660-8.
15. Singer BA, Feng J, Chiong-Rivero H. Early use of high-efficacy therapies in multiple sclerosis in the United States: benefits, barriers, and strategies for encouraging adoption. J Neurol. 2024; 271(6): 3116-30.
16. Program Lekowy Leczenie Chorych Na Stwardnienie Rozsiane B.29.
17. Kleinschmidt-DeMasters BK, Tyler KL. Progressive Multifocal Leukoencephalopathy Complicating Treatment with Natalizumab and Interferon Beta-1a for Multiple Sclerosis. N Engl J Med. 2005; 353: 369-74.
18. Rindi LV, Zaçe D, Braccialarghe N et al. Drug-Induced Progressive Multifocal Leukoencephalopathy (PML): A Systematic Review and Meta-Analysis. Drug Saf. 2024; 47(4): 333-54.
19. Kartau M, Sipilä JO, Auvinen E et al. Progressive Multifocal Leukoencephalopathy: Current Insights. Degener Neurol Neuromuscul Dis. 2019; 9: 109-21.
20. Rae-Grant A, Day GS, Marrie RA et al. Practice guideline recommendations summary: Disease-modifying therapies for adults with multiple sclerosis: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology. Neurology. 2018; 90(17): 777-88.
21. Ryerson LZ, Foley J, Chang I et al. Risk of natalizumab-associated PML in patients with MS is reduced with extended interval dosing. Neurology. 2019; 93(15): e1452-62.
22. Toorop AA, van Lierop ZY, Gelissen LM et al. Prospective trial of natalizumab personalised extended interval dosing by therapeutic drug monitoring in relapsing-remitting multiple sclerosis (NEXT-MS). J Neurol Neurosurg Psychiatry. 2024; 95(5): 392-400.
23. Nakashima I, Ohashi T, Yokoyama K et al. A multicenter, retrospective study in patients with multiple sclerosis treated with natalizumab in a real-world setting in Japan: The REFIND study. Mult Scler Relat Disord. 2026; 107: 107007.
24. Yamout BI, Sahraian MA, Ayoubi NE et al. Efficacy and safety of natalizumab extended interval dosing. Mult Scler Relat Disord. 2018; 24: 113-6.
25. Chitnis T, Magliozzi R, Abdelhak A et al. Blood and CSF biomarkers for multiple sclerosis: emerging clinical applications. Lancet Neurol. 2025; 24(12): 1066-78.