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Original Investigation
September 3, 2019

Progressive Multifocal Leukoencephalopathy Incidence and Risk Stratification Among Natalizumab Users in France

Author Affiliations
  • 1Université Claude Bernard Lyon 1, Faculté de Médecine Lyon Est, Lyon, France
  • 2Service de Neurologie, Sclérose en Plaques, Pathologies de la Myéline et Neuro-Inflammation, Hôpital Neurologique Pierre Wertheimer, Hospices Civils de Lyon, Lyon/Bron, France
  • 3Centre des Neurosciences de Lyon, Observatoire Français de la Sclérose en Plaques, INSERM 1028 et CNRS UMR5292, Lyon, France
  • 4Université Claude Bernard Lyon 1, Lyon, France
  • 5Hospices Civils de Lyon, Lyon, France
  • 6EDMUS Foundation, Lyon/Bron, France
  • 7Centre des Neurosciences de Lyon, FLUID Team, INSERM 1028 et CNRS UMR5292, Lyon, France
  • 8Department of Neurology, Nancy University Hospital, Nancy, France
  • 9Université de Lorraine, EA 4360 APEMAC, Vandoeuvre-Lès-Nancy, Nancy, France
  • 10CHU Pontchaillou, CIC1414 INSERM, Rennes, France
  • 11Department of Neurology, CHU de Toulouse, Toulouse, France
  • 12University of Bordeaux, Bordeaux, France
  • 13INSERM U1215, Neurocentre Magendie, Bordeaux, France
  • 14CHU de Bordeaux, CIC Bordeaux CIC1401, Bordeaux, France
  • 15Clinical Investigation Center, Department of Neurology, CHU de Strasbourg, INSERM 1434, Strasbourg, France
  • 16Department of Neurology, Assistance Publique des Hôpitaux de Paris, Pitié-Salpêtrière Hospital, Paris, France
  • 17LIRIC (Lille Inflammation Research International Center), University of Lille, CHU de Lille, INSERM UMR995, Lille, France
  • 18CHU de Montpellier, MS Unit, Montpellier, France
  • 19University of Montpellier (MUSE), Montpellier, France
  • 20Department of Neurology, CHU de la Côte de Nacre, Caen, France
  • 21CHU de Nice, Université Nice Côte d’Azur, CRCSEP Nice, Neurologie Pasteur 2, Nice, France
  • 22Department of Neurology, CHU de Dijon, EA4184, Dijon, France
  • 23CHU de Nantes, Service de Neurologie, CIC015 INSERM, Nantes, France
  • 24INSERM CR1064, Nantes, France
  • 25Department of Neurology, CHU de Besançon, Besançon, France
  • 26Department of Neurology, Neuro-Dol, CHU Clermont-Ferrand, Université Clermont Auvergne, INSERM U1107, Clermont-Ferrand, France
  • 27Pôle de Neurosciences Cliniques, Service de Neurologie, APHM, Hôpital de la Timone, Marseille, France
  • 28CRMBM UMR 7339, CNRS, Aix-Marseille Université, Marseille, France
  • 29Brain and Spine Institute, Sorbonne Universités, UPMC Paris 06, ICM, Hôpital de la Pitié Salpêtrière, INSERM UMR S 1127, CNRS UMR 7225, Paris, France
  • 30Department of Neurology, AP-HP, Saint-Antoine Hospital, Paris, France
  • 31Department of Neurology, Fondation Rothschild, Paris, France
  • 32Department of Neurology, CHU de Nîmes, Nîmes, France
  • 33Institut de Génomique Fonctionnelle, UMR5203, INSERM 1191, Université de Montpellier, Montpellier, France
  • 34Department of Neurology, Hôpital de Poissy, Poissy, France
  • 35Department of Neurology, CHU d’Amiens, Amiens, France
  • 36Department of Neurology, CHU de Rouen, Rouen, France
  • 37Department of Neurology, CHU Grenoble Alpes, Grenoble, France
  • 38Department of Neurology, CHU de la Martinique, Fort-de-France, France
  • 39Department of Neurology, CHU de Limoges, Hôpital Dupuytren, Limoges, France
  • 40Department of Neurology, Assistance Publique des Hôpitaux de Paris, Hôpital Henri Mondor, Université Paris Est, Créteil, France
  • 41Department of Neurology, CHU de Saint-Étienne, Hôpital Nord, Saint-Étienne, France
  • 42Department of Neurology, CHU de Reims, Faculté de Médecine de Reims, URCA, Reims, France
  • 43LPN EA 2027 Université Paris 8, Saint-Denis, France
  • 44Department of Neurology, CHU de Tours, Hôpital Bretonneau, CRC SEP, Tours, France
  • 45Department of Neurology, Hôpital Pierre Delafontaine, Centre Hospitalier de Saint-Denis, Saint-Denis, France
  • 46Department of Neurology, Hôpital Sud Francilien, Corbeil-Essonnes, France
  • 47Department of Neurology, Centre Hospitalier de Versailles, Le Chesnay, France
  • 48Department of Neurology, CHU de Poitiers, Hôpital La Milétrie, Poitiers, France
  • 49Department of Neurology, CHU de Bicêtre, Le Kremlin-Bicêtre, France
JAMA Neurol. Published online September 3, 2019. doi:10.1001/jamaneurol.2019.2670
Key Points

Question  Has the incidence of natalizumab-associated progressive multifocal leukoencephalopathy decreased since the introduction of the John Cunningham virus serologic test and risk-stratification recommendations?

Findings  In this multicenter study of 6318 patients with multiple sclerosis enrolled in the French multiple sclerosis registry, incidence rates were found to have decreased significantly by 23% each year since January 2013, when risk-minimization guidelines were implemented, compared with a 45% yearly increase observed before 2013.

Meaning  This study suggests that risk-minimization strategies should be continued and reinforced in the future to manage disease-modifying drug therapy in multiple sclerosis.

Abstract

Importance  Risk of developing progressive multifocal leukoencephalopathy (PML) is the major barrier to using natalizumab for patients with multiple sclerosis (MS). To date, the association of risk stratification with PML incidence has not been evaluated.

Objective  To describe the temporal evolution of PML incidence in France before and after introduction of risk minimization recommendations in 2013.

Design, Setting, and Participants  This observational study used data in the MS registry OFSEP (Observatoire Français de la Sclérose en Plaques) collected between April 15, 2007, and December 31, 2016, by participating MS expert centers and MS-dedicated networks of neurologists in France. Patients with an MS diagnosis according to current criteria, regardless of age, were eligible, and those exposed to at least 1 natalizumab infusion (n = 6318) were included in the at-risk population. A questionnaire was sent to all centers, asking for a description of their practice regarding PML risk stratification. Data were analyzed in July 2018.

Exposures  Time from the first natalizumab infusion to the occurrence of PML, natalizumab discontinuation plus 6 months, or the last clinical evaluation.

Main Outcomes and Measures  Incidence was the number of PML cases reported relative to the person-years exposed to natalizumab. A Poisson regression model for the 2007 to 2016 period estimated the annual variation in incidence and incidence rate ratio (IRR), adjusted for sex and age at treatment initiation and stratified by period (2007-2013 and 2013-2016).

Results  In total, 6318 patients were exposed to natalizumab during the study period, of whom 4682 (74.1%) were female, with a mean (SD [range]) age at MS onset of 28.5 (9.1 [1.1-72.4]) years; 45 confirmed incident cases of PML were diagnosed in 22 414 person-years of exposure. The crude incidence rate for the whole 2007 to 2016 period was 2.00 (95% CI, 1.46-2.69) per 1000 patient-years. Incidence significantly increased by 45.3% (IRR, 1.45; 95% CI, 1.15-1.83; P = .001) each year before 2013 and decreased by 23.0% (IRR, 0.77; 95% CI, 0.61-0.97; P = .03) each year from 2013 to 2016.

Conclusions and Relevance  The results of this study suggest, for the first time, a decrease in natalizumab-associated PML incidence since 2013 in France that may be associated with a generalized use of John Cunningham virus serologic test results; this finding appears to support the continuation and reinforcement of educational activities and risk-minimization strategies in the management of disease-modifying therapies for multiple sclerosis.

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