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

Educational Objective
To determine whether the incidence of progressive multifocal leukoencephalopathy has decreased since the introduction of risk stratification recommendations based on serologic testing of the John Cunningham virus.
1 Credit CME
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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CME Disclosure Statement: Unless noted, all individuals in control of content reported no relevant financial relationships. If applicable, all relevant financial relationships have been mitigated.

Article Information

Accepted for Publication: May 30, 2019.

Corresponding Author: Sandra Vukusic, MD, Service de Neurologie, Sclérose en Plaques, Pathologies de la Myéline et Neuro-inflammation, Hôpital Neurologique Pierre Wertheimer, 59 Boulevard Pinel, 69677 Bron CEDEX, France (sandra.vukusic@chu-lyon.fr).

Published Online: September 3, 2019. doi:10.1001/jamaneurol.2019.2670

Author Contributions: Dr Vukusic had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Vukusic, Rollot, Casey, Vermersch.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Vukusic, Rollot, Marignier, Guennoc, Laplaud.

Critical revision of the manuscript for important intellectual content: Rollot, Casey, Pique, Mathey, Edan, Brassat, Ruet, De Sèze, Maillart, Zéphir, Labauge, derache, Lebrun-Frénay, Moreau, Wiertlewski, Berger, Moisset, Rico-Lamy, Stankoff, Bensa, Thouvenot, Heinzlef, Al Khedr, Bourre, Vaillant, Cabre, Montcuquet, Wahab, Camdessanché, Tourbah, Hankiewicz, Patry, Nifle, Maubeuge, Labeyrie, Vermersch, Laplaud.

Statistical analysis: Vukusic, Rollot, Casey.

Obtained funding: Vukusic.

Administrative, technical, or material support: Vukusic, Pique, Lebrun-Frénay, Berger, Al Khedr, Camdessanché.

Supervision: Vukusic, Edan, De Sèze, Lebrun-Frénay, Heinzlef, Bourre, Vermersch.

Other: Maillart, Vaillant.

Conflict of Interest Disclosures: Dr Vukusic reported receiving grants, personal fees, and nonfinancial support from Biogen, Merck, Novartis, Roche, and Sanofi Genzyme; personal fees from Celgene; grants from Medday; and personal fees from Teva outside the submitted work. Dr Marignier reported receiving consulting and lecturing fees, travel grants, and research support from Biogen, Sanofi Genzyme, Novartis, Merck Serono, Roche, Sanofi-Aventis, and Teva. Dr Mathey reported receiving nonfinancial support from Biogen outside the submitted work. Dr Edan reported receiving consultancy and lecturing fees from Bayer-Schering, Biogen, LFB, Merck, Novartis, Roche, and Sanofi; receiving research grants from Bayer, Biogen, Genzyme, Merck, Novartis, Roche, Teva, and ARSEP Foundation; and being principal investigator in clinical studies conducted by Bayer, Biogen, Merck, Novartis, Sanofi-Aventis Teva, and 4 academic programs on multiple sclerosis sponsored by Rennes University Hospital. Dr Brassat reported receiving personal fees and travel support from Biogen, Novartis, Sanofi, and Roche; grants from Medday; personal fees from Teva; and consultancy fees from Chugai outside the submitted work. Dr Ruet reported receiving nonfinancial support from Biogen; grants and nonfinancial support from Teva and Roche; grants, personal fees, and nonfinancial support from Merck, Sanofi Genzyme, and Novartis; personal fees and nonfinancial support from Medday; grants from Bayer; and consultancy fees, speaker fees, research grants (nonpersonal), and honoraria approved by the institutions from Novartis, Biogen Idec, Genzyme, Medday, Roche, Teva, and Merck outside the submitted study. Dr De Sèze reported receiving grants, personal fees, and nonfinancial support from Biogen outside the submitted work, as well as consulting and lecturing fees, travel grants, and unconditional research support from Biogen, Genzyme, Novartis, Merck Serono, Roche, Sanofi-Aventis, and Teva Pharma. Dr Maillart reported receiving grants, personal fees, and nonfinancial support from Roche and Novartis; personal fees and nonfinancial support from Merck, Teva, Biogen, and Sanofi Genzyme; personal fees from Ad Scientiam outside the submitted work; consulting and lecturing fees from Biogen, Novartis, Genzyme, Teva Pharmaceuticals, Merck Serono, Roche, and Ad Scientiam; and research support from Novartis and Roche. Dr Zéphir reported receiving personal fees and nonfinancial support from Biogen Idec, Merck, Novartis, Sanofi, Bayer, and Genzyme, and grants, personal fees, and nonfinancial support from Teva and Roche outside the submitted work; consulting or lecture fees and invitations for national and international congresses from Biogen, Merck, Teva, Sanofi Genzyme, Novartis, and Bayer; research support from Teva and Roche; and academic research grants from Académie de Médecine, Ligue Française Contre la Sclérose en Plaques (SEP), Fédération Hospitalo-Universitaire, and ARSEP Foundation. Dr Labauge reported receiving consulting and lecturing fees, travel grants, and unconditional research support from Biogen, Genzyme, Novartis, Merck Serono, Roche, and Teva Pharma. Dr Derache reported receiving personal fees from Biogen, Novartis, and Teva; personal fees and nonfinancial support from Sanofi Genzyme; nonfinancial support from Roche outside the submitted work; and speaker’s honoraria from Merck Serono, Biogen Idec, Sanofi Genzyme, Novartis, and Roche. Dr Lebrun-Frénay reported receiving personal fees and nonfinancial support from Biogen, Merck, Roche, Genzyme, and Novartis, as well as personal fees from Medday during the conduct of the study. Dr Moreau reported receiving personal fees from Biogen, Teva, Sanofi Genzyme, and Novartis, and grants, personal fees, and nonfinancial support from Roche and Merck Serono, as well as grants and personal fees from Medday outside the submitted work; and fees as a scientific adviser to Biogen, Medday, Novartis, Genzyme, and Sanofi. Dr Wiertlewski reported receiving consulting and lecturing fees as well as travel grants from Biogen, Genzyme, Novartis, Merck Serono, Roche, Sanofi, and Teva Pharma. Dr Berger reported receiving research support from Biogen as well as honoraria and consulting fees from Novartis, Sanofi-Aventis, Biogen, Genzyme, Roche, and Teva Pharma. Dr Moisset reported receiving personal fees from Biogen, Novartis, Teva, Sanofi Genzyme, Merck Serono, and Roche; nonfinancial support from SOS Oxygène, Pfizer, and Sanofi Pasteur MSD; grants from Ligue Française Contre la SEP; funding from Teva, Novartis, Sanofi Genzyme, Merck Serono, and Astellas; and nonfinancial support from Biogen, Sanofi Pasteur MSD, GSK, AstraZeneca, Pfizer, and Roche outside the submitted work. Dr Stankoff reported receiving personal fees from Biogen, Novartis, and Teva and grants from Merck Serono, Roche, and Genzyme outside the submitted work; consulting and lecturing fees and travel grants from Biogen Idec, Merck Serono, Novartis, and Genzyme; and unconditional research support from Merck Serono, Genzyme, and Roche. Dr Bensa reported receiving personal fees and nonfinancial support from Novartis, Biogen, and Roche and personal fees from Merck and Genzyme outside the submitted work; and consulting and lecturing fees and travel grants from Biogen, Genzyme, Novartis, Merck Serono, Roche, and Teva Pharma. Dr Thouvenot reported receiving personal fees from Actelion, Genzyme, Merck, and Teva Pharma; grants and personal fees from Roche, Novartis, and Biogen outside the submitted work; consulting and lecturing fees, travel grants, or unconditional research support from Actelion, Biogen, Genzyme, Merck Serono, Novartis, Roche, and Teva Pharma; a patent pending for biomarkers of neurodegeneration and neuroregeneration; and academic research support from Programme Hospitalier de Recherche Clinique, and the ARSEP Foundation. Dr Heinzlef reported receiving consulting and lecturing fees from Bayer Schering, Merck, Teva, Genzyme, Novartis, Almirall, and Biogen Idec, travel grants from Novartis, Teva, Genzyme, Merck Serono, and Biogen Idec; and research support from Roche, Merck, and Novartis. Dr Bourre reported serving on scientific advisory board for Biogen, Genzyme, Merck Serono, Novartis, and Roche, as well as funding for travel and honoraria from Biogen Idec, Merck Serono, Novartis, Sanofi Genzyme, Roche, and Teva. Dr Vaillant reported receiving personal fees from Novartis, Roche, and Genzyme outside the submitted work, as well as funding from Roche, Novartis, Biogen, Merck Serono, and Teva. Dr Montcuquet reported receiving nonfinancial support from Teva and personal fees and nonfinancial support from Novartis, Biogen, Roche, Merck, and Sanofi Genzyme outside the submitted work; and funding for travel from Merck Serono, Teva, Novartis, Sanofi Genzyme, and Biogen. Dr Tourbah reported receiving grants, personal fees, and nonfinancial support from Medday and Biogen; grants and personal fees from Novartis; personal fees from Sanofi Genzyme, Merck, and Teva outside the submitted work; consulting and lecturing fees, travel grants, and research support from Medday, Biogen, Sanofi Genzyme, Novartis, Merck Serono, Teva Pharma, and Roche. Dr Guennoc reported receiving personal fees from Roche and Sanofi outside the submitted work, as well as consulting or lecture fees from Biogen, Merck, Sanofi Genzyme, and Roche. Dr Patry reported receiving honoraria and consulting fees from Novartis, Genzyme, and Roche; research support from Biogen and Novartis; travel grants from Genzyme, Novartis, and Roche; grants and personal fees from Novartis, Genzyme, Biogen, and Roche outside the submitted work. Dr Nifle reported receiving personal fees from Novartis, SAS Pharma, and Genzyme during the conduct of the study; honoraria and consulting fees from Roche and Genzyme; research support from Biogen and Novartis; and travel and inscription fees for conferences from Biogen, Sanofi Genzyme, Bayer, Novartis, Teva, Roche, and Merck Serono. Dr Labeyrie reported receiving consulting and lecturing fees from Biogen, Novartis, and Genzyme. Dr Vermersch reported receiving honoraria and consulting fees from Biogen, Sanofi Genzyme, Novartis, Teva, Merck, Roche, Servier, Celgene, Medday, and Almirall, as well as research support from Biogen, Novartis, Sanofi Genzyme, Roche, and Merck. Dr Laplaud reported receiving grants from the ARSEP Foundation and Medday; personal fees from Biogen, Sanofi Genzyme, Merck, and Teva; grants and personal fees from Novartis outside the submitted work; and consulting and lecturing fees, travel grants, and unconditional research support from Biogen, Genzyme, Novartis, Merck Serono, Roche, Sanofi-Aventis, and Teva Pharma. No other disclosures were reported.

Funding/Support: OFSEP (Observatoire Français de la Sclérose en Plaques) is supported by grant ANR-10-COHO-002 from the French state and handled by the Agence Nationale de la Recherche, within the framework of the Investments for the Future program; by the Eugène Devic EDMUS Foundation Against Multiple Sclerosis; and by the ARSEP Foundation.

Role of the Funder/Sponsor: The study protocol was elaborated by Dr Vukusic in collaboration with the OFSEP national coordinating center, and it was reviewed by the OFSEP Scientific Committee. The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

OFSEP Investigators: Francis Guillemin, MD, PhD, Nancy University Hospital; Michel Clanet, MD, PhD, Toulouse University Hospital; Bruno Brochet, MD, PhD, Bordeaux University Hospital; Jean Pelletier, MD, PhD, Assistance Publique des Hôpitaux de Marseille; François Cotton, MD, PhD, Hospices Civils de Lyon; Bertrand Fontaine, MD, PhD, Sorbonne University; Muriel Malbezin, MD, Hospices Civils de Lyon; Javier Olaiz, Claude Bernard Lyon 1 University; Claire Rigaud-Bully, EDMUS Foundation for Multiple Sclerosis; Nadine Debard, Observatoire Français de la Sclérose en Plaques; Françoise Durand-Dubief, MD, PhD, Hospices Civils de Lyon; Iuliana Ionescu, MD, Hospices Civils de Lyon; Amalle Abdelalli, Hospices Civils de Lyon; Marc Debouverie, MD, PhD, Nancy University Hospital; Amandine Ziegler, Nancy University Hospital; Emmanuelle Le Page, MD, Rennes University Hospital; Emmanuelle Leray, PhD, Ecole des Hautes Etudes en Santé Publique; Laure Michel, MD, Rennes University Hospital; Romain Muraz, Rennes University Hospital; Damien Le Port, Rennes University Hospital; Jonathan Ciron, MD, Toulouse University Hospital; Damien Biotti, MD, Toulouse University Hospital; Jean-Christophe Ouallet, MD, Bordeaux University Hospital; Katy-Kim Kounkou, Bordeaux University Hospital; Nicolas Collongues, MD, PhD, Strasbourg University Hospital; Carole Berthe, Strasbourg University Hospital; Patrick Hautecoeur, MD, PhD, Lille Catholic University; Olivier Outteryck, MD, PhD, Lille University Hospital; Fabienne Deruelle, Lille University Hospital; Caroline Papeix, MD, Assistance Publique des Hôpitaux de Paris, Pitié-Salpêtrière Hospital; Catherine Lubetzki, MD, PhD, Assistance Publique des Hôpitaux de Paris, Pitié-Salpêtrière Hospital; Mikael Cohen, MD, Nice University Hospital; Céline Callier, Nice University Hospital; Gilles Defer, MD, PhD, Caen University Hospital; Pierre Branger, MD, Caen University Hospital; Xavier Ayrignac, MD, PhD, Montpellier University Hospital; Clarisse Carra-Dalliere, MD, Montpellier University Hospital; Frédéric Pinna, Montpellier University Hospital; Agnès Fromont, MD, PhD, Dijon University Hospital; Alexia Protin, Dijon University Hospital; Natacha Jousset, Nantes University Hospital; Nathalie Devys-Meyer, MD, Besancon University Hospital; Mathieu Bereau, MD, Besancon University Hospital; Chrystelle Cappe, Besancon University Hospital; Pierre Clavelou, MD, PhD, Clermont-Ferrand University Hospital; Frédéric Taithe, MD, Clermont-Ferrand University Hospital; Emilie Dumont, Clermont-Ferrand University Hospital; Bertrand Audoin, MD, PhD, Assistance Publique des Hôpitaux de Marseille; Bernadette Di Lelio, Assistance Publique des Hôpitaux de Marseille; Giovanni Castelnovo, MD, Nîmes University Hospital; Claire Giannesini, MD, Assistance Publique des Hôpitaux de Paris, Saint-Antoine Hospital; Ombeline Fagniez, MD, Poissy-Saint-Germain Hospital; Clémence Laage, MD, Poissy-Saint-Germain Hospital; Romain Lefaucheur, MD, Rouen University Hospital; David Maltete, MD, Rouen University Hospital; Christine Vimont, MD, Rouen University Hospital; Sabrina Sehaki, Amiens University Hospital; Olivier Gout, MD, PhD, Fondation Rothschild; Antoine Guegen, MD, Fondation Rothschild; Irène Tabellah Kasonde, MD, Martinique University Hospital; Aymeric De Vilmarrest, MD, Martinique University Hospital; Laurent Magy, MD, PhD, Limoges University Hospital; Marie Nicol, Limoges University Hospital; Olivier Casez, MD, Grenoble-Alpes University Hospital, Grenoble, France; Maty Diop Kane, CRA, Grenoble-Alpes University Hospital; Vincent Visneux, Saint-Etienne University Hospital; Stéphane Beltran, MD, Tours University Hospital; Géraldine Meunier, Tours University Hospital; Alain Creange, MD, PhD, Assistance Publique des Hôpitaux de Paris, Henri Mondor Hospital; Jérôme Hodel, MD, PhD, Assistance Publique des Hôpitaux de Paris, Henri Mondor Hospital; Mohamed Abdellaoui, MD, Assistance Publique des Hôpitaux de Paris, Henri Mondor Hospital; Corinne Pottier, MD, Pontoise Hospital; Iuliana Slesari, MD, Pontoise Hospital; Mathilde Sampaio, CRA, MD, Pontoise Hospital; Jean-Philippe Neau, MD, PhD, Poitiers University Hospital; Emilie Rabois, Poitiers University Hospital; Edwige Lescieux, Corbeil-Essones Hospital; Jérôme Servan, MD, Versailles University Hospital; Fernando Pico, MD PhD, Versailles University Hospital; Virginie Chatagner, CRA, Versailles University Hospital; Carole Henry, MD, Saint-Denis Hospital; Thomas De Broucker, MD, Saint-Denis Hospital; Cédric Castex, Amiens University Hospital; and Sadou-Safa Diallo, Assistance Publique des Hôpitaux de Paris.

Additional Contributions: We are indebted to the patients for their participation in the OFSEP project. Irena Vukusic, RN, assisted in the project management as the academic project coordinator for OFSEP.

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