Sandra Vukusic1,2,3, Fabien Rollot1,4,5,6, Romain Casey1,4,5,6, Julie Pique1,2, Romain Marignier1,2,7, Guillaume Mathey8,9, Gilles Edan10, David Brassat11, Aurélie Ruet12,13,14, Jérôme De Sèze15, Elisabeth Maillart16, Hélène Zéphir17, Pierre Labauge18,19, Nathalie Derache20, Christine Lebrun-Frenay21, Thibault Moreau22, Sandrine Wiertlewski23,24, Eric Berger25, Xavier Moisset26, Audrey Rico-Lamy27,28, Bruno Stankoff29,30, Caroline Bensa31, Eric Thouvenot32,33, Olivier Heinzlef34, Abdullatif Al-Khedr35, Bertrand Bourre36, Mathieu Vaillant37, Philippe Cabre38, Alexis Montcuquet39, Abir Wahab40, Jean-Philippe Camdessanché41, Ayman Tourbah42,43, Anne-Marie Guennoc44, Karolina Hankiewicz45, Ivania Patry46, Chantal Nifle47, Nicolas Maubeuge48, Céline Labeyrie49, Patrick Vermersch17, David-Axel Laplaud23,24. 1. Université Claude Bernard Lyon 1, Faculté de Médecine Lyon Est, Lyon, France. 2. Service de Neurologie, Sclérose en Plaques, Pathologies de la Myéline et Neuro-Inflammation, Hôpital Neurologique Pierre Wertheimer, Hospices Civils de Lyon, Lyon/Bron, France. 3. Centre des Neurosciences de Lyon, Observatoire Français de la Sclérose en Plaques, INSERM 1028 et CNRS UMR5292, Lyon, France. 4. Université Claude Bernard Lyon 1, Lyon, France. 5. Hospices Civils de Lyon, Lyon, France. 6. EDMUS Foundation, Lyon/Bron, France. 7. Centre des Neurosciences de Lyon, FLUID Team, INSERM 1028 et CNRS UMR5292, Lyon, France. 8. Department of Neurology, Nancy University Hospital, Nancy, France. 9. Université de Lorraine, EA 4360 APEMAC, Vandoeuvre-Lès-Nancy, Nancy, France. 10. CHU Pontchaillou, CIC1414 INSERM, Rennes, France. 11. Department of Neurology, CHU de Toulouse, Toulouse, France. 12. University of Bordeaux, Bordeaux, France. 13. INSERM U1215, Neurocentre Magendie, Bordeaux, France. 14. CHU de Bordeaux, CIC Bordeaux CIC1401, Bordeaux, France. 15. Clinical Investigation Center, Department of Neurology, CHU de Strasbourg, INSERM 1434, Strasbourg, France. 16. Department of Neurology, Assistance Publique des Hôpitaux de Paris, Pitié-Salpêtrière Hospital, Paris, France. 17. LIRIC (Lille Inflammation Research International Center), University of Lille, CHU de Lille, INSERM UMR995, Lille, France. 18. CHU de Montpellier, MS Unit, Montpellier, France. 19. University of Montpellier (MUSE), Montpellier, France. 20. Department of Neurology, CHU de la Côte de Nacre, Caen, France. 21. CHU de Nice, Université Nice Côte d'Azur, CRCSEP Nice, Neurologie Pasteur 2, Nice, France. 22. Department of Neurology, CHU de Dijon, EA4184, Dijon, France. 23. CHU de Nantes, Service de Neurologie, CIC015 INSERM, Nantes, France. 24. INSERM CR1064, Nantes, France. 25. Department of Neurology, CHU de Besançon, Besançon, France. 26. Department of Neurology, Neuro-Dol, CHU Clermont-Ferrand, Université Clermont Auvergne, INSERM U1107, Clermont-Ferrand, France. 27. Pôle de Neurosciences Cliniques, Service de Neurologie, APHM, Hôpital de la Timone, Marseille, France. 28. CRMBM UMR 7339, CNRS, Aix-Marseille Université, Marseille, France. 29. Brain and Spine Institute, Sorbonne Universités, UPMC Paris 06, ICM, Hôpital de la Pitié Salpêtrière, INSERM UMR S 1127, CNRS UMR 7225, Paris, France. 30. Department of Neurology, AP-HP, Saint-Antoine Hospital, Paris, France. 31. Department of Neurology, Fondation Rothschild, Paris, France. 32. Department of Neurology, CHU de Nîmes, Nîmes, France. 33. Institut de Génomique Fonctionnelle, UMR5203, INSERM 1191, Université de Montpellier, Montpellier, France. 34. Department of Neurology, Hôpital de Poissy, Poissy, France. 35. Department of Neurology, CHU d'Amiens, Amiens, France. 36. Department of Neurology, CHU de Rouen, Rouen, France. 37. Department of Neurology, CHU Grenoble Alpes, Grenoble, France. 38. Department of Neurology, CHU de la Martinique, Fort-de-France, France. 39. Department of Neurology, CHU de Limoges, Hôpital Dupuytren, Limoges, France. 40. Department of Neurology, Assistance Publique des Hôpitaux de Paris, Hôpital Henri Mondor, Université Paris Est, Créteil, France. 41. Department of Neurology, CHU de Saint-Étienne, Hôpital Nord, Saint-Étienne, France. 42. Department of Neurology, CHU de Reims, Faculté de Médecine de Reims, URCA, Reims, France. 43. LPN EA 2027 Université Paris 8, Saint-Denis, France. 44. Department of Neurology, CHU de Tours, Hôpital Bretonneau, CRC SEP, Tours, France. 45. Department of Neurology, Hôpital Pierre Delafontaine, Centre Hospitalier de Saint-Denis, Saint-Denis, France. 46. Department of Neurology, Hôpital Sud Francilien, Corbeil-Essonnes, France. 47. Department of Neurology, Centre Hospitalier de Versailles, Le Chesnay, France. 48. Department of Neurology, CHU de Poitiers, Hôpital La Milétrie, Poitiers, France. 49. Department of Neurology, CHU de Bicêtre, Le Kremlin-Bicêtre, France.
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.
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.
Authors: Per Soelberg Sørensen; Antonio Bertolotto; Gilles Edan; Gavin Giovannoni; Ralf Gold; Eva Havrdova; Ludwig Kappos; Bernd C Kieseier; Xavier Montalban; Tomas Olsson Journal: Mult Scler Date: 2012-02 Impact factor: 6.312
Authors: Sandra Vukusic; Romain Casey; Fabien Rollot; Bruno Brochet; Jean Pelletier; David-Axel Laplaud; Jérôme De Sèze; François Cotton; Thibault Moreau; Bruno Stankoff; Bertrand Fontaine; Francis Guillemin; Marc Debouverie; Michel Clanet Journal: Mult Scler Date: 2018-12-13 Impact factor: 6.312
Authors: Joseph R Berger; Allen J Aksamit; David B Clifford; Larry Davis; Igor J Koralnik; James J Sejvar; Russell Bartt; Eugene O Major; Avindra Nath Journal: Neurology Date: 2013-04-09 Impact factor: 9.910
Authors: A Vennegoor; J A van Rossum; C Leurs; M P Wattjes; T Rispens; J L A N Murk; B M J Uitdehaag; J Killestein Journal: Eur J Neurol Date: 2016-03-27 Impact factor: 6.089
Authors: Chris H Polman; Paul W O'Connor; Eva Havrdova; Michael Hutchinson; Ludwig Kappos; David H Miller; J Theodore Phillips; Fred D Lublin; Gavin Giovannoni; Andrzej Wajgt; Martin Toal; Frances Lynn; Michael A Panzara; Alfred W Sandrock Journal: N Engl J Med Date: 2006-03-02 Impact factor: 91.245
Authors: Kedar R Mahajan; Moein Amin; Matthew Poturalski; Jonathan Lee; Danielle Herman; Yufan Zheng; Caroline Androjna; Mark Howell; Robert J Fox; Bruce D Trapp; Stephen E Jones; Kunio Nakamura; Daniel Ontaneda Journal: Mult Scler Date: 2021-03-22 Impact factor: 5.855