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

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. 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 Francais de la Sclerose 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. This study uses a French multiple sclerosis cohort to examine the risk of developing progressive multifocal leukoencephalopathy before and after the release of nationwide risk-minimization recommendations among people with multiple sclerosis who used natalizumab.