Progressive Multifocal Leukoencephalopathy Incidence and Risk Stratification Among Natalizumab Users in 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 PARTICIPANTSThis 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 MEASURESIncidence 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 RELEVANCEThe 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.

Effects of disease-modifying therapy on peripheral leukocytes in patients with multiple sclerosis

“…JC polyomavirus (JCPyV), the causative agent of PML, is common in the general population with a reported prevalence of 30-70% and a continuous rise with age [75,76]. Drug-related PML has been described with CD4+ and CD8+ T cell deficiencies [77,78].…”

Reduction of the risk of PML in natalizumab treated MS patients in Sweden: An effect of improved PML risk surveillance

“…The reported number of PML cases since NTZ was launched in 2006 is 804 and the PML incidence has increased until mid-2016 where it appears to stabilize with approximately 4.18-4.24/1000 patients (Giovannoni et al, 2019). However, a recent registry study observed a decline of the PML incidence in France by 23% annually between 2013 and 2016 (Vukusic et al, 2020). Although the study was based on the national registry, it is not population-based and represents only one-half of the patients with MS in France (Vukusic et al, 2020).…”

“…However, a recent registry study observed a decline of the PML incidence in France by 23% annually between 2013 and 2016 (Vukusic et al, 2020). Although the study was based on the national registry, it is not population-based and represents only one-half of the patients with MS in France (Vukusic et al, 2020). Sweden is a high-risk country for MS with 17,500 registered MS patients in 2008, an estimated prevalence of 188.9/100,000 (95% CI 186.1-191.7) (Ahlgren et al, 2011), recently updated to a total of approximately 20,000 patients according to the Swedish MS registry (NeuroReg) and with approximately 1,000 new cases annually (Ahlgren et al, 2014).…”

Impfungen gegen Infektionskrankheiten bei Multipler Sklerose

“…Ins ZNS gelangen die mit Natalizumab behandelten Immunzellen jedoch in deutlich reduzierter Anzahl. In diesem Kompartiment erzielt der primäre Immunmodulator also gewissermaßen eine zellspezifische Immunsuppression, die wiederum mit einer reduzierten immunologischen Abwehrlage gegen das John-Cunningham-Virus (JCV) assoziiert ist [21,22].…”