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.

In most of the patients with acute stroke receiving AR-R15896AR the intended high plasma levels were reached within a short time period. However, active treatment produced more side effects than placebo, thus indicating safety concerns and tolerability issues for use in high doses in an acute stroke population.

No abstract

Background: Natalizumab and fingolimod were the first preparations recommended for disease breakthrough in priorly treated relapsing-remitting multiple sclerosis. Of three published head-to-head studies two showed that natalizumab is the more effective to prevent relapses and EDSS worsening. Methods: By re-analyzing original published results from MSBase, France, and Denmark using uniform methodologies, we aimed at identifying the effects of differences in methodology, in the MS-populations, and at reevaluating the differences in effectiveness between the two drugs. We gained access to copies of the individual amended databases and pooled all data. We used uniform inclusion/ exclusion criteria and statistical methods with Inverse Probability Treatment Weighting. Results: The pooled analyses comprised 968 natalizumab-and 1479 fingolimod treated patients. The ontreatment natalizumab/fingolimod relapse rate ratio was 0.77 (p=0.004). The hazard ratio (HR) for a first relapse was 0.82 (p=0.030), and the HR for sustained EDSS improvement was 1.4 (p=0.009). There were modest differences between each of the original published studies and the replication study, but the conclusions of the three original studies remained unchanged: in two of them natalizumab was more effective, but in the third there was no difference between natalizumab and fingolimod. Conclusion:The results were largely invariant to the epidemiological and statistical methods but differed between the MS populations. Generally, the advantage of natalizumab was confirmed.with the Center for Data Review applications (j. nr. 2012-58-0004/VD-2018-121 I-suite 6361). Declaration of Competing InterestJ.B. Andersen received travel grant and congress participation support from Merck.N. Koch-Henriksen received support for participation in congresses and symposia by Biogen, Merck, Novartis, and Teva.F. Sellebjerg served on scientific advisory boards, been on the steering committees of clinical trials, served as a consultant, received support for congress participation, received speaker honoraria, or received research support for his laboratory from Biogen, Merck, Novartis, Roche, Sanofi Genzyme and Teva. P. S. Sørensen received personal compensation for serving on scientific advisory boards, steering committees, independent data monitoring committees or have received speaker honoraria for Merck, Novartis, TEVA, GlaxoSmithKline, MedDay Pharmaceuticals, SanofiAventis/Genzyme, and Celgene.C. Hilt received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Genzyme, Biogen, Roche, Novartis, and Merck P.V. Rasmussen received speaker honoraria from TEVA, Biogen, Roche and Novartis, support for congress participation from Merck, Roche, Sanofi and TEVA, fees for serving on advisory boards from Merck, Roche, Novartis, Biogen, and Sanofi.M.B. Jensen served on scientific advisory boards, served as a consultant, received support for congress participation or received speaker honoraria from Biogen, Merck, Novartis, Roch...

Background and purpose: Therapeutic management of relapsing-remitting multiple sclerosis (RRMS) has evolved towards early treatment. The objective was to assess the impact of early treatment initiation on disability progression amongst RRMS first-line-treated patients. Methods: This study included all incident RRMS cases starting interferon or glatiramer acetate for the first time from 1 January 1996 to 31 December 2012 (N = 5279) from 10 MS expert Observatoire Français de la Sclérose en Plaques centres. The delay from treatment start to attaining an irreversible Expanded Disability Status Scale (EDSS) score of 3.0 was compared between the early group (N = 1882; treated within 12 months following MS clinical onset) and the later group using propensity score weighted Kaplan-Meier methods, overall and stratified by age.Results: Overall, the restricted mean time before reaching EDSS 3.0 from treatment start was 11 years and 2 months for patients treated within the year following MS clinical onset and 10 years and 7 months for patients treated later. Thus, early treated patients gained 7 months (95% confidence interval [CI] 4-11 months) in the time to reach EDSS 3.0 compared to patients treated later (treatment start delayed by 28 months). The difference in restricted mean time was respectively 6 months (95% CI 1-10 months) and 14 months (95% CI 4-24 months) in the ≤40 years age group and in the >40 years age group, in favour of the early group. Conclusions:Early treatment initiation resulted in a significant reduction of disability progression amongst patients with RRMS, and also amongst older patients.