Retrospective comparison clinical presentation and outcome of Natalizumab and Fingolimod-associated PML
Raphael Bernard-Valnet1, Julie Blant1, Nicola De Rossi2, Christoph Schroeder3, Aude Maurousset4, Markus Krämer5, Kodai Kume 6, Tatsuro Misu 7, Jean Ouallet8, Maud Pallix Guyot9, Ralf Gold10, Simonetta Gerevini 11, Ilya Ayzenberg10, Renaud Du Pasquier1
1Centre Hospitalier Universitaire Vaudois, 2Regional Multiple Sclerosis Center, 3Neurology, St. Josef-Hospital, Ruhr University, 4Neurology, Centre hospitalier régional universitaire de Tours, Hôpital Bretonneau, 5Neurology, Alfried Krupp von Bohlen und Halbach Hospital, 6Epidemiology, Research Institute for Radiation Biology and Medicine, 7Tohoku University Hospital, 8CHU de Bordeaux Pellegrin Tripode, 9Neurology, Centre Hospitalier Régional d'Orléans, 10St. Josef-Hospital, Ruhr University Bochum, 11Papa Giovanni XXIII Hospital
Objective:
To compare the presentation and outcome in Fingolimod (FTY) and Natalizumab (NTZ) associated with Progressive multifocal leukoencephalopathy (PML).
Background:
PML is a severe neurological disease caused by the JC virus (JCV) reactivation in immunocompromised individuals. Several multiple sclerosis treatments have been associated with the risk of developing PML. If Natalitumab-associated PML has been largely described, data on the course of Fingolimod-associated-PML are scarce.
Design/Methods:
We conducted a retrospective multicenter cohort study in Japan, Germany, France, Italy, and Switzerland. All consecutive patients admitted at participating centers between 2009 and 2021 for iatrogenic PML related to Fingolimod and Natalizumab were included. Our primary outcome was the occurrence of an immune reconstitution inflammatory syndrome (IRIS) in the two groups. Exploratory variables were survival and disability (measured by Modified Ranking Scale – mRS) at 12 months. We also analyzed the clinical and radiological presentation in these two etiologies.
Results:
54 patients met the inclusion criteria and 53 were included in the final analysis (10 in the Fingolimod group and 43 in the Tysabri one). PML associated with Fingolimod occurred in older patients (median (IQR25-75): 51 (41-58) vs 44 (38-47) years, p=0.023) and after a longer treatment duration (median (IQR25-75): 68 (44.5-87.42) vs 36 (23.39-49.00) months, p=0.003). Initial characteristics of PML were similar except for more frequent inflammatory signs (iPML defined as gadolinium-enhancing lesions) at onset in the Fingolimod-treated patients (60 vs 34.9 %, p=0.169). Despite these early inflammatory signs, Natalizumab-associated PML were more prone to develop IRIS (60% vs 87.2%, p= 0.07). Yet, the 12 months disability (median mRS (IQR25-75): 2 (2-3.5) vs 3 (2-4), p = 0.257) and the overall survival (10% vs 16.3%, p =1.000) were similar in the two groups.
Conclusions:
Our study shows that Fingolimod-associated PML exhibits a peculiar presentation and course that should be acknowledged to recognize and treat this severe neurological complication.