Background and objectives: Progressive multifocal leukoencephalopathy (PML) is a rare and severe neurological disease caused by reactivation of the JC virus (JCV) in immunocompromised individuals. The underlying causes of immunosuppression can be diverse, but PML secondary to immune- modulatory treatments has been increasing since it was first described as a complication of natalizumab treatment for multiple sclerosis. More recently, fingolimod, a sphingosine 1-phosphate receptor modulator prescribed for multiple sclerosis, has also been associated with PML. In this retrospective multicenter study, we aimed to compare the presentation and outcome of PML associated with fingolimod to PML associated with natalizumab.
Methods: We conducted a retrospective multicenter cohort study in Japan, Germany, France, Italy, and Switzerland. Data were collected from patients who developed PML following treatment with natalizumab or fingolimod for multiple sclerosis between 2009 and 2021. Our primary outcome was the occurrence of an immune reconstitution inflammatory syndrome (IRIS) and exploratory variables included survival and disability (measured by Modified Ranking Scale – mRS) at 12 months and at the last follow-up.
Results: A total of 54 patients met the inclusion criteria but one was excluded due to incomplete data. Of the 53 patients selected, 10 patients developed PML following treatment with fingolimod (FTY), and the remaining 43 patients developed PML following treatment with natalizumab (NTZ). Our results suggested a tendency for less IRIS in the fingolimod group compared to the natalizumab group (FTY: 6/10, 60% vs NTZ: 34/43, 87.2%, p = 0.07). However, no significant difference was observed in the comparison of disability measured at 12 months post-PML (median mRS FTY: 2 (IQR25-75 2-3.5) vs NTZ: 3 (IQR25-75 2-4), p = 0.257) and after a median follow-up of 15 months (median mRS FTY: 3 (IQR25-75 2- 3.5) vs NTZ: 3 (IQR25-75 2-4), p = 0.550). In addition, mortality (FTY: 1/10, 10% vs NTZ: 7/43, 16.3%, p = 1.000) did not differ between both groups.
Discussion: Because of its potential to generate more rapid immune reconstitution, plasmapheresis appears to be associated with earlier and more severe IRIS. The higher proportion of patients treated with plasmapheresis in the natalizumab group, compared to the fingolimod one (FTY: 3/10, 30% vs NTZ: 31/43, 72.1%, p = 0.025), may explain the increased prevalence of IRIS in this group. Then, fingolimod withdrawal could be associated with a slower T cells reconstitution within the CNS resulting in a lower incidence of IRIS.