Progressive multifocal leukoencephalopathy associated with sphingosine-1-phosphate receptor modulators: A large case...

Risk factors for progressive multifocal leukoencephalopathy (PML) associated with sphingosine-1-phosphate receptor (S1PR) modulators are not as well-characterized as for natalizumab. We characterized S1PR modulator-associated PML cases and risk factors for PML using spontaneous adverse event reports.

We reviewed case reports from the FDA Adverse Event Reporting System database and the medical literature.

We identified 57 PML cases encompassing all marketed S1PR modulators approved for multiple sclerosis, the majority (n = 53) associated with fingolimod. Ten cases reported a fatal outcome. Length of S1PR modulator exposure (≥18 months) appears to be a robust risk factor for PML. Patient age ≥50 years was identified as a potential risk factor, although this may be the result of several biases. We propose that prior immunosuppressant exposure should be considered as a potential risk factor for further validation. No conclusions could be drawn regarding JC virus serology and lymphopenia severity.

Spontaneous adverse event reports support the observation that extended S1PR modulator exposure appears to be a robust PML risk factor. As a result, the U.S. Prescribing Information for each product in the S1PR modulator class was updated. Validation of other potential risk factors would support efforts to stratify and mitigate the risk of S1PR modulator-associated PML.