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Classifying PML risk with disease modifying therapies

Multiple Sclerosis and Related Disorders, Volume 12, February 2017, Pages 59–63



To catalogue the risk of PML with the currently available disease modifying therapies (DMTs) for multiple sclerosis (MS).


All DMTs perturb the immune system in some fashion. Natalizumab, a highly effective DMT, has been associated with a significant risk of PML. Fingolimod and dimethyl fumarate have also been unquestionably associated with a risk of PML in the MS population. Concerns about PML risk with other DMTs have arisen due to their mechanism of action and pharmacological parallel to other agents with known PML risk. A method of contextualizing PML risk for DMTs is warranted.


Classification of PML risk was predicated on three criteria:: 1) whether the underlying condition being treated predisposes to PML in the absence of the drug; 2) the latency from initiation of the drug to the development of PML; and 3) the frequency with which PML is observed.


Among the DMTs, natalizumab occupies a place of its own with respect to PML risk. Significantly lesser degrees of risk exist for fingolimod and dimethyl fumarate. Whether PML will be observed with other DMTs in use for MS, such as, rituximab, teriflunomide, and alemtuzumab, remains uncertain.


A logical classification for stratifying DMT PML risk is important for both the physician and patient in contextualizing risk/benefit ratios. As additional experience accumulates regarding PML and the DMTs, this early effort will undoubtedly require revisiting.


  • To date, several disease modifying therapies (DMTs) have been associated with progressive multifocal leukoencephalopathy (PML).
  • Both physicians and patients frequently conflate the risk of PML observed with the various DMTs despite very different incidence rates.
  • DMTs can be classified in three separate risk categories based on three factors: 1) whether PML is observed in the context of treating multiple sclerosis with that DMT or only when it is employed in the treatment of other conditions; 2) the latency from the time of drug initiation to the development of PML; and 3) the incidence rate of PML with the agent.
  • A risk stratification table assists physicians in putting the risk of PML with DMTs into a readily understood framework.

Keywords: Disease modifying therapy, Multiple sclerosis, Progressive multifocal leukoencephalopathy, Natalizumab, Fingolimod, Dimethyl fumarate, Rituximab.


Department of Neurology, Perelman School of Medicine, University of Pennsylvania, 3400 Spruce Street, Gates 3W, Philadelphia, PA 19104, USA