title: Classifying PML risk with disease modifying therapies.
abstract: OBJECTIVE
  To catalogue the risk of PML with the currently available disease modifying therapies (DMTs) for multiple sclerosis (MS).
  
  
  BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Neurology, Perelman School of Medicine, University of Pennsylvania, 3400 Spruce Street, Gates 3W, Philadelphia, PA 19104, USA. Electronic address: joseph.berger@uphs.upenn.edu.
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Berger
mesh_terms: D006801:Humans; D007155:Immunologic Factors / Q000009:adverse effects* / Q000627:therapeutic use*; D007968:Leukoencephalopathy, Progressive Multifocal / Q000145:classification* / Q000453:epidemiology / Q000209:etiology*; D009103:Multiple Sclerosis / Q000150:complications / Q000188:drug therapy* / Q000453:epidemiology*; D012306:Risk
chemical_list: D007155:Immunologic Factors
keywords: Dimethyl fumarate; Disease modifying therapy; Fingolimod; Multiple sclerosis; Natalizumab; Progressive multifocal leukoencephalopathy; Rituximab