title: Dimethyl fumarate-associated lymphopenia: Risk factors and clinical significance.
abstract: BACKGROUND
  Dimethyl fumarate (DMF), a disease-modifying therapy for multiple sclerosis (MS), causes lymphopenia in a fraction of patients. The clinical significance of this is unknown. Several cases of progressive multifocal leukoencephalopathy in lymphopenic fumarate-treated patients have raised concerns about drug safety. Since lymphocytes contribute to MS pathology, lymphopenia may also be a biomarker for response to the drug.
  
  
  OBJECTIVE
  The objective of this manuscript is to evaluate risk factors for DMF-induced lymphopenia and drug failure in a real-world population of MS patients.
  
  
  METHODS
  We conducted a retrospective cohort study of 221 patients prescribed DMF at a single academic medical center between March 2013 and February 2015.
  
  
  RESULTS
  Grade 2-3 lymphopenia developed in 17% of the total cohort and did not resolve during DMF treatment. Older age (>55), lower baseline absolute lymphocyte count and recent natalizumab exposure increased the risk of developing moderate to severe lymphopenia while on DMF. Lymphopenia was not predictive of good clinical response or of breakthrough MS activity on DMF.
  
  
  CONCLUSIONS
  Lymphopenia develops in a significant minority of DMF-treated patients, and if grade 2 or worse, is unlikely to resolve while on the drug. Increased vigilance in lymphocyte monitoring and infection awareness is particularly warranted in older patients and those switching from natalizumab.
authors.affiliation: Washington University in St. Louis, Department of Neurology, 660 S. Euclid Ave., Campus Box 8111, St. Louis, MO 63110, USA.
authors.forename: Erin E
authors.initials: EE
authors.lastname: Longbrake
authors.affiliation: Department of Neurology, Washington University in St. Louis, USA.
authors.forename: Robert T
authors.initials: RT
authors.lastname: Naismith
authors.affiliation: Department of Neurology, Washington University in St. Louis, USA.
authors.forename: Becky J
authors.initials: BJ
authors.lastname: Parks
authors.affiliation: Department of Neurology, Washington University in St. Louis, USA.
authors.forename: Gregory F
authors.initials: GF
authors.lastname: Wu
authors.affiliation: Department of Neurology, Washington University in St. Louis, USA.
authors.forename: Anne H
authors.initials: AH
authors.lastname: Cross
keywords: Multiple sclerosis; dimethyl fumarate; drug safety; lymphopenia; progressive multifocal leukoencephalopathy