title: Fludarabine add-on therapy in interferon-beta-treated patients with multiple sclerosis experiencing breakthrough disease.
abstract: BACKGROUND
  Patients with relapsing-remitting multiple sclerosis (RRMS) may experience breakthrough disease despite effective interferon beta (IFNβ) therapy. Fludarabine (FLU) is a chemotherapeutic agent used in lymphoproliferative disorders that may be synergistic when combined with immunomodulatory therapy to control active multiple sclerosis (MS).
  
  
  OBJECTIVE
  The objective of this study was to explore the safety and tolerability of FLU versus monthly methylprednisolone (MP) in IFNβ-treated RRMS patients with breakthrough disease. Clinical and MRI effects of IFNβ-1a plus FLU were evaluated.
  
  
  METHODS
  Eighteen patients with breakthrough disease [⩾2 relapses over the prior year and ⩾1.0-point increase in Expanded Disability Status Scale (EDSS) score sustained for ⩾3 months] after >1 year of IFNβ therapy were enrolled in this prospective, open-label, randomized, proof-of-concept, pilot study. Patients received intravenous (IV) MP 1 g daily for 3 days and then were randomized to receive 3 monthly IV infusions of FLU 25 mg/m(2) daily for 5 consecutive days (n = 10) or MP 1 g (n = 8). All patients maintained their intramuscular IFNβ-1a treatment throughout the study. Analyses explored safety signals and directional trends; this preliminary study was not powered to detect clinically meaningful differences.
  
  
  RESULTS
  Both combination treatments were safe and well tolerated, with all adverse events mild. Patients treated with IFNβ-1a plus FLU had similar relapse rates, EDSS scores, and MS Functional Composite scores, but significantly less acute corticosteroid use for on-study relapses and better responses on some MRI outcomes, versus patients treated with IFNβ-1a plus MP.
  
  
  CONCLUSIONS
  Further study of FLU for breakthrough disease in patients with RRMS is warranted.
authors.affiliation: Clinical Development, Neuroscience Global Pharmaceutical R&D, Abbvie Inc. 1 North Waukegan Road AP-31-1 North Chicago, IL 60064, USA.
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Greenberg
authors.affiliation: Buffalo Neuroimaging Analysis Center, The Jacobs Neurological Institute, Department of Neurology, Buffalo General Hospital, Buffalo, NY, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Zivadinov
authors.affiliation: The Jacobs Neurological Institute, Department of Neurology, Buffalo General Hospital, Buffalo, NY, USA.
authors.forename: Peterkin
authors.initials: P
authors.lastname: Lee-Kwen
authors.affiliation: Buffalo Neuroimaging Analysis Center, The Jacobs Neurological Institute, Department of Neurology, Buffalo General Hospital, Buffalo, NY, USA.
authors.forename: Jitendra
authors.initials: J
authors.lastname: Sharma
authors.affiliation: The Jacobs Neurological Institute, Department of Neurology, Buffalo General Hospital, Buffalo, NY, USA.
authors.forename: Margaret
authors.initials: M
authors.lastname: Planter
authors.affiliation: The Jacobs Neurological Institute, Department of Neurology, Buffalo General Hospital, Buffalo, NY, USA.
authors.forename: Margaret
authors.initials: M
authors.lastname: Umhauer
authors.affiliation: The Jacobs Neurological Institute, Department of Neurology, Buffalo General Hospital, Buffalo, NY, USA USA.
authors.forename: Norman
authors.initials: N
authors.lastname: Glenister
authors.affiliation: Jack, Sadie and David Breakstone Professor of Neurology and Radiology, Harvard Medical School, Director, Laboratory for Neuroimaging Research, Partners MS Center, Brigham and Women's Hospital, One Brookline Place, Suite 602, Brookline, MA 02445, USA.
authors.forename: Rohit
authors.initials: R
authors.lastname: Bakshi
keywords: adjunct therapy; breakthrough disease; fludarabine; interferon beta; methylprednisolone; multiple sclerosis