title: Treatment of progressive multiple sclerosis with pulse cyclophosphamide/methylprednisolone: response to therapy is linked to the duration of progressive disease.
abstract: OBJECTIVE
  To determine if there are variables linked to responsiveness to pulse cyclophosphamide/methylprednisolone therapy in progressive Multiple Sclerosis (MS).
  
  
  BACKGROUND
  MS is a presumed autoimmune disease of the CNS in which immunosuppressive and immunomodulatory treatments are being used. We have treated patients with the progressive form of MS using a regimen consisting of pulse cyclophosphamide/methylprednisolone that is given as an outpatient at 4 - 8 week intervals similar to lupus nephritis protocols.
  
  
  METHODS
  We investigated a series of 95 consecutive progressive MS patients treated in an open label fashion in an effort to identify factors linked to response to treatment. Clinical outcome measures included status at 12 months and time to failure determined by EDSS change and global physician impression. For each endpoint, associations were examined between outcome and patient characteristics including gender, age at onset of disease and treatment, EDSS 1 year previously and at start of treatment, duration of MS, previous treatment, age at onset and duration of progression, and primary vs secondary progressive MS.
  
  
  RESULTS
  Of the variables studied, age, gender, age at onset, and age at treatment did not correlate with response to therapy. The most significant variable that correlated with response was length of time the patient was in the progressive phase (P=0.048, 12 month change in EDSS; P=0.017, risk for time to failure). Patients that improved on therapy at 12 months had progressive disease for an average of 2.1 years prior to treatment, whereas those stable or worse had progressive disease for 5.0 and 4.1 years respectively. There was a trend (P=0.08) favoring positive clinical responses in secondary progressive as opposed to primary progressive patients.
  
  
  CONCLUSIONS
  Our data suggest that progressive MS may become refractory to immunosuppressive therapy with time and early intervention when patients enter the progressive stage should be considered. Furthermore, in trials of immunosuppressive agents for progressive MS, duration of progression should be considered as a randomization and analysis variable.
authors.affiliation: Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, 77 Avenue Louis Pasteur, HIM 730, Boston, Massachusetts, MA 02115-5817, USA.
authors.forename: M J
authors.initials: MJ
authors.lastname: Hohol
authors.forename: M J
authors.initials: MJ
authors.lastname: Olek
authors.forename: E J
authors.initials: EJ
authors.lastname: Orav
authors.forename: L
authors.initials: L
authors.lastname: Stazzone
authors.forename: D A
authors.initials: DA
authors.lastname: Hafler
authors.forename: S J
authors.initials: SJ
authors.lastname: Khoury
authors.forename: D M
authors.initials: DM
authors.lastname: Dawson
authors.forename: H L
authors.initials: HL
authors.lastname: Weiner
mesh_terms: D000328:Adult; D017668:Age of Onset; D003513:Cycloheximide / Q000627:therapeutic use*; D016208:Databases, Factual; D018450:Disease Progression; D004359:Drug Therapy, Combination; D005260:Female; D005500:Follow-Up Studies; D005938:Glucocorticoids / Q000627:therapeutic use*; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D008297:Male; D008775:Methylprednisolone / Q000627:therapeutic use*; D009103:Multiple Sclerosis / Q000188:drug therapy* / Q000503:physiopathology*; D012008:Recurrence; D012189:Retrospective Studies; D013997:Time Factors; D017211:Treatment Failure
chemical_list: D005938:Glucocorticoids; D007166:Immunosuppressive Agents; D003513:Cycloheximide; D008775:Methylprednisolone