title: Factors associated with the time to next attack in neuromyelitis optica: accelerated failure time models with random effects.
abstract: OBJECTIVE
  Neuromyelitis optica (NMO) is an inflammatory demyelinating disorder of the central nervous system with a relapsing and remitting course. We aimed to identify factors associated with the time to next attack, including the effect of the natural disease course and the diverse treatment regimens, by applying a longitudinal statistical analysis to the individual attacks of each patient.
  
  
  METHODS
  In total, 184 acute attacks among 58 patients with either NMO or NMO spectrum disorder with anti-aquaporin-4 antibody were assessed retrospectively. Patient demographics, clinical characteristics at each attack, and type of treatment during inter-attack periods were assessed. The dependent variable was defined as the time from each attack to the next attack (inter-attack interval). An exponential accelerated failure time model with shared gamma frailty was adapted for statistical analysis.
  
  
  RESULTS
  A multivariable analysis revealed that the time from each attack to the next attack in NMO increased independently by 1.31 times (95% confidence interval (CI), 1.02-1.67; p = 0.035) with each additional cumulative attack experienced, by 5.34 times (95% CI, 1.57-18.13; p = 0.007) with combined azathioprine treatment and continued oral prednisolone, and by 4.26 times (95% CI, 1.09-16.61; p = 0.037) with rituximab treatment.
  
  
  CONCLUSIONS
  The time to next attack in NMO can increase naturally in the later stages of the disease as the number of cumulative attacks increases. Nevertheless, both combined azathioprine treatment with continued oral prednisolone and rituximab treatment were also associated with a longer time to next attack, independently of the natural disease course of NMO.
authors.affiliation: Department of Neurology, Seoul National University, College of Medicine, Seoul, Korea.
authors.forename: Sung-Min
authors.initials: SM
authors.lastname: Kim
authors.affiliation: Medical Research Collaborating Center, Seoul National University Hospital, Seoul, Korea.
authors.forename: Junwoo
authors.initials: J
authors.lastname: Park
authors.affiliation: Medical Research Collaborating Center, Seoul National University Hospital, Seoul, Korea.
authors.forename: Sun Hee
authors.initials: SH
authors.lastname: Kim
authors.affiliation: Department of Neurology, Seoul National University, College of Medicine, Seoul, Korea.
authors.forename: Su-Yeon
authors.initials: SY
authors.lastname: Park
authors.affiliation: Department of Neurology, Seoul National University, Bundang Hospital, Gyeonggi, Korea.
authors.forename: Jee Young
authors.initials: JY
authors.lastname: Kim
authors.affiliation: Department of Neurology, Seoul National University, College of Medicine, Seoul, Korea.
authors.forename: Jung-Joon
authors.initials: JJ
authors.lastname: Sung
authors.affiliation: Department of Neurology, Seoul National University, College of Medicine, Seoul, Korea ; Department of Neurology, Seoul National University, Bundang Hospital, Gyeonggi, Korea.
authors.forename: Kyung Seok
authors.initials: KS
authors.lastname: Park
authors.affiliation: Department of Neurology, Seoul National University, College of Medicine, Seoul, Korea.
authors.forename: Kwang-Woo
authors.initials: KW
authors.lastname: Lee
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D058846:Antibodies, Monoclonal, Murine-Derived / Q000627:therapeutic use; D051401:Aquaporin 4 / Q000276:immunology*; D001323:Autoantibodies; D001379:Azathioprine / Q000627:therapeutic use; D002648:Child; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D008962:Models, Theoretical; D009471:Neuromyelitis Optica / Q000175:diagnosis* / Q000188:drug therapy / Q000276:immunology; D011239:Prednisolone / Q000627:therapeutic use; D012008:Recurrence; D012189:Retrospective Studies; D012307:Risk Factors; D000069283:Rituximab; D013997:Time Factors; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D058846:Antibodies, Monoclonal, Murine-Derived; D051401:Aquaporin 4; D001323:Autoantibodies; D007166:Immunosuppressive Agents; D000069283:Rituximab; D011239:Prednisolone; D001379:Azathioprine