Factors Associated With the Time to Next Attack in Neuromyelitis Optica: Accelerated Failure Time Models With Random Effects

Sung-Min Kim,Junwoo Park,Su-Yeon Park,Sun Hee Kim,Jung-Joon Sung,Jee Young Kim,Kyung Seok Park,Kwang-Woo Lee,Pablo Villoslada

doi:10.1371/journal.pone.0082325

Abstract

Background and ObjectiveNeuromyelitis 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.MethodsIn 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.ResultsA 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.ConclusionThe 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.

Highlights

Neuromyelitis optica (NMO) is an inflammatory demyelinating disorder of the central nervous system that involves primarily the optic nerve and the spinal cord [1,2].As most patients with NMO experience relapsing and remitting disease courses without secondary progression [3], the rate of relapses is a major factor in their prognosis
Univariable analysis (Table 2) The exponential accelerated failure time model (AFT) model revealed that a longer disease duration, a higher cumulative number of attacks, most recent attacks at the spinal cord, continued oral prednisolone treatment, higher dose of azathioprine treatment, azathioprine treatment combined with oral prednisolone for more than 6 months, azathioprine treatment combined with continued oral prednisolone, and rituximab treatment were significantly associated with a longer time to attack
Multivariable analysis (Table 3) The cumulative number of attacks, disease duration, the most recent attacks at the optic nerve, azathioprine treatment combined with oral prednisolone, rituximab treatment, and treatment with interferon beta, cyclophosphamide, and methotrexate were included in our multivariable analysis, based on the results of the univariable analysis and the minimum value of the Akaike information criterion (AIC) [21]

Summary

Introduction

Neuromyelitis optica (NMO) is an inflammatory demyelinating disorder of the central nervous system that involves primarily the optic nerve and the spinal cord [1,2].As most patients with NMO experience relapsing and remitting disease courses without secondary progression [3], the rate of relapses is a major factor in their prognosis. We aimed to identify factors associated with the time to 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. Conclusion: The time to attack in NMO can increase naturally in the later stages of the disease as the number of cumulative attacks increases. Both combined azathioprine treatment with continued oral prednisolone and rituximab treatment were associated with a longer time to attack, independently of the natural disease course of NMO

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Methods

Results