587752

research-article2015

MSJ0010.1177/1352458515587752Multiple Sclerosis JournalJeong

MULTIPLE SCLEROSIS MSJ JOURNAL

Original Research Paper

Comparative analysis of treatment outcomes in patients with neuromyelitis optica spectrum disorder using multifaceted endpoints

Multiple Sclerosis Journal 1­–11 DOI: 10.1177/ 1352458515587752 © The Author(s), 2015. Reprints and permissions: http://www.sagepub.co.uk/ journalsPermissions.nav

In Hye Jeong, Boram Park, Su-Hyun Kim, Jae-Won Hyun, Jungnam Joo and Ho Jin Kim

Abstract Background: There is still an unmet need for comparative analyses of available treatment options for neuromyelitis optica spectrum disorder (NMOSD). Objective: We aimed to compare the efficacies of the immunosuppressants most commonly prescribed for patients with NMOSD using multifaceted endpoints. Methods: We conducted a retrospective analysis of treatment outcomes in 138 NMOSD patients treated with azathioprine, mycophenolate mofetil (MMF), or rituximab. The primary outcome measures were the annualized relapse rate (ARR), annualized severe relapse rate, time to first relapse, and time to first severe relapse. Results: A comparison of any relapse among the groups revealed that the azathioprine had a significantly higher risk of relapse relative to the rituximab (hazard ratio: 1.82; 95% CI: 1.1–3.1; p=0.03). A comparison of severe relapse among the groups revealed that the hazard ratios of severe relapse for the azathioprine and MMF relative to the rituximab were 11.66 (95% CI: 2.6–52.3; p=0.001) and 5.96 (95% CI: 1.0–35.1; p=0.048), respectively. The times to first relapse and first severe relapse were also significantly different among the treatment groups Conclusions: The present study showed that reductions in the risks of relapse and severe relapse differed among patients who were initially treated with azathioprine, MMF, and rituximab.

Keywords:  Neuromyelitis optica, treatment, azathioprine, mycophenolate mofetil, rituximab Date received 27 January 2015; revised 30 March 2015; accepted 15 April 2015

Introduction Neuromyelitis optica spectrum disorder (NMOSD) is an immune-mediated inflammatory disease of the central nervous system (CNS) that is characterized by severe attacks.1,2 The clinical disabilities associated with NMOSD are exclusively attack-related and, thus, the primary treatment goal is the prevention of attacks. Although no randomized controlled trials have compared preventative treatments for NMOSD attacks, several retrospective studies have demonstrated the clinical benefits of immunosuppressive therapies such as azathioprine,2–4 mycophenolate mofetil (MMF),5,6 rituximab,7–13 mitoxantrone,14,15 and methotrexate16,17 for reducing relapse rates. However, there is considerable uncertainty regarding the relative benefits and harms associated with each

of these immunosuppressive treatment options. For example, simple comparison of relapse rates before and after therapy has a limitation for evaluating the therapeutic efficacy of these drugs because the clinical impacts of individual relapses may differ significantly. While a single severe relapse may have a devastating influence on the rest of a patient’s life, minor relapses may not affect the progression of the disability. Thus, potentially devastating relapses should be distinguished from minor relapses, and appropriate comparison of treatment efficacy between the treatment agents needs to consider the reduction of severe relapse in addition to any relapse. Here we evaluated the treatment efficacies using conventional endpoints (relapse rates and disability) as well

Correspondence to: Ho Jin Kim Department of Neurology, Research Institute and Hospital of National Cancer Center, 323 Ilsan Street, Ilsandong-gu, Goyang-si, Gyeonggi-do, Korea. [email protected] In Hye Jeong Su-Hyun Kim Jae-Won Hyun Ho Jin Kim Department of Neurology, Research Institute and Hospital of National Cancer Center, Korea Boram Park Jungnam Joo Bio, Research Institute and Hospital of National Cancer Center, Korea

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Multiple Sclerosis Journal  as relatively novel endpoints, including severe relapse rates, the times to any first relapse, and first severe relapse. These treatment outcomes were compared among patients with NMOSD who were initially treated with the three most commonly prescribed immunosuppressants: azathioprine, MMF, and rituximab.

calculated using the total number of relapses per patient–year. The ARR, annualized severe relapse rate, and EDSS score of each group were compared before and after initial treatment. The times to first relapse of any kind, severe relapse, and drug-related adverse events that necessitated a cessation of treatment, were also estimated.

Methods Patients The Institutional Review Board of the National Cancer Center approved the present study and waived the requirement of obtaining consent forms because de-identified data were used. Patients with relapsing NMO (according to the 2006 diagnostic criteria18) or NMOSD19 who received azathioprine, MMF, or rituximab as their initial immunosuppressive therapy were consecutively recruited from May 2005 to July 2014. Patients with previous exposure to other immunosuppressants, such as mitoxantrone, methotrexate, and cyclophosphamide, were excluded from the present study, but patients who had previously received immunomodulators, such as interferon-beta, were not excluded. Patients concurrently taking prednisolone were considered as a concurrent treatment if the duration of therapy was at least three months. Clinical assessment All clinical data were obtained by a retrospective review of medical records. A relapse was defined as a new worsening of neurological function that increased a patient’s existing Expanded Disability Status Scale (EDSS) score by ⩾ 0.5 points, or if there was an increase of ⩾ 1 point in two functional systems, or an increase of ⩾ 2 points in one functional system that lasted for at least 24 hours in the absence of other identifiable causes such as fever or infection. A severe relapse was defined as an EDSS score of ⩾ 6 (requires a walking aid to walk 100 m with or without resting) at the nadir of the attack, or an increase of ⩾ 0.5 points if the patient had a baseline EDSS score ⩾ 6.0. In cases of optic neuritis (ON), a severe relapse was defined as a new worsening of visual acuity (VA) ⩽ 0.1 in patients with baseline VA > 0.1. If baseline vision was light perception, hand motion, or counting fingers, any decrease, which was accompanied with MRI evidence of ON, was regarded as a severe relapse. The occurrences of relapse were analyzed for as long as 36 months prior to the initiation of therapy and for the entire duration of therapy. The annualized relapse rate (ARR) and annualized severe relapse rate were

Statistical analysis To compare the clinical characteristics of the groups, either an analysis of variance (ANOVA) or a Kruskal– Wallis test was used for continuous variables, and either a chi-squared test or Fisher’s exact test was used for categorical variables. The Wilcoxon signedrank test was used to compare the ARR and EDSS scores before and after immunosuppressive treatment. The hazard ratios of relapses after the initiation of therapy were calculated by applying the Frailty model as an extension of the Cox proportional hazard model for repeated events. The times to first relapse and first severe relapse were described using the Kaplan– Meier (KM) method and then compared among the groups using the log-rank test. The models were adjusted for age at onset, disease duration, sex, aquaporin (AQP)-4 antibody positivity, concurrent use of prednisolone, previous use of beta-interferon, pretreatment EDSS score, and initial immunosuppressive therapy. The factors that were associated with severe relapse were assessed with a univariable analysis, and eight baseline variables were evaluated using a multivariable analysis with the backward variable selection method (alpha = 0.1). The safety was analyzed using the descriptive statistics of the safety population. A p value < 0.05 was considered to indicate statistical significance, and the SAS version 9.3 (SAS institute Inc.; Cary, NC, USA) and R 3.0.2 statistical software packages were used for all analyses. Results Baseline characteristics The final analyses of the present study included 138 patients divided into groups based on initial pharmacotherapy: azathioprine (n = 49), MMF (n = 34), and rituximab (n = 55). Table 1 summarizes the demographic and baseline clinical characteristics of the three groups. Gender, current and onset age, and aquaporin-4 antibody-positive rates did not differ among the groups. The ratio of NMO/NMOSD was lower in the MMF group than the azathioprine and rituximab groups and, thus, the proportion of the

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IH Jeong, B Park et al. Table 1.  Demographic characteristics of patients with immunotherapy. Initial treatment

Azathioprine (n=49) (%)

Mycophenolate mofetil (n=34) (%)

Rituximab (n=55) (%)

p-value

Number NMO/NMOSD, n (%)a Female, n (%)a AQP-4 antibody positivity, n (%)b Concurrent use of prednisone, n (%)a Previous use of interferons, n (%)a Median current age, years (range)c Median age at onset, years (range)c Median disease duration, months (range)d Median disease duration before immunotherapy, months (range)d Median duration of treatment, months (range)d Median pre-treatment EDSSd Median post-treatment EDSSd

49 29/20 40 (81.6) 45 (91.8) 34 (69.4) 17 (34.7) 41 (17–65) 31 (6–57) 85.8 (14.2–375.8) 37.1 (0.4–346.2)

34 12/22 29 (85.3) 32 (94.1) 9 (26.5) 4 (11.8) 39 (14–63) 35 (10–53) 51.7 (13–213.4) 15.6 (1.1–192.8)

55 34/21 50 (90.9) 52 (94.5) 1 (1.8) 29 (52.7) 42 (15–68) 34 (8–59) 108.8 (10.1–319.9) 41.7 (2.1–231.5)



15.1 (0.3–141.5) 3.0 (0–7.5) 3.0 (0–7.5)

26.1 (5.5–68.6) 3.0 (0–7.0) 2.0 (0–7.0)

64.7 (6.2–99.8) 4.5 (0–8.5) 3.0 (0–8.0)

0.04 0.38 0.91 < 0.001

Comparative analysis of treatment outcomes in patients with neuromyelitis optica spectrum disorder using multifaceted endpoints.

There is still an unmet need for comparative analyses of available treatment options for neuromyelitis optica spectrum disorder (NMOSD)...
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