The effect of interferon β-1a on optic neuritis relapse in patients with multiple sclerosis
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- Chen, Y., Yang, C., Wang, I. et al. Graefes Arch Clin Exp Ophthalmol (2010) 248: 231. doi:10.1007/s00417-009-1207-2
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To evaluate the clinical effect of interferon β-1a on optic neuritis (ON) relapse in patients with multiple sclerosis (MS) in Taiwan.
Data were collected from 23 MS patients with ON at National Taiwan University Hospital between January 1, 1993 and February 1, 2007. Twenty-three MS patients with ON received interferon β-1a (Rebif) 44 µg via subcutaneous injection three times weekly. All patients received corticosteroids pulse therapy followed by oral prednisolone for acute ON. The annual relapse rate (ARR) of ON in these MS patients before and after the use of interferon β-1a (Rebif) was the main clinical parameter of outcome in this study.
The ARR of ON was lower in the posttreatment period than in the pretreatment period (P = 0.0068). Thirteen patients (56.5%) had improved final visual acuity (>2 lines), and the other ten patients (43.5%) had stable final visual outcome (−2 lines < X < 2 lines). In addition, no recurrence of ON was noted in 15 patients (65.2%) during the posttreatment period.
The use of interferon β-1a 44 µg via subcutaneous injection three times weekly did not increase the ON attacks in MS patients receiving this treatment. In addition, beneficial effects were found with the use of interferon β-1a on these patients.
KeywordsOptic neuritisMultiple sclerosisInterferon β-1aImmune-modulation agents
Multiple sclerosis (MS) is an autoimmune disorder in which the immune system attacks the central nervous system (CNS). Optic neuritis (ON) is frequently involved in MS. ON is the presenting symptom of MS in approximately 25% of patients, and 65% of MS patients experience ON at some time during the disease course . A very high percentage (94–99%) of patients with multiple sclerosis show plaque lesions in the optic nerve of autopsy studies [2, 3]. According to previous reports, 13% to 87% of patients with idiopathic ON eventually convert to clinically definite MS (CDMS) in Europe and North America [4–6]. The prevalence of MS in most Asia countries is low . Previous studies in Taiwan showed a prevalence of 0.8–1.9 cases per 100,000 people [8, 9]. In Taiwan, the MS conversion rate is relative low in patients with idiopathic ON (0.78–14.3% on the 5-year cumulative probability) [10, 11]. Since the approval of the use of interferon β for MS patients in 1993, many studies have documented the benefit of the immune-modulation agents (IMAs) in reducing the relapse rate of MS and delaying the progression of disability [12–15]. Rebif (Serono, Geneva, Switzerland), one of the principal medications in the market for interferon β-1a, was first introduced into Taiwan in 2000. MS patients with (1) two or more attacks in 2 years and (2) Expanded Disability Status Scale (EDSS) < 6 were considered for using these IMAs according to the Taiwan Neurology Association’s guideline of usage. In 2001, the CHAMPS study also found that initiating interferon β-1a at the time of first episode of ON occurring in patients at high risk for MS lowered the rates of clinically definite MS (CDMS) and combined MS/MRI outcome . However, the clinical benefit of interferon β-1a on ON in MS patients has not been shown yet. A recent article claimed an early relapse of ON with the use of interferon β-1a in Chinese MS patients . Nowadays, more and more MS patients with frequent disease attacks are receiving this treatment at neurologists’ clinics. If the use of interferon β-1a leads to an early ON relapse, then the use of this expensive medication should be carefully monitored. In this way, we would like to report our observation of the clinical response to interferon β-1a on ON in MS patients in Taiwan.
Materials and methods
From January 1, 1993 to February 1, 2007, we conducted a retrospective study to evaluate the clinical response to interferon β-1a (Rebif) of ON in MS patients at National Taiwan University Hospital (NTUH). Forty-four patients (potential study patients) with a diagnosis of MS associated with a visual impairment history were enrolled. Inclusion criteria were MS patients with unilateral or bilateral optic neuritis, and MS patients with (1) two or more disease attacks in 2 years and (2) Expanded Disability Status Scale (EDSS) < 6, receiving interferon β-1a according to the Taiwan Neurology Association’s guideline of usage at the neurologist's clinic. The diagnosis of MS was according to the criteria of McDonald . Patients with neuromyelitis optica (NMO, Devic’s syndrome) by the revised diagnostic criteria from Wingerchuk et al.  or with ON due to chronic relapsing inflammatory optic neuropathy (CRION) were excluded. Patients with (1) a history of other systemic disease, (2) a history of glaucoma, high myopia, or other retinal disease, (3) follow-up of less than 6 months, or (4) incomplete chart record were also excluded. The chart review included the times of ON attack and the therapeutic regimens.
A total of 23 patients of MS with ON were enrolled in the study. These 23 patients had received interferon treatment according to the Taiwan Neurology Association’s guideline of usage. Interferon β-1a (Rebif) 44 µg was given subcutaneously three times weekly to these patients. All 23 patients received pulse therapy with intravenous methylprednisolone 250 mg every 6 hours for 3 days consecutively, followed by oral prednisolone for 1 to 2 weeks, to treat acute ON according to the protocol of the Optic Neuritis Treatment Trial (ONTT) . ON was defined according to the clinical criteria of Perkin & Rose  as “a condition causing a relatively rapid onset of visual failure, in which no evidence for a toxic, vascular, or compressive etiology can be discovered, and where local retinal lesions have been excluded” with clinical and radiographic examinations to rule out other cause to vision loss. Recurrent attacks were defined as second ON episodes occurring more than 1 month later. ON episodes were considered persistent if they occurred within 1 month of the first attack. The annual relapse rate of ON (ON-ARR) was defined as the average ON attack rate per year in each patient during the period of follow-up. We compared the ON-ARR between the pretreatment and posttreatment periods within these patients. For pre-treatment and post-treatment ON-ARR analysis, paired t-test was used. P values quoted are two-tailed, and considered statistically significant when <0.05. Institutional review board approval by the Ethics Committee of National Taiwan University Hospital was obtained, and all the research followed the guidelines in the Declaration of Helsinki.
Demographic data of patients in this study
Number of patients
Age (years, range)
31.8 ± 10.0 (16–50)
Duration of follow-up (years): mean
ON-affected eye: n(%)
Clinical characteristics at initial presentation: n (%)
log MAR 0.18 to 1.6
- RAPD positive
Color vision affected
Visual field abnormality
Central visual field loss
MRI of optic nerve (n = 13)
MRI of CNS (n = 22)
- Brain MS lesion
- Spinal cord MS lesion
ON is an acute inflammatory optic neuropathy that predominantly affects young females. It may occur in patients with confirmed MS or as an isolated neurologic finding. According to a recent ONTT report, patients with ON with reduced visual acuity or disability owing to MS had poorer visual function than the MS-free population . The typical clinical findings of MS include sudden loss of vision, visual field defect, color vision and contrast sensitivity abnormalities. Early studies showed that the use of intravenous methylprednisolone as treatments for ON could speed the recovery of visual loss and result in a slightly better vision at 6 months, while oral prednisolone alone might increase the new episodes of ON [23, 24]. A previous study also showed that a 3-day course of high-dose intravenous methylprednisolone followed by a short course of prednisolone could reduce the rate of development of MS over a 2-year period . In recent years, many studies have addressed the finding that interferon β could slow down the progression from clinically isolated syndromes (CIS) to clinically definite MS, and emphasized the use of these IMAs on ON patients with substantial risk of developing CDMS [26–29]. Saida et al. also reported the dose-dependent efficacy of interferon β-1b treatment in Japanese MS patients . However, the effect of interferon on ON relapse in MS patients has been limited to a few reports to date. In 2006, Wang and associates reported that interferon β-1a had no effect on the prevention of ON attacks . Instead, they claimed that the use of interferon β-1a should be carefully monitored because of an early relapse of ON. In our study, we evaluated the efficacy of interferon β-1a on ON relapse in patients with MS. Among all 23 patients receiving interferon β-1a treatment, the average ON-ARR decreased from 1.01 to 0.21 from the pretreatment to the posttreatment period, with a significant difference (P = 0.0068). In our study, more than half of the patients (13 out of 23 patients) had improved final visual acuity after interferon β-1a usage, and the other ten patients had stable final visual acuity, which was different from the previous report by Wang and associates . In addition, we found that 15 patients (65.2%) had no ON attack during the posttreatment follow-up period and only one patient had an initial ON attack occurring within 3 months of the initial dose. This result was also quite different from the previous report. In our study, we used interferon β-1a (Rebif) 44 µg subcutaneously three times weekly, which was twice the dosage of the previous study . Saida and associates had reported that the efficacy of interferon beta-1b treatment in Japanese MS patients was dose-dependent . The different dosage of the interferon treatment might lead to different results [30, 31]. The 22 µg interferon β-1a (Rebif) subcutaneously three times weekly might be the reason for the different results regarding ON attacks in MS patients in the study by Wang and associates. In addition, in Wang’s study, they applied the Wingerchuk’s 1999 diagnostic criteria of NMO , in which cases with clinical manifestations attributable to brain lesions are excluded from NMO. In other words, NMO cases with brain lesions can be diagnosed as MS, and might have been included in Wang’s study. However, recent studies on aquaporin-4(AQP4) antibody, an NMO-specific autoantibody, indicated that brain lesions are not uncommon in NMO. Wingerchuk’s 1999 criteria did not include AQP4 antibody status, since AQP4 antibody or NMO-IgG was first reported in 2004 . NMO is not uncommon in Japan, Taiwan and other Asian countries . In addition, there is growing evidence that the therapeutic efficacy of interferon β in NMO is unclear [34, 35]. This might also explained the different results of these two studies. Like other studies, our study was also limited by the small sample size, which can be attributed to the low prevalence rate of MS in Taiwan.
Since there is no strong evidence that ON is a distinct demyelinating event when compared to any other attacks in MS, the ability of interferon β-1a to reduce the frequency of recurrent ON among MS patients with a history of ON is thought to be with no difference. The results of our study showed at least that interferon β-1a did not cause an early ON relapse in MS patients, but had beneficial effects on ON relapse and final visual outcome of patients, which corresponds to previous positive impacts on other clinical attacks in MS patients [26–29]. Nonetheless, the efficacy of the interferon β-1a treatment might be influenced by the different dosage of the treatment. In this study, only MS patients who met the criteria of usage by the guideline of the Taiwan Neurology Association received the interferon β-1a. These MS patients were thought to have more active disease with frequent disease attacks. A recent study demonstrated that interferon β-1b didn’t succeed not only in neuromyelitis optica (NMO) patients but also in MS patients with severe optic–spinal demyelination in Japan . For ON patients with less MS disease attacks, purely recurrent ON patients without MS presentation or ON patients with atypical MS, further studies are needed to evaluate the clinical effect of this treatment on these ON patients. In addition, since our hospital is a tertiary referral center in Taiwan, most patients with frequent disease attacks who met the criteria of interferon β-1a usage received the interferon β-1a treatment in our hospital. In this way, it was really difficult to have a control group for comparison of the effect of interferon β-1a in these MS patients. In our opinion, further multicenter and large patient number studies with a control group are needed to confirm these results.
In our study, we proved that interferon β-1a did not cause an early relapse of ON in MS patients receiving this treatment. Instead, an adequate dose of interferon β-1a had positive impacts on ON relapse and final visual acuity in MS patients with ON. Considering the relatively low number of patients, lack of a control group, the single dosage used in the study and relative short duration reviewed, the results of the study should be confirmed in a well-designed, large-number, long-term duration, and multicenter clinical study.