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Ther Adv Neurol Disord. 2017 January; 10(1): 41–50.
Published online 2016 November 16. doi:  10.1177/1756285616676065
PMCID: PMC5400156

Peginterferon beta-1a reduces disability worsening in relapsing–remitting multiple sclerosis: 2-year results from ADVANCE



In the pivotal phase III 2-year ADVANCE study, subcutaneous peginterferon beta-1a 125 mcg every 2 weeks demonstrated significant improvements in clinical outcomes, including disability endpoints, in patients with relapsing–remitting multiple sclerosis (RRMS). Here, we aim to further evaluate disability data from ADVANCE, and explore associations between confirmed disability progression (CDP), functional status, and health-related quality of life (HRQoL).


In total, 1512 patients were randomized to placebo or peginterferon beta-1a 125 mcg every 2 or 4 weeks. After 1 year, patients on placebo were re-randomized to peginterferon beta-1a every 2 or 4 weeks. CDP was defined as [gt-or-equal, slanted]1.0 point increase from a baseline Expanded Disability Status Scale (EDSS) score [gt-or-equal, slanted] 1.0, or [gt-or-equal, slanted]1.5-point increase from baseline 0, confirmed 12 or 24 weeks after onset.


Peginterferon beta-1a every 2 weeks significantly reduced risk of 12- and 24-week CDP at 1 year compared with placebo (12-week CDP: 6.8% versus 10.5%, p = 0.038; 24-week CDP: 4% versus 8.4%, p = 0.0069, peginterferon beta-1a every 2 weeks versus placebo, respectively). Benefits were maintained over 2 years (11.2% and 7.7%, peginterferon beta-1a every 2 weeks in 12- and 24-week CDP, respectively). Approximately 90% of patients with 24-week CDP had simultaneous worsening by [gt-or-equal, slanted]1 point in at least one functional system score, most commonly pyramidal. Displaying a 24-week CDP was associated with worse scores on the Multiple Sclerosis Functional Composite (MSFC) scale and several HRQoL instruments; the impact of CDP was attenuated by treatment with peginterferon beta-1a every 2 weeks.


Peginterferon beta-1a has the potential to prevent/delay worsening of disability in patients with relapsing–remitting multiple sclerosis. Furthermore, improved benefits in disability status with peginterferon beta-1a were also associated with improved functional status and HRQoL

[ identifier: NCT00906399].

Keywords: functional score disability evaluation, multiple sclerosis, patient-reported outcomes, peginterferon beta-1a, pegylated interferon, phase III clinical trial, relapsing–remitting multiple sclerosis


Preventing or delaying the development of long-term disability is an important therapeutic goal of disease-modifying treatments for multiple sclerosis (MS) [Goodin et al. 2002]. Disability is associated with impairment of health-related quality of life (HRQoL) in MS patients [Baumstarck et al. 2015; Newsome et al. 2015] and carries a substantial economic impact [Naci et al. 2010; Patwardhan et al. 2005].

The most widely recognized measure of disability in MS, used in the majority of treatment trials, is the Expanded Disability Status Scale (EDSS) [Meyer-Moock et al. 2014; Kurtzke, 1983]. An increased EDSS score is typically considered to indicate worsening disability if it persists for 3 months; however, confirmation after 6 months is increasingly being used to provide a more robust assessment of disability [Scott et al. 2015]. Confirmed worsening on the EDSS is often referred to as sustained disability progression; however, the term ‘sustained’ may imply greater permanence than can be assumed based on 3- or 6-month confirmation [Lublin et al. 2014] and so confirmed disability progression (CDP) is preferred. It should be noted that the term ‘CDP’ is used here in the context of worsening disability within the relapsing–remitting phase of MS, and does not refer to progressive MS.

The Multiple Sclerosis Functional Composite (MSFC) score [Cutter et al. 1999] is an additional multidimensional measure of neurologic function in MS, widely used as a secondary endpoint to monitor disability status in MS trials [Meyer-Moock et al. 2014]. Patient-reported outcomes (PROs) are known to be influenced by disability in MS [Baumstarck et al. 2015; Newsome et al. 2015], although their utility as indicators of disease status is uncertain and further research into how PROs correlate with more established measures is necessary [Lublin et al. 2014].

Peginterferon beta-1a is a pegylated form of interferon beta, with a prolonged pharmacokinetic profile enabling more convenient, less frequent dosing than nonpegylated interferon beta therapies for MS [Kieseier and Calabresi, 2012]. Its efficacy was established in the 2-year, phase III ADVANCE study, in which peginterferon beta-1a significantly reduced relapse rates and improved MRI measures, compared with placebo over 1 year, in patients with relapsing–remitting MS (RRMS), with clinical and MRI benefits maintained through year 2 [Calabresi et al. 2014; Kieseier et al. 2015]. The peginterferon beta-1a safety profile was similar to established interferon beta treatments; injection-site reactions, influenza-like symptoms, pyrexia, and headache were the most commonly reported treatment-related adverse events (AEs) [Calabresi et al. 2014; Kieseier et al. 2015]. Significant benefits on disability outcomes were also demonstrated: peginterferon beta-1a 125 mcg every 2 weeks reduced the risk of 12-week CDP by 38% (p = 0.038) compared with placebo in year 1 [Calabresi et al. 2014], with the benefit maintained through year 2 [Kieseier et al. 2015] (Supplementary Table 1).

The current analysis is a comprehensive assessment of the effects of peginterferon beta-1a on disability in RRMS based on EDSS, accompanied by an assessment of individual EDSS functional system scores (FSS). Additionally, the relationships between EDSS and MSFC and a range of PROs are explored.


Study design and patients

ADVANCE was a 2-year, randomized, double-blind, parallel-group, phase III study with a 1-year placebo-controlled period. Patients were recruited between June 2009 and November 2011. The study design has been described in detail elsewhere [Calabresi et al. 2014; Kieseier et al. 2015]. Briefly, key inclusion criteria were: diagnosis of RRMS according to McDonald criteria [Polman et al. 2005], age 18–65 years, EDSS score 0–5, and at least two clinically documented relapses in the previous 3 years, with at least one occurring within the past 12 months. Patients with progressive forms of MS were excluded, as were those who had previously received interferon treatment for longer than 4 weeks or within 6 months prior to study entry.

Patients were randomized (1:1:1) to receive subcutaneous injections with prefilled syringes of peginterferon beta-1a 125 mcg every 2 weeks, peginterferon beta-1a 125 mcg every 4 weeks or matching placebo every 2 weeks for 1 year; patients assigned to the every-4-weeks active treatment regimen received alternating injections of peginterferon beta-1a 125 mcg and placebo every 2 weeks to maintain treatment-blinding. During year 2, patients receiving peginterferon beta-1a remained on the same dose frequency and patients receiving placebo were re-randomized to peginterferon beta-1a 125 mcg every 2 or 4 weeks (‘delayed treatment’).

The ADVANCE study protocol was approved by the Institutional Review Board at each site and was performed in accordance with the International Conference on Harmonization Guidelines for Good Clinical Practice and the Declaration of Helsinki. All patients provided written informed consent before entering the study.

Study assessments and endpoints

Assessments for the primary endpoint, annualized relapse rate, have been described previously [Calabresi et al. 2014]. Secondary and tertiary endpoints included measures of disability, functional status, and HRQoL.

EDSS scoring was based on detailed neurological examination performed at baseline, every 12 weeks thereafter, and at the time of suspected relapse (evaluated during unscheduled visits within 5 days of onset of relapse symptoms) by a nontreating (examining) neurologist who was blinded to study treatment and potential AEs. To ensure consistent EDSS assessments across sites in the study, examining neurologists underwent a standardized training session on EDSS scoring prior to enrollment of patients (independent certification provided by An Independent Neurology Evaluation Committee reviewed EDSS data to corroborate changes in EDSS scores.

CDP was defined as an increase in EDSS score of [gt-or-equal, slanted]1.0 point from a baseline score of [gt-or-equal, slanted]1.0, or a [gt-or-equal, slanted]1.5-point increase from a baseline score of 0, confirmed 12 or 24 weeks after the first documentation of increased EDSS score. In a supplementary analysis, CDP was defined as EDSS score worsening by [gt-or-equal, slanted]1.0 point from baseline < 5.5, or [gt-or-equal, slanted]0.5 points from baseline [gt-or-equal, slanted] 5.5, an alternative definition recommended by the European Medicines Agency (EMA) in recognition that changes in the upper end of the scale are more easily perceptible than changes in the lower end [Meyer-Moock et al. 2014; European Medicines Agency, 2015].

Functional status was assessed by a blinded examining technician using the three tests comprising the MSFC [timed 25-foot walk, nine-hole peg test and 3-second paced auditory serial addition test (PASAT3)], conducted at the same time-points as EDSS assessments. Patients completed three sets of practice tests prior to randomization, to minimize any learning effect.

HRQoL was assessed at baseline and at 12, 24, 48, 72, and 96 weeks, using the 29-item Multiple Sclerosis Impact Scale (MSIS-29) [Hobart et al. 2001], and two generic HRQoL instruments: the 12-item Short Form Health Survey (SF-12) [Ware et al. 1996] and the EuroQoL-5D (EQ-5D) [EuroQol Group, 1990].

Statistical analyses

The primary analysis of CDP was based on time to onset of 12-week CDP; an ad hoc sensitivity analysis evaluated time to onset of 24-week CDP. Kaplan–Meier plots were generated to estimate the proportion of patients in each group with onset of CDP within year 1 and within the 2-year study period. In year 1, proportions of patients with CDP in each peginterferon beta-1a group were compared with the placebo group. For the 2-year analysis, continuous peginterferon beta-1a treatment groups were compared with the combined delayed treatment group (patients re-randomized to either peginterferon beta-1a every 2 or 4 weeks after receiving placebo in year 1). Hazard ratios and p values for between-group comparisons were based on a Cox proportional hazards model adjusted for baseline EDSS and age (<40 or [gt-or-equal, slanted]40 years). EDSS scores were also evaluated in terms of mean change from baseline, based on descriptive statistics only.

In patients who experienced CDP, changes in individual FSS concurrent with CDP were evaluated. FSS worsening was deemed to coincide with CDP if a simultaneous change of [gt-or-equal, slanted]1 point in the pyramidal, cerebellar, brainstem, sensory, bowel/bladder, visual, or cerebral FSS was maintained during the 12- or 24-week period from onset to confirmation of disability progression. The relationship between CDP and [gt-or-equal, slanted]2-point simultaneous worsening in individual FSS domains was also analyzed.

Scores for the variables within the MSFC tests were converted to a single common metric (‘Z score’) for each component and combined into an overall composite Z score per patient assessment [Cutter et al. 1999]; these were compared between patients with and without 24-week CDP using analysis of variance. Correlations between EDSS change from baseline and change from baseline in MSFC overall Z score and individual component scores were assessed using Spearman’s rank correlation.



The analyses described in this article were conducted in the ADVANCE study intent-to-treat (ITT) population (n = 1512). Baseline characteristics, as previously reported, including measures of disability, were similar across treatment groups (Table 1). A total of 1332 patients completed year 1 of the study and continued with active treatment in year 2 (438 each on continuous peginterferon beta-1a every 2 weeks and every 4 weeks; 456 on delayed treatment after switching from placebo to peginterferon beta-1a every 2 or 4 weeks) [Calabresi et al. 2014; Kieseier et al. 2015].

Table 1.
Baseline characteristics (intention-to-treat population).

Expanded Disability Status Scale at year 1 and over 2 years

In year 1, significantly lower proportions of patients in each peginterferon beta-1a group experienced 12-week CDP compared with the placebo group [6.8% of patients in each peginterferon beta-1a group, versus 10.5%; hazard ratio (HR), 0.62; p = 0.038; Supplementary Table 1] [Calabresi et al. 2014]. The sensitivity analysis of 24-week CDP confirmed significantly reduced risk of disability progression in the peginterferon beta-1a every-2-weeks group in year 1, by 54% compared with placebo (HR, 0.46; p = 0.007; Figure 1). In the peginterferon beta-1a every-4-weeks group there was a 33% reduction in risk of 24-week CDP, but this did not reach statistical significance (HR, 0.67; p = 0.112).

Figure 1.
Proportions of patients with 24-week confirmed disability progression over 1 year.

As has been previously reported, reduced risk of CDP among patients on continuous peginterferon beta-1a every 2 weeks was maintained over 2 years [Kieseier et al. 2015]. By the end of year 2, significantly fewer patients in the peginterferon beta-1a every-2-weeks group had 12-week CDP compared with the delayed-treatment group (p = 0.026). Results for 24-week CDP were broadly consistent, showing significant reduction in risk of CDP with peginterferon beta-1a every 2 weeks versus delayed treatment (p = 0.0137), but also versus every-4-week treatment (p = 0.046). This is consistent with observations across other endpoints in the ADVANCE study that the approved dosage of peginterferon beta-1a every 2 weeks provides greater efficacy over 2 years than every-4-weeks administration [Kieseier et al. 2015]. Results for 24-week CDP over 2 years assessed using alternative criteria requiring a smaller change in EDSS score at the upper end of the scale (0.5-point change for patients with baseline EDSS score [gt-or-equal, slanted] 5.5) showed consistent trends with those described above (Figure 2).

Figure 2.
Proportions of patients with 24-week confirmed disability progression over 2 years, based on worsening on Expanded Disability Status Scale by [gt-or-equal, slanted] 1.0 point from baseline < 5.5, or [gt-or-equal, slanted] 0.5 points from baseline [gt-or-equal, slanted] 5.5.

Data for change from baseline in EDSS scores showed a trend for decreasing mean EDSS score over 2 years in the peginterferon beta-1a every-2-weeks group, while mean EDSS score increased over 2 years in the delayed treatment group (Supplementary Figure 1).

Functional system score

In year 1, across all treatment groups, approximately 90% of patients with 12-week CDP had simultaneous worsening by [gt-or-equal, slanted]1 point in at least one FSS, and approximately 39% of patients had simultaneous worsening by [gt-or-equal, slanted]2 points in at least one FSS. Similar proportions of patients with 12-week CDP over 2 years had simultaneous FSS worsening by [gt-or-equal, slanted]1 point or by [gt-or-equal, slanted]2 points (89% and 40%, respectively). Results were similar when considering 24-week CDP over 1 year (90% and 39%, respectively) and over 2 years (88% and 38%, respectively; Table 2). Across these analyses, simultaneous FSS worsening occurred most frequently in the pyramidal domain (54–59%), followed by the sensory (28–33%) and cerebellar (28–31%) domains (Figure 3).

Table 2.
Simultaneous worsening of functional system score alongside confirmed disability progression: number of functional system domains with [gt-or-equal, slanted]1 or [gt-or-equal, slanted]2 points simultaneous worsening.
Figure 3.
Proportions of patients with (A) 12-week confirmed disability progression (CDP) in year 1, (B) 24-week CDP in year 1, (C) 12-week CDP over 2 years, and (D) 24-week CDP over 2 years, with simultaneous worsening of [gt-or-equal, slanted]1 point in any functional system ...

Relationship between Expanded Disability Status Scale and other outcomes over 2 years

Significant association was observed between 24-week CDP and deterioration in MSFC scores. In the overall study population, patients who experienced 24-week CDP had significantly worse composite Z scores than those who did not experience CDP; significant associations were also observed with the individual MSFC component Z scores for the nine-hole peg test and timed 25-foot walk, although PASAT3 appeared less sensitive to CDP status and Z score was not significantly worse in patients with than without 24-week CDP (Supplementary Table 2). Furthermore, an analysis of correlation between change from baseline in EDSS and MSFC scores (treating EDSS as a continuous variable rather than stratified into patients with and without 24-week CDP) showed that, for all treatment groups combined, there was significant negative correlation between change from baseline to week 96 in EDSS score and MSFC composite Z score, nine-hole peg test Z score, and timed 25-foot walk Z score (all p < 0.0001).

Significant association was also observed between disability status and a range of PROs. For all treatment groups combined, patients with 24-week CDP reported significantly worse outcomes than those without 24-week CDP in MSIS-29 physical impact and psychological impact scores; SF-12 physical component and mental component scores, and all individual domains; and EQ-5D Index score and EQ-5D subject assessment of health (Supplementary Table 2).

Inspecting trends across treatment groups, differences between patients with and without 24-week CDP tended to be smaller in the peginterferon beta-1a every-2-weeks group than in other groups. Mean scores on the MSIS-29, SF-12, and EQ-5D were not significantly worse for patients who experienced CDP than for those who did not in the peginterferon beta-1a every-2-weeks group, whereas significant differences were found in other groups, driving the overall significant impact of CDP (Supplementary Table 2). On the MSFC, composite and component Z scores were significantly worse in patients with than without 24-week CDP in all treatment groups, although magnitude of differences tended to be numerically smaller in the peginterferon beta-1a every-2-weeks group. Furthermore, the analysis of correlation between EDSS change from baseline and change in MSFC score showed weaker correlation in the peginterferon beta-1a every-2-weeks group [correlation coefficients approximately −0.1 for MSFC composite Z scores (p = 0.04) and nine-hole peg test and timed 25-foot walk Z scores (p > 0.05)] than in patients receiving delayed treatment [correlation coefficients approximately −0.2 (all p < 0.01)].


This extended evaluation of disability data from the ADVANCE study expands on the previous findings that peginterferon beta-1a every 2 weeks significantly reduced risk of disability progression, as measured by 12- and 24-week CDP on the EDSS [Calabresi et al. 2014; Kieseier et al. 2015], by examining the individual FSS that contribute to EDSS scores, and associations between EDSS and other measures of patients’ functional status.

Assessing disability worsening within the timeframe of a clinical trial can be challenging, since long-term disability in MS evolves over many years [Goodin et al. 2002]. Nevertheless, well defined measures of CDP based on EDSS are accepted outcomes in clinical trials of disease-modifying therapies in RRMS, and disease progression based on the same CDP definition used in this study has been used as a primary endpoint in previous pivotal trials, including the Multiple Sclerosis Collaborative Research Group trial of interferon beta-1a [Jacobs et al. 1996] and the natalizumab AFFIRM study [Polman et al. 2006].

In ADVANCE, where they were secondary endpoints, CDP endpoints demonstrated significant reduction in risk of 12- and 24-week CDP with peginterferon beta-1a every 2 weeks compared with placebo in year 1, with benefits maintained in year 2. Broadly consistent results in year 1 and year 2 increase confidence in initial interpretations made on the basis of year 1 results. These results were also generally consistent for 12- and 24-week CDP, although 24-week confirmation provided the most rigorous assessment and appeared more sensitive to differences between the two peginterferon beta-1a regimens. An exploratory analysis of EDSS change from baseline was supportive of the main analysis, suggesting a positive treatment effect of peginterferon beta-1a every 2 weeks on EDSS scores.

EDSS assessments of worsening disability are more robust if accompanied by assessment of individual functional system(s) in which worsening occurs, to ensure that CDP reflects continued meaningful worsening in a particular functional system, rather than an average worsening score that might represent fluctuating changes across several systems [Lublin et al. 2014]. In this analysis, approximately 90% of patients who experienced CDP across all treatment groups had concurrent worsening in at least one FSS, indicating that CDP assessments predominantly reflected true disease worsening. The pyramidal system was the most commonly affected functional system, followed by sensory and cerebellar domains. A considerable proportion of patients with 12- or 24-week CDP had deterioration in multiple functional systems during periods of worsening disability.

This analysis also provided evidence for associations between disability status and other outcomes relating to functional status and HRQoL. In the overall patient population, MSFC scores and PROs at week 96 (study end) tended to be significantly worse in patients who experienced CDP during the study than in those who did not. These associations were consistently weaker in the peginterferon beta-1a every-2-weeks group than in the delayed treatment group, indicating that effective treatment that improves disability outcomes has the potential to positively impact functionality and HRQoL. This appears to reflect positive treatment effects in addition to those detected in EDSS assessments, since even in patients who did experience 24-week CDP during the study, deterioration in other outcomes, particularly HRQoL measures, tended to be attenuated in the peginterferon beta-1a every-2-weeks group compared with other treatment groups. This is consistent with a previous analysis of PROs in year 1 of the ADVANCE study that showed the impact of CDP on HRQoL was reduced with peginterferon beta-1a compared with placebo. Patients in the peginterferon beta-1a every-2-weeks group experiencing 12-week CDP had a significantly lesser degree of worsening in scores on the MSIS-29 physical subscale, SF-12 physical component summary, EQ-5D health utility, and EQ-5D visual analogue scales, compared with those with 12-week CDP in the placebo group [Newsome et al. 2015].

A negative correlation between change from baseline in EDSS and MSFC scores over 2 years in the overall study population was also observed, as is to be expected; worsening disability over time is reflected in increasing EDSS scores, with concurrent decline in performance on MSFC tests. Correlation was weaker in the peginterferon beta-1a every-2-weeks group than in other groups in this analysis too, possibly reflecting weaker trends for worsening on either scale.

In the ADVANCE population, approximately half of patients who experienced CDP did so following a relapse that did not fully resolve and left residual deficits, while the remainder had CDP that was not associated with relapse. Previous ADVANCE study publications have reported that peginterferon beta-1a may improve disability outcomes through a combination of reducing the risk of relapse (and therefore reducing likelihood of incurring residual deficits following relapse) and improving recovery when relapses occur [Kieseier et al. 2014]. The current analysis encompassed all data on accumulation of disability during the ADVANCE study, both related to and independent of relapse.

Overall, the effects observed with peginterferon beta-1a on improving measures of disability, alongside previously reported improvements in relapse and MRI endpoints [Calabresi et al. 2014; Kieseier et al. 2015], support its potential to achieve the key aim of preventing/delaying worsening of disability [Goodin et al. 2002] in patients with RRMS.

Supplementary Material

Supplementary material:
Supplementary material:


We would like to thank the patients and study site personnel who participated in the ADVANCE study. The authors were assisted in the preparation of the manuscript by Samantha Stanbury, PhD, a professional medical writer contracted to CircleScience (Tytherington, UK). Writing support was funded by the study sponsor. All authors were involved in reviewing the manuscript critically for important intellectual content. The authors had full editorial control of the manuscript and provided their final approval of all content.


Funding: The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was funded by Biogen (Cambridge, MA, USA).

Conflict of interest statement: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: SDN has participated in scientific advisory boards for Biogen, Genzyme, and Novartis, and has received research support from Biogen, Novartis, and the National MS Society. BCK was not affiliated to Biogen at the time of study conduct and data analysis, but is now an employee and stock holder of Biogen. SL, XY, EK, SH, and BS are employees and stockholders of Biogen.

Contributor Information

Scott D. Newsome, Johns Hopkins Neuroimmunology and Neuroinfectious Diseases, Johns Hopkins Hospital, 600 North Wolfe Street, Pathology 627, Baltimore, MD 21287, USA.

Bernd C. Kieseier, Department of Neurology, Medical Faculty, Henrich-Heine University, Düsseldorf, Germany Biogen, Cambridge, MA, USA.

Shifang Liu, Biogen, Cambridge, MA, USA.

Xiaojun You, Biogen, Cambridge, MA, USA.

Elizabeth Kinter, Biogen, Cambridge, MA, USA.

Serena Hung, Biogen, Cambridge, MA, USA.

Bjoern Sperling, Biogen, Cambridge, MA, USA.


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