The accepted standard treatment of relapsing multiple sclerosis consists of medications for disease symptoms, including treatment for acute exacerbations. However, currently there is no therapy that alters the progression of physical disability associated with this disease. The purpose of this study was to determine whether interferon beta-1a could slow the progressive, irreversible, neurological disability of relapsing multiple sclerosis. Three hundred one patients with relapsing multiple sclerosis were randomized into a double-blinded, placebo-controlled, multicenter phase III trial of interferon beta-1a. Interferon beta-1a, 6.0 million units (30 micrograms¿, was administered by intramuscular injection weekly. The primary outcome variable was time to sustained disability progression of at least 1.0 point on the Kurtzke Expanded Disability Status Scale (EDSS). Interferon beta-1a treatment produced a significant delay in time to sustained EDSS progression (p = 0.02). The Kaplan-Meier estimate of the proportion of patients progressing by the end of 104 weeks was 34.9% in the placebo group and 21.9% in the interferon beta-1a-treated group. Patients treated with interferon beta-1a also had significantly fewer exacerbations (p = 0.03) and a significantly lower number and volume of gadolinium-enhanced brain lesions on magnetic resonance images (p-values ranging between 0.02 and 0.05). Over 2 years, the annual exacerbation rate was 0.90 in placebo-treated patients versus 0.61 in interferon beta-1a-treated patients. There were no major adverse events related to treatment. Interferon beta-1a had a significant beneficial impact in relapsing multiple sclerosis patients by reducing the accumulation of permanent physical disability, exacerbation frequency, and disease activity measured by gadolinium-enhanced lesions on brain magnetic resonance images. This treatment may alter the fundamental course of relapsing multiple sclerosis.

Objective: To characterize whole-brain atrophy in relapsing-remitting MS (RRMS) patients over an 8-year period. The specific goals of this study were to determine if brain atrophy is related to subsequent disability status and to identify MRI correlates of atrophy progression. Methods: A follow-up study was conducted to reassess patients from a phase III trial of interferon-1a (IFN-1a) 8 years after randomization. Clinical and MRI data from 172 patients followed over 2 years in the original trial were used as baseline data. Follow-up data were obtained on 160 patients, including 134 patients with follow-up MRI examinations. Brain atrophy was estimated by automated calculation of brain parenchymal fraction. The relation between atrophy during the original trial and disability status at follow-up was determined. Correlations were also determined between lesion measurements from the original trial and the brain parenchymal fraction at follow-up. Results: Brain atrophy was correlated with subsequent disability status. Atrophy rate during the original trial was the most significant MRI predictor of disability status at follow-up. Brain atrophy at follow-up was related to lesion volumes measured during the original trial. Conclusions: The relation between atrophy progression and subsequent neurologic disability status suggests that atrophy progression during RRMS is clinically relevant. Therefore, atrophy progression may be a useful marker for disease progression in clinical trials. The relation between lesions and subsequent atrophy indicates that brain atrophy may be related to focal tissue damage at earlier points in time, but important predisposing or other factors contributing to atrophy remain undefined. MRI has fallen short of expectations in terms of providing a surrogate marker in MS. The lack of robust correlations between conventional MRI measures of pathology and clinical measures of disability has been attributed to various shortcomings of both MRI and clinical assessments. At least part of the discrepancy may be due to the use of MRI measurements that include both reversible and irreversible components of MS pathology. Conventional MRI lesion measurements also neglect to account for diffuse abnormalities in normal-appearing tissue in MS. One of the alternative MRI measures that have been proposed to monitor MS progression is the estimation of CNS atrophy. 1-11 In contrast to MRI-visible lesions, CNS atrophy is believed to reflect the net effect of severe and potentially irreversible processes such as demyelination and axonal loss. Measurement of the size of CNS structures may provide an indication of the total amount of tissue damage that has occurred up to a given point in time. New computer-assisted methods have been developed to precisely and reliably quantify tissue loss in MRI, 5-13 and atrophy has been shown to occur even in the early stages of MS. 3,4,6-9 However, previous longitudinal studies in MS 3,6-9,14-16 have not shown very strong or consistent relations between brain atrophy and disability...

The Multiple Sclerosis Collaborative Research Group trial was a double-blind, randomized, multicenter, phase III, placebo-controlled study of interferon beta-1a (IFNbeta-1a; AVONEX) in relapsing forms of multiple sclerosis. Initial magnetic resonance imaging results have been published; this report provides additional results. Treatment with IFNbeta-1a, 30 microg once weekly by intramuscular injection, resulted in a significant decrease in the number of new, enlarging, and new plus enlarging T2 lesions over 2 years. The median increase in T2 lesion volume in placebo and IFNbeta-1a patients was 455 and 152 mm3, respectively, at 1 year and 1,410 and 628 mm3 at 2 years, although the treatment group differences did not reach statistical significance. For active patients, defined as those with gadolinium enhancement at baseline, the median change in T2 lesion volume in placebo and IFNbeta-1a patients was 1,578 and -12 mm3 and 2,980 and 1,285 mm3 at 1 and 2 years, respectively. Except for a minimal correlation of 0.30 between relapse rate and the number of gadolinium-enhanced lesions, correlations between MR and clinical measures at baseline and throughout the study were in general poor. Once weekly intramuscular IFNbeta-1a appears to impede the development of multiple sclerosis lesions at an early stage and has a favorable impact on the long-term sequelae of these inflammatory events as indicated by the slowed accumulation of T2 lesions.

MSFC scores in patients with RR-MS predict the level of disability and extent of brain atrophy 6 to 8 years later. MSFC scores may prove useful to assign prognosis, monitor patients during early stages of MS, and to assess treatment effects.

Brain atrophy measurement can provide an estimate of the amount of tissue destruction due to the pathologic processes in multiple sclerosis. The potential usefulness of atrophy as a marker of disease progression depends upon the concurrent and predictive relationships between atrophy and disability. A follow-up study was performed to measure atrophy and disability scores in patients from the Multiple Sclerosis Collaborative Research Group's phase III trial of IFNbeta-1a (Avonex) in relapsing- remitting multiple sclerosis. New data were obtained on 160 out of 172 eligible patients from the original trial were enrolled in the follow-up study approximately 8 years after randomization. The follow-up visit consisted of several tests and questionnaires including a clinical exam to determine Expanded Disability Status Score (EDSS) and Multiple Sclerosis Functional Composite (MSFC), and a magnetic resonance imaging exam to calculate the brain parenchymal fraction. Brain parenchymal fraction was correlated with both EDSS and MSFC at each of the four time points for which data were available (baseline 1, 2 and 8 years). Furthermore, the change in BPF was correlated with the changes in disability scores from the end of the phase III trial to the follow-up exam. These data suggest that brain atrophy may be a useful and clinically relevant marker of disease progression in relapsing--remitting MS.