www.elsevier.com/locate/jns

Journal of the Neurological Scie

Can glatiramer acetate reduce brain atrophy development in

multiple sclerosis?

Marco Rovaris*, Giancarlo Comi, Massimo Filippi

Neuroimaging Research Unit, Department of Neurology, Scientific Institute and University Ospedale San Raffaele, via Olgettina 60-20132 Milan, Italy

Available online 20 April 2005

Abstract

The assessment of brain volume changes on serial magnetic resonance imaging (MRI) scans can provide an objective measure of

progressive atrophy reflecting the neurodegenerative aspects of multiple sclerosis (MS) pathology. The present article reviews the results of

studies assessing the effect of glatiramer acetate (GA) treatment in preventing MS-related, MRI-measurable brain volume decrease.

Whilst data from the extended, open-label follow-up of the US trial seem to indicate that long-term treatment with GAmight prevent the loss

of brain parenchyma in relapsing–remitting MS patients, longitudinal data from the European/Canadian MRI trial suggest that, over a short-

term period of treatment, GA does not have a clear-cut impact on the decrease of brain volume. The effect of GA on MS-related brain atrophy

might, therefore, be delayed and dissociated in time from those exerted on other clinical and MRI measures of disease activity. However, the

modest magnitude of this effectmakes it difficult to evaluate its impact on the actual disease progression. Further studies of adequate duration are

now required to address this issue, as well as to confirm the sustained efficacy of GA treatment over long periods of follow-up.

D 2005 Elsevier B.V. All rights reserved.

Keywords: Glatiramer acetate; Brain atrophy; Multiple sclerosis

1. Introduction

The assessment of brain volume changes on serial

magnetic resonance imaging (MRI) scans can provide an

objective measure of progressive atrophy reflecting the

neurodegenerative aspects of multiple sclerosis (MS)

pathology [1–9]. Several clinical trials assessed the efficacy

of immunomodulating and immunosuppressive therapies in

the reduction of brain atrophy development in MS, but the

vast majority of treatments were found to lack a substantial

efficacy in preventing brain volume decrease, despite their

marked effects on clinical and MRI outcomes of disease

activity [10].

Glatiramer acetate (GA; Copaxone\, TEVA Pharma-

ceutical Industries Ltd., Israel) is an immunomodulating

drug currently approved in several countries for the treat-

ment of relapsing–remitting (RR) MS [11,12]. GA is the

acetate salt of a mixture of synthetic polypeptides and it

0022-510X/$ - see front matter D 2005 Elsevier B.V. All rights reserved.

doi:10.1016/j.jns.2005.03.013

* Corresponding author. Tel.: +39 2 26433054; fax: +39 2 26433054.

E-mail address: rovaris.marco@hsr.it (M. Rovaris).

appears to act against MS via production of specific T-

suppressor cells that cross react with myelin basic protein in

the central nervous system [13,14]. On stimulation, these

cells secrete regulatory cytokines of the type that character-

ize Th2 or regulatory T cells [15,16]. GA-specific T cells

also seem to produce brain-derived neurotrophic factor

(BDNF) [17], with a potential neuroprotective effect.

Clinically, GA significantly reduces the frequency of

relapses in RRMS [11,12]. In addition, a multicenter,

placebo-controlled study [18] has demonstrated that GA is

also effective in reducing MS activity and accumulated

burden of disease as measured by serial MRI scans of the

brain, with a sustained efficacy over 18 months of

observation [19]. In the latter trial, additional data analysis

based upon individual lesion evolution tracking has revealed

that GA has a favorable effect not only on the formation of

new MS lesions, but also in preventing re-enhancement and

tissue loss once lesions are formed [20].

The present article reviews the results of studies

assessing the effect of GA treatment in preventing MS-

related, MRI-measurable brain volume decrease.

nces 233 (2005) 139 – 143

M. Rovaris et al. / Journal of the Neurological Sciences 233 (2005) 139–143140

2. GA treatment and brain atrophy: data from the US

trial

The pivotal phase III, double-blind, placebo-controlled

US GA trial [11,12] did not formally addressed the issue of

treatment efficacy in preventing brain atrophy. However, in

a pilot study of 27 patients enrolled at one site (University of

Pennsylvania, Philadelphia), Ge et al. [21] measured brain

volume changes on yearly MRI scans using a fully-

automated technique. Surprisingly, no significant treatment

effect on clinical (relapse rate) or MRI (number of contrast-

enhancing and active T2-hyperintense lesions) measures of

MS activity was observed in this subcohort of patients,

whereas the rate of brain volume decrease was found to be

significantly higher in placebo than in treated patients

(�1.8% vs. �0.6% per year, respectively, p =0.0078).

A recent, cross-sectional analysis of data from the

extended, open-label follow-up of the US trial [22]

investigated the consequences of long-term GA treatment

on several MRI markers of MS activity and disease burden,

including absolute and normalized cerebrospinal fluid (CSF)

volumes, which can be viewed as ‘‘inverse’’ measures of the

extent of brain atrophy. Data from 135 patients (i.e., 54% of

the cohort of 251 patients originally enrolled) entered this

analysis. At the time of MRI follow-up, the mean duration

of active drug exposure was 2433 days for patients

originally randomized to GA and 1476 days for those

randomized to placebo. Absolute and normalized CSF

volumes were found to be significantly lower for patients

who had the longer exposure to GA treatment and the group

difference remained statistically significant after correcting

for patients’ age, disability and disease duration. Despite the

methodological limitations related to an open-label study,

this analysis seems to indicate that long-term treatment with

GA might prevent the loss of brain parenchyma in RRMS

patients.

3. GA treatment and brain atrophy: data from the

European/Canadian MRI trial

The study was designed to assess the efficacy of GA on

MRI-derived measures of RRMS activity and consisted of a

9-month, double-blind, placebo-controlled phase followed

by a 9-month open-label phase [18,19]. All patients had a

RR disease course [23], an Expanded Disability Status Scale

(EDSS) score [24] of 0.0–5.0, at least one documented

relapse in the preceding 2 years and at least one gadolinium

(Gd)-enhancing lesion on their screening brain MRI.

Patients underwent brain MRI scans every month during

the first phase and every 3 months during the second phase

of the study. The MRI acquisition and postprocessing

protocol was designed following international consensus

guidelines [25], that have been established to optimize the

accuracy, reproducibility and sensitivity of MRI-derived

measures to be used in MS studies. In an ancillary study

[26], brain volume was measured from the scans obtained at

baseline, the end of the double-blind phase and the end of

the study. A seed growing technique for brain tissue

segmentation was used [9]. The absolute brain parenchymal

volume was calculated for a slab of tissue including the

seven contiguous slices rostral to the velum interpositum.

Comparison with subsequent scans from each individual

patient allowed consistent slice choice and reduced the

effects of volume variation due to patient positioning on

serial scans. Such an approach includes the regions where

MS pathology is more frequent. Percentage brain volume

changes (PBVC) between two subsequent scans were

computed from the corresponding absolute values.

From the original trial cohort, image sets from 113/119

patients randomized to GA and 114/120 randomized to

placebo treatment were evaluated for brain atrophy analysis.

The average brain volume at study entry was not signifi-

cantly different between patients in the two study arms.

During the double-blind phase, an average brain volume

reduction of 0.7% and 0.8% was seen in placebo- and GA-

treated patients, with a measurement standard deviation

(S.D.) of 2.2% and 1.9%, respectively. The rate of brain

volume decrease was lower during the open-label phase for

the subjects that had been on continuous GA treatment from

randomization (0.6% loss for those originally on placebo,

0.4% for those always on GA), but these differences were

not significant. After 18 months, brain volume was

decreased by 1.4% (S.D. 2.3%) and 1.2% (S.D. 2.4%) in

patients originally randomized to placebo and GA treatment,

respectively. Neither the absolute nor the percentage

changes of brain volume were significantly different

between the two study arms. Covariate analysis was

performed that included age, gender, center, disease

duration and brain volume at baseline. No significant effect

of treatment was found on PBVC during the double-blind

phase of the study, even when the analysis was repeated

after adding the number of Gd-enhancing lesions at baseline

to the covariates. Brain volume changes and patients’

relapse rate or EDSS changes were not significantly

correlated during either the study phases.

More recently, a post hoc analysis [27] was run in which

the atrophy dataset of the European/Canadian GA trial was

re-assessed using a fully-automated, normalized technique

with whole brain coverage, the Structural Image Evaluation

of Normalized Atrophy (SIENA) software [28]. These

results were compared with those of the semi-automated,

non-normalized technique with partial brain coverage

(OLD) used for the original study [25]. PBVC between

month 18 and months 9 and 0 was measurable with both the

techniques for 97 placebo and 97 GA patients. In this

subcohort of patients, the average PBVC values calculated

using the OLD technique did not differ from those of the

larger cohort of the original study [26]. No significant

differences of PBVC values were found between the OLD

and the SIENA methods, during the double-blind and the

open-label phase of the study, as well as over the whole

M. Rovaris et al. / Journal of the Neurological Sciences 233 (2005) 139–143 141

study period. Using the SIENA technique, PBVC during the

double-blind phase was slightly, but not significantly lower

in GA-treated than in placebo patients. During the open-

label phase, the mean SIENA-calculated PBVC resulted to

be significantly lower for patients that had been treated with

GA since randomization (�0.6%) than for those originally

on placebo (�1.0%, p =0.015). The between-group differ-

ence in favor of patients who had always been treated with

GA was also found to be significant over the entire study

period ( p =0.037). Using a simulation algorithm, the

between-subject variability of PBVC from month 0 to

month 9 of the study was estimated to be 0.84%. The

variability due to measurement error of the OLD technique

was estimated to be 2.05%, while that of the SIENA

technique was estimated to be 0.80%. This means that the

between-subjects PBVC variability had the same magnitude

as the measurement error of the SIENA technique, whereas

the measurement error of the OLD technique was much

higher.

4. Discussion

Whilst data from the extended, open-label follow-up of

the US trial [22] seem to indicate that long-term treatment

with GA might prevent the loss of brain parenchyma in

RRMS patients, longitudinal data from the European/

Canadian MRI trial [26] suggest that, over a short-term

period of treatment, GA does not have a clear-cut impact on

the decrease of brain volume.

Several reasons may explain why, in the latter study [26],

the effect of GA in reducing clinical and MRI-measured MS

activity [18–20] was not paralleled by an effect on the

decrease of patients’ brain volume. First, the short duration

of the placebo-controlled phase may have decreased the

ability to detect an effect of GA treatment on brain volume

change. In this patient group, an effect of GA on MRI

measures of inflammation was discernible by 4 to 6 months

after initiating treatment and the magnitude of the effect of

active treatment increased over time [18,19]. However, the

effect of GA on relapses and on other MRI measures of MS

activity became significant only after 6 months of treatment

[18]. These findings fit well with the timing of drug action

in the modulation of T-cell immune responses [16]. Thus, if

the effect of GA treatment in slowing the loss of brain

volume in MS is similarly delayed, it may not be surprising

that no effect was evident over the 9-month placebo-

controlled comparison.

A second explanation for our findings might be the

limited ability of GA to modify the pathological mecha-

nisms leading to global tissue loss in MS. A similar apparent

divergence between the anti-inflammatory effects and the

prevention of brain volume reduction over time was

reported for interferon beta-1b [29], cladribine [30],

Campath 1H [31,32] and autologous hematopoietic stem

cell transplantation [33]. The modest magnitude of the

correlation between Gd enhancement and brain tissue loss

also supports the hypothesis that the impact of treatment on

MRI measures closely related to inflammatory activity may

not necessarily be rapidly or fully translated into a beneficial

effect on other MRI measures which reflect irreversible

neurodegeneration. On the other hand, pathological studies

[34] have shown that axonal damage occurs in inflammatory

MS lesions, thus suggesting that preventing brain inflam-

mation should have at least a partial effect on the

progressive loss of tissue seen in MS patients. The

magnitude of this effect might, however, be too small to

be detected by MRI measurements of brain tissue volume

over relatively short intervals.

Third, methodological issues may also play a role. The

use of regional segmentation algorithms such as seed

growing [9] allows a measurement reproducibility of about

1.5% to be achieved. Comparisons between groups of

patients can, however, be confounded by the presence of

substantial inter-subject variations in head size that can

mask differences attributable to atrophy. The normalization

of brain volumes to head size may be successful in reducing

these confounders [8]. Normalized volumes also remove the

variability of volume data due to scanner instability, as all

structures in the image will experience the same amount of

artefactual scaling due to such an effect. It is noteworthy

that, in both MS trials showing a treatment efficacy against

MS-related brain atrophy [35,36], a normalized measure

(brain parenchymal fraction—BPF) was used. Thus, the

rationale for using SIENA to re-analyze the GA trial atrophy

dataset [27] was to reduce all the potential methodological

limitations of the OLD measurement technique and, by

comparing the results obtained with the two techniques in

the same sample of patients, to be able to estimate the role

played by ‘‘non-biological’’ factors in determining the

atrophy results of MS trials.

We found that the average PBVC values observed in both

the treatment arms of the European/Canadian GA trial did

not greatly change when using the SIENA vs. the OLD

technique. Conversely, the standard deviations of SIENA-

measured PBVC were markedly lower, with values that are

more than a half than those of the OLD technique

measurements. Since the between-subject PBVC variability

in a given sample of patients does not change whatever

technique is used to quantify it, the standard deviation

reduction we observed for SIENA vs. the OLD technique

implies that the former has a lower measurement error. The

most immediate result of this measurement error reduction

is a change of the statistical significance related to the

observed difference in PBVC between treatment arms. As a

consequence, when using SIENA, PBVC in the open-label

phase and over the entire period of the study resulted to be

significantly lower in patients originally randomized to GA

than in those treated with placebo for the first 9 months of

the study. Due the post-hoc nature of this analysis, the effect

of GA on brain atrophy in this study cohort has to be

considered with caution. However, such a delayed effect of

M. Rovaris et al. / Journal of the Neurological Sciences 233 (2005) 139–143142

GA treatment on brain atrophy development is consistent

with data from a double-blind, placebo-controlled trial of

interferon beta-1a [35].

5. Conclusions

The effect of GA on MS-related brain atrophy seems to

be delayed and dissociated in time from those exerted on

other clinical and MRI measures of disease activity. The

modest magnitude of this effect makes it difficult to evaluate

its impact on the actual disease progression and further

studies are required to address this issue, as well as to

confirm the sustained efficacy of treatment over long

periods of follow-up.

The results of the post hoc analysis of atrophy data from

the European/Canadian GA study also indicate that the

interpretation of atrophy measurement results in MS trials

has always to take into account technical factors. Fully-

automated, normalized techniques with whole brain cover-

age seem to be able to reduce the measurement error well

below the between-patient variability of brain volume

changes observed in RRMS patients over a short period of

time, thus increasing the statistical power of a given study.

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