Journal of the Neurological Sciences 312 (2012) 7–12
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Journal of the Neurological Sciences
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Effect of disease-modifying therapies on brain volume in relapsing–remittingmultiplesclerosis: Results of a five-year brain MRI study
Omar Khan a,b,⁎, Fen Bao a, Megha Shah a, Christina Caon b, Alexandros Tselis b, Ronald Bailey d,Bruce Silverman e, Imad Zak c
a MR Image Analysis Laboratory, Department of Neurology, Wayne State University School of Medicine, USAb Multiple Sclerosis Center, Department of Neurology, Wayne State University School of Medicine, USAc Department of Radiology, Wayne State University School of Medicine, Detroit, USAd Riverside Medical Center, Riverside, USAe Providence Hospital, Southfield, USA
Objective: To compare the long-term effect of disease-modifying therapies (DMT) on brain volume loss inrelapsing–remitting MS (RRMS) patients.Methods: We conducted a study to examine the effect of daily glatiramer acetate (GA), weekly low doseinterferon beta (LD-IFNB), and high-dose high-frequency interferon beta disease (HD-IFNB) on brain vol-ume loss over 5 years in RRMS patients. All patients were previously treatment naïve, had disease duration≤5 years at the time of initiating DMT, and subsequently received the same DMT for 5 years continuously.The percentage change in brain volume (PCBV) was measured using fully automated software. MRI anal-ysis was performed blinded to treatment allocation.Results: The adjusted PCBV from baseline to year 5 was −2.27% in GA, −2.62% in LD-IFNB, and −3.21% inthe HD-IFNB groups (−2.27 vs −2.62, p=0.0036; −2.27 vs −3.21, pb0.0001; −2.62 vs −3.21,pb0.0001). These data remained unchanged from year 1 to year 5, after adjusting for pseudoatrophy in
the first year. A group of RRMS patients that remained untreated for a period ranging from 8 to 24 months,served as controls. All treatment groups were significantly better than the rate of projected brain volumeloss in the untreated group over 5 years (pb0.0001).Conclusions: Global brain volume loss is a dynamic process even in relatively early RRMS patients that oc-curs despite intervention with therapy. However, all DMT significantly reduced the loss of brain volumecompared to no treatment. The GA-treated group experienced the least reduction in brain volume over5 years, compared to the LD-IFNB and HD-IFNB treated groups. These differences could be partly relatedto the immunologic consequences of GA therapy in RRMS.
The decrease of brain parenchymal volume leading to global brainatrophy or brain volume loss in MS is well recognized [1]. The patho-logic substrate of brain atrophy in MS is complex but broadly com-prised of diffuse demyelination and axonal loss that occurs both inT2 lesions as well as the so-called normal appearing brain tissue[2,3]. Several longitudinal studies have established the utility ofstudying brain atrophy in MS, which arguably remains one of thebest prognostic tools to predict disability in MS [4–6]. There is noclear distinction in the MS literature between the terms “brain atro-phy” and “brain volume loss”. We have used the term brain volumeloss instead of atrophy in the context of our study, which we believe
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more accurately represents the measurements performed by fullyautomated software techniques.
Interferon-beta (IFNB) and glatiramer acetate (GA) have been thestandard first-line disease-modifying therapies (DMT) in relapsingforms of MS for over a decade. With the availability of these DMTand the growing emphasis on the importance of brain volume lossas a marker of destructive tissue pathology in MS, there is anexpected interest in how DMT therapies may influence brain volumeloss in MS. Numerous studies in RRMS have examined the effect ofIFN and GA on brain volume loss yielding highly variable results[7–12]. This is partly explained by the differences in the study popu-lation and trial designs, imaging techniques used to quantify brainvolume loss, and the mechanisms of action of IFNB and GA, amongother factors [13].
Short-term studies of change in brain volume in MS are furthercomplicated by the fact that brain volume loss can be significantlyinfluenced by reactive gliosis and tissue water content fluctuations.
Treatment naïve RRMS patients with EDSS < 3.0 and disease duration < 5.0 years
n=608
Treatment naïve RRMS patients on the same DMT for five years n=469
Treatment naïve RRMS patients with baseline and year 5 brain MRIscans on the same scanner using same protocol
n=318
Treatment naïve RRMS patients with baseline and year 5 brain MRIscans that could be analyzed with SIENA
n=275
Breakdown of the final 275 patients included in the analysis GA n=121; HD-IFNB n=101; LD-IFNB n=53
Fig. 1. Data acquisition scheme. The patients in the study were included in 4 consecu-tive steps as shown in the figure. A total of 275 were included in the study for analysis.
8 O. Khan et al. / Journal of the Neurological Sciences 312 (2012) 7–12
Referred to as “pseudoatrophy”, the accelerated loss of brain volumein a short period of time with no associated cell loss is a well-recognized feature in MS, often observed early after initiating DMT[14,15]. Equally challenging is separating pseudoatrophy from truebrain tissue loss and how the former may influence long-term out-comes. Therefore, long-term studies observing change in brain vol-ume may be more desirable to quantify this complex destructivepathology in MS.
We conducted a long-term study to examine the effect of DMT(IFNB and GA) on brain volume over a 5-year period in patientswith RRMS who were previously naïve to any DMT.
2. Patients and methods
2.1. Patient recruitment
This was a retrospective study in which RRMS patients treatedwith DMT (IFNB and GA), and followed at our Center were included.The study was approved by the local Institutional Review Board.Major inclusion criteria for the study were: (i) clinically definiteRRMS, (ii) disease duration ≤5 years at the time of initiating DMT,(iii) EDSS≤3.0 at the time of initiating DMT, (iv) received the sameDMT at the recommended dose for five years continuously withoutinterruption, (iv) naïve to any DMT at the time of initiating their cur-rent DMT, and (v) undergone baseline (at the time of initiating DMT)and year 5 brain MRI scans, using the same scanner with the same im-aging protocol. Patients with SPMS or PPMS were excluded. Patientswho did not continuously use the same DMT for five years wereexcluded. Patients who were not compliant with their DMT injectionswere also excluded. Neurological examination and EDSS recordingwere available for all patients. Relapses were treated with corticoste-roids if confirmed by the treating neurologist and clinically war-ranted. Since this is was not a prospectively designed study, mostrelapses were treated with 5 days of intravenous methylprednisolone(IVMP) without oral prednisone taper but in some instances, thetreating neurologist preferred a brief oral prednisone taper followingIVMP.
A group of untreated RRMS who had never received DMT previ-ously, was also included for comparison. The primary reason for thethese patients to remain untreated was needle phobia while a smallernumber had contemplated pregnancy, and others had previously par-ticipated in clinical trials but were randomized to placebo arm whichwas verified upon completion of the studies.
2.2. MRI scans
All brain MRI scans were performed on a 1.5 T scanner using a stan-dard clinical protocol. Whole brain imageswere acquired parallel to theline connecting the genu and the splenium, two points on the inferiorborder of the corpus callosum, with 5 mm contiguous slices, in-planeresolution of 1×1 mm, and 256×192 matrix. The sequences acquiredincluded T1W (TR 550; TE 12 ms), T2W (TR 5000; TE 84 ms); andFLAIR (TR 10,000; TE 121 ms). Post-contrast T1W imageswere repeated5 min after the administration of a single dose of 0.1 mmol/kg ofgadolinium-diethylene triamine penta-acetic acid (gadolinium-DTPAor Gd).
2.3. Image analysis
All image analysis was performed masked to treatment alloca-tion. Three experienced observers by consensus identified theT1-weighted and T2-weighted lesions, and a semi-automated localthresholding technique was used to quantify lesion volume. Normal-ized brain volume was measured in all patients at baseline and thepercentage change in brain volume (PCBV) was calculated at year 5
with SIENA (Structural Image Evaluation, using Normalization, ofAtrophy: rate) software FSL version 4.0 [16].
2.4. Statistical analysis
Baseline characteristics were compared among the differentgroups using Kruskal–Wallis non-parametric one-way of varianceand chi-square statistic as appropriate. The PCBV were comparedamong different groups using a non-parametric analysis of covariancemodel. This was performed after adjusting for baseline age, diseaseduration, EDSS, T1W lesion volume, T2W lesion volume, and wholebrain volume (all volume values were log transformed). That approachwas also applied to adjust for year 1 to year 5 analysis. All p valuesbelow 0.05 were considered significant.
3. Results
Patient inclusion was carried out systematically in 4 steps asshown in Fig. 1. Data analysis was conducted in 2007–08. The studyperiod included patients who started DMT in 2001–02 and subse-quently received the same DMT for five years. A total of 275 metthe study criteria with brain MRI scans that could be analyzed withSIENA. The breakdown of the final 275 patients included in the anal-ysis was: (i) GA 20mg SC daily n=121 (Copaxone®); (ii) high doseIFNB (HD-IFNB, Betaseron®) 250 μg SC qod n=101; (iii) Low doseIFNB 30 μg IM qw (LD-IFNB, Avonex®) n=53. Of the 101 patients inthe HD-IFNB group, only 7 were on IFNB-1a 44 μg sc tiw (Rebif®),after the therapy was approved in the U.S. in March of 2002.
Table 1 shows the baseline characteristics of the three treatmentgroups that did not show any significant differences except for ageas noted (patients in the GA group were younger than HD-IFNB).However, all treatment groups had significant differences with thepatients in the untreated control group. The latter were significantlyolder, had longer disease duration, and had MRI features reflectinggreater tissue injury i.e. significantly higher T2W and T1W lesion vol-umes. During the course of the study period, the 34 patients in theuntreated group, initiated therapy and no patient remained untreatedfor more than two years. Prior to initiating DMT, the patients inthe untreated group underwent brain MRI scan as a reference, cus-tomary clinical practice at our Center. All untreated patients alsohad prior brain MRI scans on no therapy that could be analyzedwith SIENA. Therefore, the duration of period observed between
All data shown are mean (SD) unless noted otherwise.ns = not significant.
a Comparison among the three treatment groups (the only variable that showedstatistical difference among the treatment groups was age between GA and HD-IFNB,p=0.0108).
b Comparison between each treatment group and the untreated group.
9O. Khan et al. / Journal of the Neurological Sciences 312 (2012) 7–12
two MRI scans in the untreated group ranged from 8 to 24 months(mean: 16.7 months). The rate of brain volume loss was annualizedand then projected over 5 years assuming a constant rate of brainvolume loss over 5 years. This approach was adopted to provide acomparison to the treatment arms as expecting patients remainuntreated for 5 years would be highly unlikely for various reasons.
Fig. 2 shows percentage change in brain volume (PCBV) over anobserved period of five years in the three treatment groups. In con-trast, the PCBV shown for the untreated group is projected over aperiod of five years (actual observed period ranging from 8 to24 months). Compared to baseline, all four groups showed significantdecline in PCBV over a five-year period (pb0.0001). However, over afive-year period, compared to the untreated group, all treatmentsshowed significantly less brain volume loss (pb0.0001). Amongst
-4.75
-3.2
-6
-5
-4
-3
-2
-1
0
Untreated HD-IFN
PC BV: Year 0 to Year 5
(%)
n=34 n=1n=34 n=1
Fig. 2. Effect of therapies on percent change in brain volume (PCBV) over five years. The PCBVgroups (−2.21% vs−2.62%, p=0.0036;−2.21% vs−3.21%, pb0.0001;−2.62% vs−3.21%, pb(pb0.0001). The PCBV in the treatment groups was actually observed over 5 years in contrast
the treatment groups, the GA treatment group demonstrated lessPCBV compared to patients receiving LD-IFNB (−2.27 vs −2.62,p=0.0036) and HD-IFNB (−2.27 vs −3.21, pb0.0001). Patients inthe LD-IFNB also showed significantly less PCBV than HD-IFNB group(pb0.0001). These comparisons were adjusted for baseline variablesincluding age, disease duration, EDSS, T1W lesion volume, T2W lesionvolume, and brain volume.
We also attempted to address the issue of pseudoatrophy thatmay have occurred in the first year after initiating DMT and potential-ly affect outcomes at year 5. Brain MRI scans obtained one year afterinitiating DMT that met the entry criteria i.e. same scanner, identicalimaging protocol, and could be analyzed with SIENA, were availablefor approximately 90% of the patients in each of the three treatmentgroups. Fig. 3 shows the actual PCBV in the first year after initiatingDMT in the three treatment groups while the PCBV in the untreatedgroup (−0.95%) is shown as an “annualized” rate. All three treat-ments showed an appreciable decline in brain volume that was great-er in the HD-IFNB group (−1.1%) than the LD-IFNB (−0.79%) and GA(−0.79%) groups (−1.1% vs −0.79%, p=0.003). Adjusting for base-line characteristics, the PCBV observed between year 1 and year 5 (datanot shown) for all groups yielded results similar to the PCBV observedbetween baseline and year 5.
The study was not designed to investigate clinical outcomes.While the relapse rate was not recorded in this retrospective design,the change in mean EDSS at year 5 was not significantly differentamong the three treatment groups: GA +0.37±1.22, HD-IFNB +0.47±1.5, and LD-IFNB +0.41±1.36.
4. Discussion
This study provides several observations with important clinicalimplications. First, this study confirms that global brain volume lossinvolving both gray and white matter is a dynamic process, even inrelatively early and mildly affected RRMS patients. This process oc-curred despite continuous treatment with DMT, which also supportsthe view that currently available DMT are partially effective. Howev-er, it was reassuring to know that intervention with DMT significantlyreduced the rate of brain volume loss compared to no treatment. Thisobservation also reinforces the need to start treatment early, a viewalso supported by the data from the clinically isolated syndrome stud-ies and endorsed by all scientific agencies engaged in MS research.
1-2.62
-2.27
B LD-IFNB GA
p<0.0001
p=0.0036p<0.0001
01 n=53 n=12101 n=53 n=121
over 5 years was−2.21% in the GA,−2.62% in the LD-IFNB, and−3.21% in the HD-IFNB0.0001). All treatment groups demonstrated significantly less PCBV in the untreated groupto the PCBV in the untreated group that was projected over 5 years.
Untreated HD-IFNB LD-IFNB GA
n=34 n=91 n=47 n=121n=34 n=91 n=47 n=121
-0.95 -1.01
-0.79 -0.79
-1.25
-1.05
-0.85
-0.65
-0.45
-0.25
-0.05
Loss of brainvolume in the first
year
p=0.003
p=0.003
p=ns
Fig. 3. Effect of therapies on percent change in brain volume (PCBV) in the first year after initiating therapy. Brain MRI scans at year 1 that could be analyzed with SIENA, wereavailable for approximately 90% of the patients in each treatment group. The PCBV in the first year after initiating therapy was −0.79% in the GA and the LD-IFNB groups, and−1.01% in the HD-IFNB group (−0.79% vs −1.01%, p=0.003). The PCBV in the untreated group was −0.95% in the untreated group and not significantly different from theHD-IFNB and significantly greater than the LD-IFNB and GA groups (−0.79% vs −0.95%, p=0.003). The relatively accelerated loss of the brain volume in the first year in all treat-ments groups, most likely reflects pseudoatrophy.
10 O. Khan et al. / Journal of the Neurological Sciences 312 (2012) 7–12
The second observation relates to the question raised in clinicalpractice to consider discontinuation of DMT if patients have longstanding stable disease as determined by the lack of clinical or MRIactivity [17]. However, our study demonstrates that despite the rela-tive stability in disease progression with minimal change in disabilityover five years, all patients continued to display significant brainvolume loss compared to baseline. Therefore, discontinuing DMTbecause of “presumed” lack of disease progression may not be agood estimate of disease “inactivity” as demonstrated by ongoingglobal brain volume loss. This observation was originally made byFisher et al. showing that increased rate of brain volume loss maylead to long term clinical disability that may not be apparent inshort-term observations [18]. Furthermore, because brain volumeloss continued to accumulate despite five years of continuous therapyin all treatment groups, it reinforces the need for better treatments ortreatment strategies in RRMS.
Another important phenomenon that may influence change inbrain volume is pseudoatrophy, commonly thought to represent anaccelerated brain volume reduction with no associated loss of cellstructures [13]. Whether pseudoatrophy is inseparable from truebrain volume loss remains unclear. Furthermore, how it may influ-ence long-term clinical outcomes is unknown. The most likely expla-nation of the pseudoatrophy seen following initiation of DMT is thatbrain volume occurs from loss of intracellular water. In our study,we examined the possibility of pseudoatrophy during the first yearof DMT in a population previously naïve to any DMT. There was anaccelerated rate of brain volume loss in the first year in all treatmentgroups, suggesting pseudoatrophy, which was most prominent in theHD-IFNB group. A similar rate of brain volume loss in one year wasalso observed in the untreated group that most likely reflected trueloss of brain tissue. Despite adjusting for pseudoatrophy in the firstyear, the rate of brain volume decline over the subsequent 4 yearswere consistent with the rate of brain volume loss observed overthe entire 5 years. In contrast, short-term observations even in well-designed prospective, randomized studies may not be adequate to as-sess brain volume loss. Several studies in RRMS have exemplifiedthe limitations of brain volume loss in short-term studies in whichthe negative results observed in the first year were reversed duringthe second year of therapy, leaving the final interpretation of the
data inconclusive [8,12,19]. Thus, we feel that long-term studies arenecessary to quantify the rate of brain volume loss in MS.
Comparing therapies for any outcome in MS remains contentious.The primary objective of this study was to compare the effect of thethree DMT on brain volume loss in RRMS. Among the three DMT com-pared over a five-year period in our study, GA therapy showed theleast brain volume loss followed by LD-IFNB and HD-IFNB in thatorder. We speculate that these observations may be partly relatedto the complex and unique mechanism of action of GA [20]. Differentstudies with GA in RRMS have shown reduction in tissue destruction,axonal metabolic injury, and brain atrophy as well as long-termclinical stability [8,21–23] in the absence of a robust effect at theblood–brain-barrier level [24]. Other studies in RRMS have alsoshown a significant effect of GA on reducing brain volume loss. In apost-hoc analysis of 239 RRMS patients randomized to GA or placeboover a 9-month double-blind period, followed by a 9-month open-label period during which all patients received GA, a treatment effectwas identified in a re-analysis of the data using SIENA [8]. In an open-label study of 135 RRMS patients enrolled in the extension of theoriginal U.S. GA pivotal trial, patients originally randomized to theplacebo had larger CSF volumes, indicating more brain volume losscompared with patients originally assigned to GA treatment [9].Most data with LD-IFNB indicates a significant ability to reducebrain volume loss. In the pivotal trial of weekly IM IFNB-1a forRRMS (n=140), there was a 55% reduction in the rate of brain vol-ume loss in the weekly IM IFNB-1a treated group in the second yearof treatment, compared with the placebo group [12]. In a large sub-group analysis of the European weekly IM IFNB-1a Dose Comparisontrial, comparison of annualized brain volume rates showed significantreduction in the brain atrophy in the second and third years [25]. In alarge cohort of patients with clinically isolated syndrome, once week-ly 22 μg SC IFNB-1a reduced the rate of brain volume loss at 2 years[26]. In contrast, several studies with HD-IFNB in RRMS have failedto show a significant effect on reducing brain volume loss. In thepost-hoc analysis of the pivotal trial of SC IFNB-1a 66 or 132 μg week-ly for RRMS (n=519), there was no significant treatment effect onbrain volume loss over 2 years [11]. Extended open-label results ofthis study after a long-term follow-up (up to 8 years) showed thatbrain volume loss over the first 24 months was significantly greater
11O. Khan et al. / Journal of the Neurological Sciences 312 (2012) 7–12
in patients originally randomized to 132 μg SC weekly compared tothose in the late treatment group or the 66 μg SC weekly group[27]. In a small, open-label, 3-year follow-up study of 30 patientswith RRMS who received SC IFNB-1b 8 MIU every other day, no sig-nificant difference in brain volume loss over any yearly intervalwas observed [28]. Other open-label studies in Relapsing MS usingHD-IFNB did not show effectiveness on slowing down brain volumedecline [10,29]. Moreover, it has been suggested that interventionwith highly potent anti-inflammatory therapy could partly result inloss of brain volume unrelated to parenchymal water content thatmay be irreversible [30]. Collectively, these data would support theplausibility of a greater effect of GA and LD-IFNB in reducing brainvolume loss than HD-IFNB.
In contrast to the above-mentioned studies, two large prospec-tively conducted randomized studies have directly compared theeffect of GA and HD-IFNB on brain volume loss although that wasnot the primary endpoint of the studies [31,32]. In a multicenter, ran-domized open-label study of 764 RRMS patients, 386 were assignedto IFNB-1a SC 132 μg weekly and 378 to GA SC 20 mg daily [31].While the primary endpoint of time to first relapse showed no signif-icant difference between the two groups after 96 weeks, there was asignificantly greater reduction in brain volume in the IFNB-1a groupcompared with the GA group (p=0·018). It was argued that thiscould have been due to greater reduction in inflammatory edema(pseudoatrophy) in the IFNB group, registered as smaller brain vol-ume by the automated SIENA software computation. In another pro-spective, multicenter study, 2244 RRMS patients were randomlyassigned to receive one of two doses of IFNB-1b (250 μg or 500 μg)SC every other day or 20 mg GA SC daily [32]. The primary endpointof relapse risk at two years showed no difference among the threetreatment arms. The overall median change in brain volume frombaseline to last available scan was similar in each group, although atyear 1, patients treated with IFNB-1b had a significantly greaterbrain volume loss than did patients treated with GA (250 μg IFNB-1b vs GA p=0·02; 500 μg IFNB-1b vs GA p=0·007). The observa-tions in the first year of the study could have been partly attributedto pseudoatrophy. Though these two comparative studies providedcontradictory results with respect to the effect on brain volume loss,it emphasizes the need for long-term studies to accurately investigatethe effect of DMT on brain volume loss.
Several limitations of our study warrant discussion. First, this wasnot a prospectively designed study and the bias introduced due tothe retrospective design and the lack of randomization could not beeliminated. However, because the MRI scans were analyzed blindedto treatment allocation using a fully automated technique, the biasdue to the study design is minimized. Second, we did not have anuntreated control group that could be observed over 5 years. Addi-tionally, we annualized the rate of brain volume loss in the untreatedgroup and projected it over 5 years assuming that such rate of brainvolume loss would remain constant over 5 years. This approachcould have limitations but no untreated group of RRMS patient hasbeen studied for 5 years to provide insight into long-term brain vol-ume loss. This is further complicated by the fact that our untreatedcontrol group was older and more affected that could have partlyinfluenced a greater loss of brain volume. Nonetheless, the ability toretain an RRMS patient cohort untreated for 5 years would be highlyunlikely besides raising ethical questions. Our study included only275 patients that could potentially affect the results. However, it hasbeen suggested that for SIENA to show a difference of 30% betweentreatments over 3 years, only 111 patients are needed per arm andpresumably an even smaller number over a 5-year period [33]. Thedifference between GA (n=121) and HD-IFNB (n=101) over a 5-year period was 29%, and therefore within the power estimatesusing SIENA for PCBV. This is in part achieved by the relatively lowmeasurement error associated with SIENA [16]. Nonetheless, only aprospectively designed and adequately powered study over 5 years
can validate our findings. Another consideration that could affectour results was the potential development of neutralizing antibodies(NAB) that could have developed in the IFNB groups with a greaterlikelihood in the HD-IFNB treated patients [34]. We did not measureNAB at any point in this study. The negative impact of NAB on theefficacy of HD-IFNB is well documented and needs to be kept inmind while interpreting our study findings [35].
5. Conclusion
Our study demonstrates the occurrence of global brain volumeloss in early and mildly affected RRMS patients despite continuoustherapy for 5 years. This reinforces the need for early institution ofDMT as well better interventions to minimize brain volume loss inRRMS. However, compared to no treatment, intervention with DMTreduced the rate of brain volume loss over 5 years. The fact that globalbrain volume loss remains a dynamic process despite therapy, strong-ly argues against discontinuation of therapy in RRMS patients deter-mined to be “clinically” stable for prolonged period of time. Furtherinvestigations probing mechanism of gray matter loss and how DMTmay alter this critical aspect of MS pathology are urgently needed.
Acknowledgment
This study was supported by the Wayne State University Neurosci-ence Program. No support from the industrywas received for any aspectof the study.
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