The Latest Evidence-Based Medicine in the Treatment of Relapsing Remitting Multiple Sclerosis
This report was reviewed for medical and scientific accuracy by Andrew Goodman, MD , Department of Neurology, University of Rochester Medical Center, New York.
Results of the 3-year, Double-blind, Placebo-controlled Study of Interferon beta-1a (Rebif®) in Secondary-progressive Multiple Sclerosis
Donald W. Paty, MD, Division of Neurology, University of British Columbia, Canada
Interferon beta-1a (Rebif®) demonstrated no treatment effect in the progression of disability in patients with secondary-progressive multiple sclerosis in the Secondary Progressive Interferon beta-1a Multiple Sclerosis (SPIMS) study, according to results presented at the annual meeting of the European Neurological Society. However, the drug reduced the rate of relapse by 31% compared to placebo, and significantly decreased MRI activity and burden of disease. For reasons that remain unclear, the results were confounded by a significant treatment-by-sex interaction.
The multicenter, randomized, double-blind, Phase III study compared Rebif® 22 micrograms and Rebif® 44 micrograms three times a week subcutaneously versus placebo for three years. The study enrolled 618 patients at 22 centers in 9 countries in Europe, Australia and Canada. Ultimately 571 patients (92.4%) completed the trial. Analysis by intent-to-treat included those patients who dropped out, up until the time they were lost to follow-up, reported Donald W. Paty, MD, Division of Neurology, University of British Columbia, Canada. The primary endpoint was confirmed progression in disability, assessed by recording the time to progression by 1 point on the EDSS, or by 0.5 points for patients with a baseline EDSS equal or greater than 5.5. Progression had to be confirmed at two consecutive visits three months apart.
Eligibility criteria included an age of 18 to 55 years; clinically definite secondary progressive MS, defined as having a progressive deterioration of disability of at least 6 months and an Expanded Disability Status Score (EDSS) increase of at least 1 point over the preceding 2 years (or 0.5 points for patients with an EDSS of between 6 and 6.5), with or without superimposed exacerbations; an EDSS score of between 3 and 6.5; and evidence of pyramidal function score on the Kurtzke Expanded Scale of greater than 2. Exacerbations were not an entry criteria for the study.
Roughly two thirds of the study population were women. Duration of MS, EDSS at entry, and duration of secondary-progressive MS were evenly balanced across the study. The median burden of disease at entry was slightly higher in the placebo group than in the two treated groups, but the differences were not statistically significant.
Kaplan-Meier curve analysis revealed statistically significant separation between the treatment groups and placebo in terms of disability progression early in the trial. The differences disappeared with time, so that overall no treatment effect was seen in disability progression.
A strong treatment-by-sex interaction, significant to a level of p = 0.02, obligated an analysis by sex. At baseline, EDSS was equivalent in men and women. Females in both treatment groups had a statistically significant reduction in EDSS progression compared with placebo over the course of the study. In males, in contrast, the placebo group had less disability progression than either of the treatment groups.
A gender difference was seen in MRI outcomes as well. Women in both dose groups exhibited a treatment effect, whereas for men, only the high dose showed efficacy. Interestingly, females in the placebo arm of the trial showed a 15% increase in accumulation of burden of disease over the course of the study, while males in the placebo group showed a 12% increase.
"The inflammatory component was probably increasing less aggressively in males than females," Dr. Paty said. "However, there was a treatment effect for males at the high dose, suggesting that even though there is less accumulation of disease in the males, there is an inflammatory component that is perhaps more resistant to therapy and therefore requires a higher dose."
Dr. Paty also theorized that the degenerative aspects of secondary-progressive MS "may be more important earlier in men than we found in this study." He noted that the gender gap was consistent at sites throughout Scandinavia, Europe, Australia and Canada. "This suggests it's real, not statistical," he said. Covariant analysis was also carried out, taking into consideration duration of secondary-progressive MS and EDSS change prior to the study. When covariants were considered, high-dose treatment showed borderline statistical significance in reduction of disability progression for the overall cohort. Looking at females alone, both doses significantly reduced disability progression, irrespective of covariants.
Secondary endpoints of the SPIMS trial included exacerbations, proportion of relapse-free patients, time to first relapse, relapse severity, MRI burden of disease accumulation and MRI activity. The exacerbation rate per patient per year was 0.71 in the placebo group versus 0.50 in each of the treatment groups, a 31% reduction. At the high dose only, there was significant improvement over placebo in the proportion of relapse-free patients, time to first relapse, relapse severity and hospitalization. Both treatment groups showed major reductions in median number of T2 active lesions per patient per scan.
Injection-site necrosis occurred at a rate of 1 in 12,500 injections in the low- dose group and 1 in 6,000 in the high-dose group, Dr. Paty reported. Three patients dropped out and three required hospitalization due to necrosis. Injection site reactions occurred in 8% of placebo patients, 21% of low-dose patients and 32% of high-dose patients. Local inflammation occurred in 16% of placebo patients, and 67% of patients in each of the treatment groups.
Neutralizing antibody titers greater than 20 occurred in 23% of the low-dose group and 16.2% of the high-dose group, compared with 0.5% of the placebo group. The only other trial of INF-beta in secondary-progressive MS, carried out in Europe using interferon beta-1b (Betaferon®), found a highly significant difference in time to confirmed progression of disability favoring treatment.
"Immediately we wanted to see why we had these differences in comparison to the European Betaferon® trial," Dr. Paty said. Comparing the two trials, the SPIMS cohort was older, with longer duration of MS, longer duration of SPMS, higher EDSS at entry, and a higher proportion of significantly disabled patients, he said. But the most significant difference may be that there were far fewer relapsing patients in the SPIMS study-48% versus 70% in Betaferon® study.
Dr. Paty also discussed implications of the SPIMS for clinical practice. "I think we need to treat early with a partially effective preventive strategy rather than waiting late in the course of the disease to treat them," he said. "Perhaps there is a transitional phase between inflammatory and progressive disease where these anti-inflammatory therapies may still be useful. Since the degenerative component is probably secondary to theprimary inflammatory damage that occurs early in the course of the disease, perhaps if we treat our patients earlier we'll get a better treatment effect. The most effective treatment is going to be the earliest treatment."
"This drug shows efficacy and safety in the trial in secondary-progressive MS," Dr. Paty concluded."For disability, the results were non significant. However, when covariants were considered there was a trend toward significance in the high dose. In women it was significant at both doses irrespective of the covariant. There were significantly positive results for relapses, relapse-free patients, time to first relapse, MRI activity and MRI burden of disease, with an overall trend favoring the higher dose."
"Because there were more women than men, the effect in the women overrode some of the negative features of the men throughout this study," Dr. Paty added.
ERAZIMUS: Early Azathioprine versus Beta-Interferon Treatment in Multiple Sclerosis: Results of a Pilot Safety Study
Thibauld Moreau, MD, S. Blanc, G. Riche, Christian Confavreux, Lyon, France
As single therapies, both Avonex® and azathioprine (Imuran®) have proven efficacy in patients with relapsing-remitting multiple sclerosis. Administered together, the two drugs' immunosuppressant, immunomodulatory and anti- inflammatory properties could have additive, synergistic effects.
According to Dr. Moreau, a single-center, open pilot study of the drug combination has confirmed its safety and tolerability, opening the way for Phase III efficacy testing of the dual therapy. Results of the study were presented at this meeting. [Avonex® and Imuran® are under investigation for use in combination therapy and are not currently approved for combination use by the FDA or the European Union.]
The study included 30 patients who had been receiving azathioprine for relapsing-remitting MS for at least 6 months prior to enrollment (mean duration of azathioprine therapy was 4 years). The first 10 consecutive patients were assigned to receive 50 mg azathioprine daily, the next 10 patients received 100 mg daily, and the last 10 patients received 150 mg daily. Assignment to the first two groups entailed a reduction in the standard dose of azathioprine (150 mg daily). Patients in the three groups were similar in terms of age, gender, disease duration and disability.
All patients received their assigned daily dose of azathioprine for at least 30 days before receiving their first intramuscular injection of Avonex® 6 MIU. All patients received weekly Avonex® injections thereafter, in combination with azathioprine, for 4 months. Patients were seen weekly during the first month, and then monthly.
A flu-like syndrome occurred in 9 patients in the low-dose and medium-dose azathioprine groups, and in 8 patients in the high-dose group. Flu-like symptoms were probably over-estimated due to the frequent follow-up schedule in the study, the researchers said. In the high-dose group, a woman experienced a CMV infection that resolved without intervention and appeared to be unrelated to immunosuppressive therapy.
Four relapses treated with steroids occurred in the low-dose group, three in the medium-dose group and none in the high-dose group. No increases in disability were observed during the study.
The researchers suggested two possible explanations for the high relapse rate in the two lower-dose groups: the frequent follow-up in the first month of the study, and the decrease in azathioprine dosage in these groups before the onset of the study.
Serum and urine neopterin levels were elevated the second day after each injection, but stayed within a range that is expected in beta-interferon therapy. Levels of 6-thioguanine nucleotides were in the expected range for azathioprine monotherapy.
Two patients withdrew from each of the three-azathioprine dose groups. In the low-dose group, one patient withdrew due to hyperthyroidism and one dropped out due to an exacerbation of a pre-existing depression. In the medium-dose group, one patient withdrew due to cervical cancer and one dropped out without a reason. In the high-dose group, one patient withdrew due to leukopenia and the second dropped out after developing a cytomegalovirus infection.
A secondary objective was to assess development of anti-interferon antibodies with the combination therapy. These results were not presented.
T1 Hypointense Lesion Load Measurements in a Double-Blind, Placebo-Controlled Trial of Interferon-beta-1b in Secondary Progressive Multiple Sclerosis
Peter A. Brex, MD, The National Hospital, Institute of Neurology, London, UK
Reporting for the European Study Group on Interferon-beta-1b in Secondary Progressive Multiple Sclerosis, Peter A. Brex, MD, presented results of an analysis that suggests hypointense lesion loads on enhanced images may have a reversible element. The analysis focused on data from the subgroup of 125 patients in the recently completed Phase III European trial of Betaferon® in secondary-progressive MS who received frequent gadolinium-enhanced T1-weighted scans.
The randomized, double-blind, placebo-controlled study, published last year (Lancet 1998;352:1491-1497), enrolled 718 patients at 32 centers in 12 European countries. Outpatients with secondary-progressive MS and scores of 3.0 to 6.5 on the Expanded Disability Status Scale (EDSS) received either 8 million MIU interferon beta-1b every other day subcutaneously, or placebo, for up to three years. Primary outcome was time to confirmed progression in disability, as measured by a 1-point increase on the EDSS, sustained for at least 3 months, or a 0.5- point increase if the baseline EDSS was 6.0 or 6.5.
Brain T2-weighted lesion load was measured annually in all 718 patients, and supplemented with visual analysis to identify any new or enlarging T2 lesions. A subgroup of 125 patients, randomized into either placebo or treatment groups, had monthly gadolinium-enhanced T1-weighted imaging for the first six months and again in months 18 through 24.
Some high-signal lesions seen on T2-weighted MRI appear as hypointense, low-signal areas when viewed on T1-weighted images. Compared with T2 lesion load, these hypointense lesions have been shown to correlate better with EDSS and disability progression in both relapsing-remitting MS and secondary-progressive MS, and may represent lesions with more severe axonal loss.
In the analysis, outlines of hypointense lesions found on the T1-weighted images taken of the study subgroup were marked on hard copies, with reference to the T2-weighted images, by a single blinded observer. A semi-automated local thresholding technique was then used to quantify the hypointense lesion load. After 2 years, the hypointense lesion load volume in the placebo group increased by a mean of 10.6% from baseline, while the treated group showed a mean decrease of 16.5%, Dr. Brex reported.
The decrease in hypointense lesion load could be due to contraction of destroyed tissue, or leakage of extra-cellular fluid from hypointense lesions, Dr. Brex said.
The Betaferon®/Betaseron® study was the first to show a therapeutic effect of beta-interferon in patients with secondary-progressive MS. Interferon beta-1b delayed progression during the 2- to 3-year study period for up to 12 months, with an odds ratio for confirmed progression of 0.65. A positive treatment effect was also found regarding time to becoming wheelchair-bound, relapse rate and severity, number of steroid treatments, hospital admissions, and MRI variables. The study was stopped after interim results yielded clear evidence of efficacy.
MRI/Clinical Correlations in the Phase III Treatment Trial of Interferon Beta-1b in Secondary-Progressive Multiple Sclerosis
David H. Miller, MD, Institute of Neurology, NMR Research Unit, London, UK
The European Betaferon® trial used both clinical and MRI outcome measures, making it possible to assess correlations between these parameters in a large cohort of secondary-progressive MS patients.
According to David H. Miller, MD, results of this assessment confirm that the relationship between clinical and MRI variables seen in relapsing-remitting MS is still apparent in secondary-progressive disease.
The relationship in secondary-progressive disease is modest, however, and suggests the need for caution in relying on MRI as a surrogate marker in secondary-progressive MS, Dr. Miller warned.
In looking at the annual MRI scans conducted in all 718-study subjects, a significant but modest correlation was identified between change in T2 lesion load and change in expanded disability status scale (EDSS) throughout the course of the study, Dr. Miller reported.
In the subgroup of 125 patients undergoing more frequent imaging, a modestly significant correlation was identified between monthly MRI activity and relapse rate in the first 24 months of the study.
Dr. Miller reported that correlations were as strong for simple visual analysis of annual T2-weighted scans as they were for quantitative analysis of the scans. Simple visual analysis revealed significant correlations for the cumulative number of active T2 lesions against both change in EDSS and relapse rate, he said.
The Effect of Treatment with Interferon-beta-1b on Gadolinium Enhancing MRI Lesion Volumes in Secondary Progressive Multiple Sclerosis
P.D. Molyneux, MD, D. G. MacManus, G.J. Barker, Peter A. Brex, C. Fogg, S. Gregory, S. Lewis, C. Middleditch, and D.H. Miller, NMR Research Unit, Institute of Neurology, London, UK
Results of data from the subgroup of 125 patients in the European beta- interferon trial who received more frequent MRI scans were presented in a poster by members of the European Study Group on interferon beta-1b in Secondary Progressive Multiple Sclerosis.
Treatment with interferon beta-1b results in a profound, significant and sustained effect on the volume of gadolinium-enhanced brain lesions, supporting the concept of an anti-inflammatory therapeutic mechanism, the study group reported.
In the analysis, all gadolinium-enhancing lesions were identified and quantified by volume. Even at one-month post-treatment, a significant beneficial treatment effect was apparent in the subgroup. By six months, the cumulative gadolinium-enhanced lesion volume in the placebo group was 1.8 cm3, compared with 0.8 cmі in the treated group.
For the second, frequent scanning period, the cumulative gadolinium-enhanced lesion volume by month 24 in the placebo and treated groups, respectively, was 1.7 and 0.3 cmі.
Measurement of Brain Atrophy in Early Multiple Sclerosis
Peter A. Brex, MD, NMR Research Group, Institute of Neurology, London, UK
A preliminary MRI study adds to the evidence that brain atrophy begins early in the course of MS, in association with inflammation, and may contribute to disability. Results of this small trial were designed to identify subtle signs of brain tissue loss at the earliest clinical stages of MS, and were reported by Peter A. Brex, MD.
From a group of patients with abnormal baseline MRI scans and isolated clinical syndromes suggestive of MS, Dr. Brex and his co-investigators retrospectively selected 9 patients who went on to develop confirmed MS within the year. These 9 patients were compared with 8 age- and sex-matched controls with normal brain scans.
T1-weighted 2-dimensional axial images were acquired at presentation and at 1 year. Brain volume and ventricular volume were calculated at both time points. At baseline, there were no significant differences between median brain volume or ventricular volume in the two groups of patients. After 1 year, however, the median ventricular volume was significantly larger in the MS group, at 5.05 cm3, than in the control group, at 3.25 cmі.
While the pathological mechanisms underlying the change remain unknown, this small study detected subtle tissue loss in the brain early in the course of MS, Dr. Brex said. He added that further study is needed to explore the role of brain atrophy measurements as a predictive variable in prognosis for patients presenting with isolated syndromes.
Cerebral Atrophy and Disability in Multiple Sclerosis: A Four-Year Serial MRI Study
Benjamin P. Turner, MD, Division of Clinical Neurology, University of Nottingham, UK
A 4-year serial MRI study confirms that cerebral atrophy is correlated with disability, and occurs faster in relapsing-remitting than in secondary- progressive multiple sclerosis. The rate of ventricular enlargement, which also correlates with clinical disability, appears to be similar at both stages of the disease.
The aim of the study was to investigate the relationship between cerebral volume changes and disability at different stages of the disease course. The study included 20 patients with relapsing-remitting MS who were recruited for the PRISMS study in interferon beta-1a, and 18 patients with secondary-progressive disease who were recruited for the SPIMS study in interferon beta-1a. EDSS was evaluated and 3-dimensional MRI was performed at baseline and month 48. Volumes for total brain and lateral ventricles were obtained using a semi-automated method.
Benjamin P. Turner, MD, reported that at 48 months, the total cohort had experienced a median 0.59% decrease in total brain volume; however, further analysis showed that 8 patients alone had accounted for this decrease. Of the 8 patients, 7 had relapsing-remitting MS and 1 had secondary-progressive MS. Of the 7 patients with relapsing-remitting MS, the median percentage change in total brain volume was -3.47%, a loss in total brain volume of nearly 1% per year.
Lateral ventricular volume increased 14% in the full cohort over the 4 years. The relapsing-remitting patients had a 15% increase, secondary-progressive patients had a similar increase of 13%. In contrast with total brain volume loss, which affected only 8 patients, ventricular volume expansion occurred in almost two-thirds of the full cohort. Increases in ventricular volume were measured in 14 of 20 relapsing-remitting patients, and 13 of 18 secondary-progressive patients.
Of the 8 patients with whole brain atrophy, 2 had no ventricular volume enlargement while 6 had significant ventricular expansion. Among the 6 patients who had concurrent decreases in total brain volume and increases in ventricular volume, the ventricular enlargement accounted for 24% of the brain atrophy. "When you consider that the lateral ventricles normally consist of about 2% of the brain volume, this is a disproportionately large amount of atrophy occurring around the ventricles," Dr. Turner said.
A positive Spearman's rho correlation was found between increase in EDSS and reduction in percentage brain volume. This correlation was significant for the full cohort and for relapsing-remitting patients, but not for secondary- progressive patients. A positive correlation was also found for increase in ventricular volume and increase in EDSS. This correlation, too, was present for the full cohort and for relapsing-remitting patients, but not for secondary- progressive patients.
For the patients who had both changes in total brain volume and ventricular volume, the EDSS increased a median of 3 points over 4 years, Dr. Turner said. For the 4 patients who had no changes in either total brain volume or ventricular volume, the EDSS decreased by 0.75 points.
"Volume changes for whole brain and lateral ventricles seem to be disassociated one doesn't necessarily follow the other," Dr. Turner noted. However, both total brain volume and ventricular volume changes correlated with disability changes, and the correlation with ventricular volume changes was particularly strong.
Brain Atrophy in Relapsing Multiple Sclerosis
Jeffrey A. Cohen, MD, Director of Experimental Therapeutics, Cleveland Clinic Foundation, Cleveland, Ohio
A novel measure of brain atrophy, the brain parenchymal fraction (BPF), has proven both robust and reproducible, and is shedding new light on atrophy progression in early, mild relapsing multiple sclerosis, reported Jeffrey A. Cohen, MD. Among other findings, the measurement provides evidence that brain atrophy may begin as early as the first presentation of multiple sclerosis, and confirms that treatment with Avonex® slows atrophy progression.
Developed at The Cleveland Clinic, the BPF is a global, rather than linear, measure of brain atrophy. The BPF is determined by a fully automated computer technique. First the total brain volume is determined based on the outer brain contour in 3 dimensions. The computer then segments the cerebrospinal fluid from the brain parenchyma to calculate brain parenchymal volume. The BPF is calculated by dividing the parenchymal volume by the brain volume.
A major advantage of the BPF measure over linear measures of atrophy is that BPF is not dependent on MRI technique. BPF can be used on T1-weighted images, FLAIR images, T2-weighted images and other pulse sequences, Dr. Cohen said. In addition, because the BPF is a 3-dimensional volume determination, it is not dependent on position.
Dr. Cohen reviewed results of a series of small pilot studies designed to evaluate BPF as a global measure of brain atrophy. He said these analyses revealed brain volume and brain parenchymal volume both to be stable and highly reproducible measures, with coefficients of variation of less than 1%.
The randomized, controlled, double-blind U.S. Phase III study of Avonex® in relapsing MS is the first large MRI data set to be analyzed using the BPF. These analyses confirm that there is continuous burden of disease on MRI throughout the relapsing-remitting stage, even in patients with very mild, stable disease and reinforce the importance of starting therapy early in the course of MS, Dr. Cohen reported.
Of the 172 patients in the Avonex® trial to complete 2 years of follow-up, 140 had MRI scans at baseline, 1 year and 2 years. By chance, 70 of these patients had been randomized to receive Avonex® and 70 had been assigned to the placebo group. The patients had an average age of 36, a disease duration of about 6 years, and an EDSS score of 2.5.
At baseline, the patients' mean BPF was 0.829, significantly below the normal range (0.87 plus or minus 2 standard deviations), suggesting substantial atrophy had already occurred by study entry.
Consistent with its clinical benefit on relapse rate and disability progression, Avonex® also showed a beneficial effect on atrophy progression as reflected by BPF, Dr. Cohen reported. All of the benefit was seen in the second year of the study. Atrophy progression in year two was reduced by 55% in the Avonex®-treated patients versus the placebo patients. During year one, in contrast, atrophy progression was comparable in the treated and placebo groups.
Dr. Cohen suggested two explanations for this finding. "The one we favor is that there is a certain time course over which interferon has clinical benefit," he said. "Secondly, we suspect that the pathological mechanisms that lead to atrophy, in particular myelin degeneration, may take a certain time to play out, and that this may be why the clinical benefit is seen predominately in the second year."
The BPF analysis of the Avonex® data suggests brain atrophy may begin at the very onset of the disease. "If you calculate a regression line using these data points (baseline, year 1 and year 2) and extrapolate back, the line in fact crosses the normal 0.87 BPF value at minus 6 years. In other words, if this phenomenon is in fact linear, brain parenchymal body actually starts to decrease at the time of the first symptom of MS," Dr. Cohen said.
The beneficial effect of Avonex® on atrophy does not appear to be due to an effect of steroid use secondary to the reduction in relapses, according to Dr. Cohen. "We looked at this in a number of different ways, and it doesn't appear to be the case," he said. One analysis, for example, looked at changes in BPF in a subset of patients who received steroids within 20 days of MRI and another subset who received steroids within 40 days of MRI during year 2 of the study. No difference was seen between these subgroups and the treatment group overall.
"The trends are identical" Dr. Cohen said. "There is a beneficial effect of Avonex® in the second year, irrespective of whether the patients received steroids prior to the MRI scan."
Baseline EDSS and volume of T1 dense lesions?so-called black holes?were the best predictors of brain atrophy at baseline and of atrophy progression over the course of the study, according to results of a multiple regression analysis. In contrast, number of clinical relapses and progression of disability proved to be poor predictors of atrophy progression.
"As you would expect, patients with the most marked disability progression had the most marked progression of atrophy," Dr. Cohen said. "However, patients who appear to be doing well clinically, with no relapses and stable disability, may also have atrophy progression. Not only is relapse rate not a very good predictor of what a patient is experiencing, but also the progression of disability at this stage of MS is not a very good predictor of atrophy."
Cognitive Dysfunction in Multiple Sclerosis: Implications for Disease Management
Jill Fischer, PhD, Mellen Center for Multiple Sclerosis Treatment and Research, The Cleveland Clinic Foundation, Ohio
A new analysis of data from the Phase III U.S. trial of Avonex® in relapsing MS confirms that interferon-beta-1a significantly improves cognitive impairment in MS patients, particularly in the specific cognitive domains in which the disease takes its greatest toll.
Jill Fischer, PhD, who presented findings of the analysis at this meeting, argued that the new data, combined with other evidence in the literature, provide a clear rationale for cognitive impairment alone to be considered an indication for therapy.
According to two large, well-controlled studies (Heaton 1985 and Rao 1991), slightly under half of all MS patients will experience measurable cognitive impairment beyond what would typically be seen in an age-matched population. Cognitive impairment correlates only weakly with physical disability as assessed by the EDSS, but is closely related to cerebral lesion load as assessed on MRI. MS does not affect cognitive function in a similar fashion across all domains.
Dr. Fischer reported results of an analysis of Rao's data, which showed that for memory measures, 22% to 31% of MS patients in the study fell below an arbitrary cut-off point (the 5th percentile for performance on the same measure by a healthy control group), making memory impairment the most common cognitive deficit. Deficits in concentration, seen on measures of information processing, were nearly as common. Impairments in visual-spatial abilities and so-called executive functions, including problem-solving and planning, formed a second group of deficits that ranked second in prevalence. From 12% to 18% of MS patients fell below the cut-off point in these domains. Impairments in language and attention span constituted a third tier of deficits that were relatively unaffected by MS.
In the Avonex® trial, 276 patients underwent psychological assessment. In her analysis, Dr. Fischer grouped this data into three sets according to the prevalence groupings identified in the Rao study. A multivariate analysis of adjusted two-year change in score for the three sets was then conducted. In this analysis, Avonex® significantly improved Set A symptoms (memory and information processing) and Set B symptoms (visual-spatial abilities and executive functions) compared with placebo, but had no treatment effect on Set C symptoms (verbal ability and attention span). Improvement in the Set A symptoms had a p-value of .038; improvement in the Set B symptoms had a p value of .043. Avonex®, according to this analysis, had the greatest treatment effect on those deficits that are most prevalent in MS patients.
Phase III trials of other agents in relapsing MS patients have also found a treatment effect in cognitive impairment. A trial of Betaseron® in 372 patients demonstrated a positive treatment effect on visual memory in the high- dose group, she said. A Copaxone® trial in 251 patients showed a non- significant effect in cognitive impairment.
Dr. Fischer stressed that cognitive impairment has practical significance in multiple domains. Unemployment is considerably higher in cognitively impaired patients than in cognitively intact patients with comparable levels of physical disability. In addition, cognitively impaired patients require more assistance in performing activities of daily living and regular household tasks. Their relatives perceive them as more confused, and more emotionally unstable. They have more difficulty performing multiple-step activities, such as cooking or following complicated treatment recommendations. Finally, these patients are more prone to accidents, both while driving and at home.
"I think we have to assume that every MS patient is at risk for cognitive impairment," Dr. Fischer said.
Review of Safety of Interferon Treatments
Robert Herndon, MD, Neurologist, AV "Sonny" Montgomery VA Hospital, Jackson, Mississippi; Professor of Neurology, University of Mississippi Medical Center, Jackson, Mississippi
Robert Herndon, MD, reported interim results of a four-year, multi-center, open-label, Phase IV study of Avonex® initiated in May 1995. The study examined safety, antigenicity and rate of IV steroid use in 382 patients receiving a standard dose of 6.0 million international units of Avonex® weekly by intramuscular injection.
The adverse event profile was similar to that seen in the Phase III U.S. trial of Avonex®, with no new problems or safety issues arising, Dr. Herndon reported. Flu-like symptoms were the most common adverse effect. Injection site reactions were uncommon, occurring in 3% of patients. No cases of injection site necrosis occurred. Overall, fewer than 1% of patients discontinued therapy due to adverse side effects.
Dr. Herndon reported that 53 patients (15%) discontinued from the study: 18 stopped because the therapy was perceived as ineffective by the patient or physician; 7 dropped out due to side effects (<1%); 7 were lost to follow-up; and 6 found the weekly injections inconvenient. Four patients discontinued due to non-compliance and 3 switched to an alternate therapy. "Other" was the reason cited by 4 discontinued patients; 2 stopped for an unspecified reason.
An additional 2 patients halted therapy because they disliked injections.
Patients were tested for neutralizing antibodies at baseline and every 3 months, using a 2-step assay. In patients with no prior interferon-beta exposure, 7% developed positive titers for neutralizing antibodies 3 to 30 months following initiation of therapy. IV steroid use was evaluated as a marker for efficacy. The number of IV steroid courses per patient per year was 0.42?lower than the 0.83 rate seen in the Phase III trial.
Patients were surveyed at 2 weeks and 26 weeks regarding administration of injections. More than 90% of patients received the injections at home at both time points (92% and 95%). About two-thirds of patients (64%) administered the injections themselves at both 2 weeks and 26 weeks. A family member administered the injections for 31% of the patients at 2 weeks, dropping to 29% at 26 weeks. A health care professional administered the injections for 4% of patients at 2 weeks and 6% at 26 weeks.
The Implementation of Beta-Interferon in Multiple Sclerosis
Christian Confavreux, MD, Lyon, Hopital de l'Antiquaille, Service de Neurologie, Lyon, France
While there is strong evidence for the efficacy of beta-interferon in multiple sclerosis, questions about the therapy remain. In a symposium on controversial treatments in neurology, Christian Confavreux, MD, reviewed the evidence and concerns about beta-interferon therapy in MS. "There is still controversy among neurologists about the utility and futility of interferon in multiple sclerosis," Dr. Confravreux said.
Utility is supported by clinical trials of Betaferon®, Avonex® and Rebif®, in which beta-interferon appears to alter the pathological processes underlying multiple sclerosis. MRI measurements of T2 lesion load and T2 activity were reduced compared with placebo in all of the clinical trials. Further evidence comes from a recent analysis of cerebral atrophy in a subgroup of 140 patients in the U.S. Phase III trial of Avonex® in relapsing-remitting MS, 70 of who received Avonex® and 70 of whom received a placebo. While MRI studies at month 12 showed similar progression of atrophy in both groups, at month 24 there was further atrophy progression only in the placebo group. Richard Rudick, MD, of the Cleveland Clinic Foundation presented the analysis at the annual meeting of the American Academy of Neurology meeting in Toronto earlier this year. Also at the Toronto meeting, Simon et al. reported that beta-interferon appears to have a beneficial effect on black holes. In that analysis of 160 patients with relapsing-remitting MS treated with Avonex® versus placebo, the volume of T1 hypointense lesions at 2 years had increased 29% in the placebo group, versus 12% in the treatment group.
The clinical trials also show efficacy for beta-interferon in reduction of relapse rate and disability progression. Betaferon®, Avonex® and Rebif® all significantly reduced the exacerbation rate and the proportion of patients with disability progression, defined as a decline of 1.0 or more in EDSS. Overall, 10% percent fewer patients in the treated groups worsened compared with placebo, Dr. Confavreux said.
Despite these positive findings, however, enthusiasm for beta-interferon therapy is limited by a number of uncertainties, Dr. Confavreux noted. Chief among these is the puzzling disassociation between MRI measurements and clinical findings. There is uncertainty as well regarding whether beta-interferon therapy truly reduces inflammation, or simply makes it less visible. Dr. Confavreux noted that merely by lengthening the interval between gadolinium injection and MR imaging, it is possible to double the number of lesions that are identified. A third uncertainty centers on the disassociation between exacerbation and progression.
"The presence or absence of relapses in the early progressive period doesn't affect progression," he commented. A fourth concern is that what appears, as a statistically significant reduction in disability progression across a large cohort may not be significant for an individual patient. Yet another controversy centers on whether or not beta-interferon treatment is truly disease modifying, or merely improves symptoms. Finally, Dr. Confavreux pointed out that sustained benefit and long-term safety remain open questions in beta-interferon therapy, given the short-term nature of the clinical trials.
Practical issues limiting enthusiasm for beta-interferon include convenience and cost, Dr. Confavreux added. According to the NARCOMS survey, 71% of patients who start taking Betaferon® discontinue the drug, as do 40% who start taking Avonex®."We have as many patients stopping therapy as we have starting it," he remarked.
In his summary, Dr. Confavreux concluded that beta-interferon has an "indisputable but modest" treatment effect. He called for research to explore combination therapies using beta-interferon. "A combined use of the different tools we have may help," he said. "We will have to rely also on Imuran®, Copaxone® and IGIV in our battle against MS." Testing is already underway of beta-interferon in combination with Copaxone® and azathioprine.
In response to a question from a member of the audience, Dr. Confavreux said that at the present time, based on the published, peer-reviewed literature, "it is very difficult to say that one of the beta-interferons is better than the other."
However, while all three agents demonstrate the same magnitude of efficacy, he noted that there are differences among the drugs. Interferon beta-1b is more immunogenic than interferon beta-1a, for example, although the clinical importance of this is unclear. Dosing frequency and mode of administration also differ. "For convenience, the lowest number of injections is better," Dr. Confavreux said. "In practice, maybe you could suggest that once a week is better. However, some patients prefer subcutaneous administration."
Cognitive Dysfunction in Multiple Sclerosis
Rose-Marie Marie, MD, CHU de Caen, Caen, France
In general, global intellectual efficiency and language are preserved in multiple sclerosis. In contrast, deficits are seen in attention, executive functions (including planning and attention-shifting ability), and memory. According to the literature, 43% to 68% of multiple sclerosis patients overall demonstrate deficits on tests of cognitive function.
Rose-Marie Marie, MD, of CHU de Caen in Caen, France, reported results of a study focusing on executive functions and memory processes in multiple sclerosis patients compared with healthy controls. The study enrolled 21 patients with multiple sclerosis. The mean age of the MS patients was 42 years; the mean duration of disease was 9 years. Of the total cohort, 4 patients had relapsing- remitting multiple sclerosis, 5 had progressive multiple sclerosis and 12 had secondary-progressive disease, according to Dr. Marie.
Study subjects were evaluated using the following cognitive assessment tools: the Mattis dementia rating scale; the language Montreal-Toulouse task; the; the working memory Brown-Peterson paradigm; the mirror reading procedural task; the Wisconsin task; and the verbal fluency task. Performances on the measures were compared to those of healthy control subjects matched for age and educational level. In addition, motor deficits were assessed by EDSS.
According to Dr. Marie, executive functions were significantly compromised in the MS patients, confirming previous research. Episodic memory also was impaired. Especially in tests of memory processes, patients with progressive forms of MS performed worse than those with remitting-relapsing disease, Dr. Marie said. The researchers found no correlation between motor deficits and overall cognitive performance.
In her presentation, Dr. Marie focused on findings related to episodic memory, a memory process that is heavily used in activities of daily living. Deficits in episodic memory form a common complaint among MS patients.
To assess the impact of MS on episodic memory, Dr. Marie and her colleagues administered the French version of the California Verbal Learning Task to MS patients and healthy controls. This assessment tool asks subjects to learn 16 words in 4 categories in 5 trials. Free and cued recall are measured following short and long delays. In addition, word recognition and discrimination abilities are assessed.
Compared with controls, the multiple sclerosis patients demonstrated significant impairment in learning the lists of words, Dr. Marie reported. The MS patients were able to recall fewer correct words following both short and long delays. Furthermore, the MS patients demonstrated a longer learning curve. Deficits were more marked for cued recall, but were also present for free recall. The MS patients also demonstrated significant impairment in word discrimination. Word recognition was poorer in the MS patients as well, but not to a significant degree.
In the next phase of the study, Dr. Marie said researchers will correlate MRI findings with cognitive performance in hopes of localizing cognitive deficits to particular cortical lesions. "We need more study," she concluded.