Multiple Sclerosis Forum Report
12th Meeting of the European Neurological Society (ENS)
Berlin, Germany

The Benefits of Immunomodulatory Therapy for the Multiple Sclerosis Patient


Frederick E. Munschauer III, MD, Professor of Clinical Neurology and Internal Medicine at the State University of New York at Buffalo, Buffalo, New York and the Jacobs Neurological Institute

At the 12th Meeting of the European Neurological Society (ENS) held June 22-26, 2002 in Berlin Germany, oral presentations and posters added to the wealth of evidence confirming the benefits of immunomodulatory therapy for patients with multiple sclerosis (MS). Results from clinical studies show that each of the four commercially available disease-modifying therapies (Avonex, Betaseron, Copaxone, and Rebif) can improve the clinical course of patients with MS. Whether measured by MRI, Expanded Disability Status Scale (EDSS) progression, MS Functional Composite (a newer, more sensitive tool to measure disability), several studies presented demonstrated that immunomodulatory therapy can attenuate disease progression. Additionally, several studies provided documentation of the long-term safety of immunomodulatory therapy.1,2

These revelations are most timely and reflect current strategies in the management of the MS patient. The Multiple Sclerosis Council for Clinical Practice Guidelines now recommend disease-modifying therapy for the majority of patients with a first exacerbation of MS.3 These recommendations are based on Class I evidence (prospective, randomized, controlled, clinical trials with blinded outcome assessment) as demonstrated in the CHAMPS and ETOMS studies.4,5

In the absence of a cure for MS, the major goal of MS treatment is prevention or delay of long-term disability. Disability evolves over years in MS. The phase III clinical trials of immunomodulatory agents in MS have been conducted over periods of 2 years or less and subsequently outcomes measures in these trials reflect relatively short-term effects. Although long-term data on the effects of treatment would provide some reassurance to both patients and clinicians, at least in relapsing forms of MS, this would require long-term placebo-controlled trials. Given the unqualified efficacy of current agents, such long-term placebo-controlled trials are ethically questionable. Open-label phase IV trials lacking a placebo control do not provide Class 1 evidence for sustained effects on disease progression. There is, however, an emerging body of evidence supporting the long-term efficacy of immunomodulatory agents in MS. In total, these studies, several of which were presented at the Berlin meeting of ENS 2002, represent solid Class 2 evidence for long-term efficacy of immunomodulatory agents.

The European Dose-Comparison Study demonstrated no difference in efficacy in delaying disease progression during 3 years of treatment with Avonex in doses of 30 mcg or 60 mcg once weekly.6 Furthermore, there were no significant differences in clinical or MRI endpoints between doses. At ENS 2002, two substudies of this large, double blind, multicenter trial confirmed that there was no difference in either safety or sustained progression of disability between the doses of Avonex studied.1,2

Multiple studies indicate that the emergence of neutralizing antibodies to interferon beta attenuate therapeutic effects. Therefore, the relative immunogenicity of interferons can have long-term therapeutic implications. Lower dose, less frequent, intramuscular interferon is associated with a lower prevalence of neutralizing antibodies.7,8 Indeed, only 2.3% of patients at 30 mcg in the European Dose-Comparison Study developed neutralizing antibodies, a prevalence substantially lower than reported among other interferon beta agents.9,10 In investigations using the same assay in the same laboratory, the highest incidence of neutralizing antibodies among the interferon beta agents has been observed with Betaseron, followed by Rebif, and finally, Avonex.7,8

In the EVIDENCE trial11, which compared Avonex with Rebif, the incidence of neutralizing antibodies at titers of ≥20 NU/mL using the same World Health Organization cytopathic assay was 25% in Rebif-treated patients compared to 2% in Avonex-treated patients. The EVIDENCE trial showed that in the first 24 weeks of therapy, Rebif had an improved treatment effect on relapse compared to Avonex. However, the differences between treatments became less pronounced over time. In the first 24 weeks, there was an 11.8% difference in percent of the cohort who were relapse free favoring Rebif, but in the second 24 weeks, a 1% difference favoring Avonex was observed. While the emergence of neutralizing antibodies to all preparations of interferon beta has been associated with an attenuation of either clinical or MRI efficacy, more longitudinal data demonstrating the effect of neutralizing antibody-positivity from long term use of these disease-modifying therapies is needed. The development of neutralizing antibodies has been associated with reduced efficacy in the treatment of many other diseases.

The results of the European Avonex Dose-Comparison Study, the Rebif/Avonex EVIDENCE trial, as well as other important studies presented at ENS 2002 are reviewed in greater depth in this Multiple Sclerosis Forum Report. Although the benefits of immunomodulatory therapy are well established, MS continues to be a debilitating disease. All current MS therapies, although measurably effective across multiple studies, unfortunately do not completely control disease progression. We hope that this review of the presentations presented at ENS 2002 will provide new insights into our current understanding of the biology of MS and the rational immunotherapy of this debilitating disease.

Importance of Neutralizing Antibodies: Long-Term Efficacy of Interferon Beta: Do Neutralizing Antibodies Matter?

Jacqueline Palace, MD, Consultant Neurologist, Radcliffe Infirmary, Oxford, England, United Kingdom

Speaking at a Satellite Symposium titled "Make a difference: the importance of efficacy in RRMS," Jacqueline Palace, MD, Consultant Neurologist, Radcliffe Infirmary, Oxford, England, United Kingdom, reviewed what is currently known about neutralizing antibodies and discussed possible future directions for study.12 Dr. Palace told the audience, "Neutralizing antibodies are a controversial issue. Antibodies to other recombinant drugs are recognized to be associated with a loss of therapeutic efficacy. Antibodies to biologics such as erythropoietin have a clearer, more dramatic effect, but the variability in clinical expression of multiple sclerosis muddies the waters regarding neutralizing antibodies." Dr. Palace explained that antibodies that bind to an interferon receptor site are not necessarily neutralizing; antibodies may be formed to interferon beta but not necessarily neutralize the biologic effect. A subset of binding antibodies are neutralizing and do block interferon beta receptor binding. Dr. Palace contends that little is known about the effect of binding but not neutralizing antibodies on MS treatment.

"It is the neutralizing antibodies that block the effects of interferon beta," she commented. Continuing, Dr. Palace stated, "Neutralizing antibodies interfere with the receptor-mediated functions of interferon beta. At least two studies have demonstrated an association between neutralizing antibody-positive patients and the loss of biological activity and clinical efficacy."[9,10]

Assays and Immunogenicity

Several different techniques can be used to determine the presence of antibodies to interferon in the serum of patients.13 Assays that measure binding antibodies include the enzyme-linked immunosorbent assay (ELISA), the radioimmuno-precipitation assay (RIPA), and the Western Blot assay. Moreover, ELISA measures antibodies to all expressed epitopes on interferon beta, including both binding and neutralizing antibodies. On the other hand, cytopathic effect (CPE) assays detect the subset of binding antibodies that are neutralizing antibodies by demonstrating the neutralization of interferon beta-induced inhibition of viral-mediated cell lysis. Currently, most diagnostic laboratories utilize the CPE assay to determine neutralizing antibody titers.

Pointing out some limitations of current assays, Dr. Palace asserted: "There is no gold standard for antibody assays. ELISA primarily measures binding antibodies, some of which are irrelevant in multiple sclerosis. The CPE assay measures neutralizing effects, not antibodies directly, and it is not clear which effects are relevant in multiple sclerosis."

However, it is clear that among available interferon beta agents, intramuscular interferon beta-1a [Avonex] is the least immunogenic. Interferon beta-1b [Betaseron] is the most immunogenic, and subcutaneous interferon beta-1a [Rebif] falls somewhere in between the two, she continued.

Factors that contribute to the immunogenicity of interferon beta may include route of administration (subcutaneous injection increases the potential for immunogenicity), chemical structure, manufacturing process and whether the interferon beta is natural or synthetic (natural product is less immunogenic). Other factors that have been identified as influencing immunogenic potential include the aggregation and purity of the specific interferon beta formulation, frequency of interferon beta administration, and length of treatment.

"The question of dose is unclear in the world of interferon betas," Dr. Palace commented. Although some studies suggest that higher doses of Betaseron are more efficacious than ineffective lower doses of Betaseron, she commented that the European Dose-Comparison study showed no difference in efficacy and safety between a higher (60 mcg once weekly) and lower dose (30 mcg once weekly) of Avonex.

In the pivotal studies for FDA approval, Betaseron had the highest percentage of patients with neutralizing antibodies (38%)14, compared to 24% of patients treated with Rebif 22 mcg three times weekly15, 13% of patients treated with Rebif 44 mcg three times weekly15, and 22% of patients who received the standard dose of Avonex (30 mcg intramuscularly once weekly).16 After the pivotal phase III study of Avonex was performed16, its manufacturer [Biogen, Inc.] instituted a change in the purification process for Avonex, and this change resulted in even lower immunogenicity, Dr. Palace said.

Effects of Neutralizing Antibodies on Efficacy

Data from large randomized studies of Betaseron and Rebif suggest that the presence of neutralizing antibodies compromises efficacy of these products.9,10 Dr. Palace indicated that she was not including Avonex data on neutralizing antibodies in her discussion of efficacy, because the number of Avonex-treated patients with neutralizing antibodies was quite low and these patients were not followed sufficiently long enough to provide meaningful comparisons to the other interferon beta formulations.

The Betaseron and Rebif studies demonstrated that the presence of neutralizing antibodies had a significant effect on increasing T2 lesion activity in years 2 and 3 in patients treated with Betaseron (P<0.001) and a significant effect on T2 lesion activity over 4 years in patients treated with Rebif (P<0.001). Positive neutralizing antibodies in Betaseron-treated patients had no significant effect on lesion burden, while the presence of neutralizing antibodies was associated with a significant increase in lesion burden in Rebif-treated patients (P<0.001).

Neutralizing antibodies are most prevalent by approximately 18 months of treatment with Betaseron and the presence of neutralizing antibodies appeared to negate the effect of Betaseron on relapse; this effect was also seen at years 3 and 4 with Rebif (P = 0.0002). Interestingly, the presence of neutralizing antibodies was associated with an increase in the EDSS in Rebif-treated patients, but not in Betaseron-treated patients.

Dr. Palace said that one possible explanation for the increase in the EDSS of Rebif-treated patients is that the presence of neutralizing antibodies reflects more active disease. After 3 years of treatment, Betaseron-treated patients who were neutralizing antibody-positive had fewer side effects than those who were neutralizing antibody-negative.

"These data suggest that the presence of neutralizing antibodies affects MRI outcomes in years 1 to 3 and relapses in years 2 to 3. Neutralizing antibodies may, therefore, reduce our ability to slow disease progression in multiple sclerosis patients," Dr. Palace stated.

Practical Considerations

Studies to date suggest neutralizing antibodies may take 12 to 18 months to develop and that over time, neutralizing antibodies remain stable and titers may decline over time. But that depends on the assays and cutoff points that are employed for detection, Dr. Palace noted. She suggested that further study is needed to clarify and validate these observations and elucidate the role and effect of neutralizing antibodies over greater periods of time. Dr. Palace suggested an independent study using standardized assays and cutoff points and comparing neutralizing antibody-positive versus neutralizing antibody-negative patients versus placebo using sera from the large randomized trials that have already been conducted.

Dr. Palace also recommended testing patients for neutralizing antibody-positivity yearly to guide future treatment decisions. If a patient presents with neutralizing antibodies on two consecutive visits, Dr. Palace suggested a washout period and initiation of therapy with Avonex. "Neutralizing antibodies should be a treatment consideration," she stated.

Ludwig Kappos, MD, Professor of Neurology and Clinical Neuroimmunology, Faculty of Medicine, University of Basel, Basel, Switzerland and chair of the Satellite Symposium, advised the audience, "If the patient's response to the [interferon beta] drug meets your expectations, don't switch treatment. Neutralizing antibody information might guide my next treatment decision in the case of suboptimal response to the present treatment. Neutralizing antibody information would also be helpful when there is uncertainty about disease management or when the physician is considering raising the dose of the [interferon beta] drug."

Short and Long-Term Brain Volume Changes After Initiation of Treatment with r-Interferon Beta-1a in Multiple Sclerosis

Martin Hardmeier, MD, Department of Neurology, University Hospitals, Basel, Switzerland

A substudy of the European Dose-Comparison Study showed that the effect of interferon beta-1a (Avonex) on brain atrophy in relapsing MS becomes evident over time and is sustained at year 2 and 3 following initiation of treatment.17

In the substudy, the greatest reduction in brain volume was observed in the first year of Avonex treatment, and 70% of this reduction was accounted for by changes during the first 4 months of treatment, explained Martin Hardmeier, MD, Department of Neurology, University Hospitals, Basel, Switzerland. Dr. Hardmeier believes that this reflects the early anti-inflammatory and anti-edematous properties of Avonex, and that early monitoring of brain atrophy does not give a true picture of the treatment effects.

"If the theory is correct, the early anti-inflammatory and anti-edematous effects of Avonex may confound atrophy measurement. The implication of our study is that the effects of immunomodulatory treatment on atrophy should not be assessed before the second half of the first year of treatment. In the first few months after treatment initiation, the beneficial treatment effects on the rate of atrophy progression might be masked by suppression of edema and inflammation," he emphasized.

Brain volume, as measured by brain parenchymal fraction (BPF) was significantly reduced at all evaluation intervals during the substudy, with the most significant difference from baseline observed in the first year of therapy. A lower, but still significant, rate of reduction in brain volume was observed in years 2 and 3 compared with the first year.

The European Dose-Comparison Study

A previous analysis of 608 evaluable patients in the original European Dose-Comparison Study showed sustained efficacy in delaying disease progression over 3 years of treatment with both standard-dose Avonex (30 mcg) or a high weekly dose (60 mcg) of Avonex.6 An extension analysis of the European Dose-Comparison study including 491 patients who continued double blind treatment for an additional year, demonstrated that treatment with once-weekly Avonex 30 mcg showed sustained efficacy through at least 4 years.1 Furthermore, levels of neutralizing antibodies remained low throughout the 4 years of treatment with Avonex.18

The efficacy of Avonex at either dose was observed in multiple outcomes, including cumulative rate of sustained disability progression, magnitude of change in the EDSS score, relapse rate, percentage of relapse-free patients, and need for intravenous steroids.

Changes in Brain Volume

The substudy results reported by Dr. Hardmeier were based on 138 patients with relapsing MS in the European Dose-Comparison Study who had frequent MRI scans. Baseline patient characteristics included a median EDSS score of 3.5 (range, 2.0-5.5), mean age of 38.5 years, and median disease duration of 7.5 years. Scans were performed 3 and 2 months before treatment and after initiation of treatment at 4, 5, 6, 10, 11, 12 months (Phase 1), at 24 months (Phase 2), and at 36 months (Phase 3). BPF was determined according to the methodology used by Rudick et al19, who reported that change in BPF was significantly slowed by 55% in year 2 of treatment with Avonex when compared to patients on placebo.

According to Dr. Hardmeier, the annualized rates of BPF change were -1.1% in the pretreatment period, -1.49% during the first 4 months, -0.35% during the following 8 months, -0.34% in the second and -0.39% in the third year of treatment.

"These rates are similar to those published by Rudick et al," Dr. Hardmeier said. The difference between the first 4 months of therapy and the first year was not significant; however, the differences for both the second year and the third year were highly significant compared to both the pretreatment phase and the first year (P<0.001).

The significant decrease in BPF after treatment initiation was paralleled by a decrease in T2 lesion load and the number of T1 gadolinium-enhanced lesions, Dr. Hardmeier added. BPF changes at year 1, 2, and 3 were significantly correlated with T2 lesion load and volume of gadolinium-enhanced lesions (P<0.05).

"In the first 4 months of treatment, the rate of atrophy was higher than in the following 8 months in the first year of treatment. If brain volume is measured at yearly intervals, only the difference between baseline and the end of year 1 will be found," Dr. Hardmeier stated.

During a subsequent question and answer session, Dr. Hardmeier told the audience that since the first scan was done at month 4 after initiation of treatment, no conclusions could be drawn about treatment effects occurring during the first three months. "If our hypothesis is true, the effects of Avonex may occur earlier than month 4," he added.

Brain Volume Changes in Patients at Presentation with Suspected Multiple Sclerosis: Results from the ETOMS Study

Giancarlo Comi, MD, San Raffaele Hospital, Milan, Italy

The double blind, placebo-controlled, randomized phase III Early Treatment of Multiple Sclerosis Study Group (ETOMS) study demonstrated the value of early treatment with low-dose interferon beta-1a (Rebif) in patients with suspected multiple sclerosis (MS).5 Subsequent analysis of ETOMS presented at ENS 2002 confirms the ability of early treatment with immunomodulatory therapy to slow the rate of brain tissue loss.20 As explained by Giancarlo Comi, MD, San Raffaele Hospital, Milan, Italy, the analysis also showed that the rate of brain tissue loss in patients with suspected MS (a single attack suggestive of MS) is close to that reported in patients with advanced disease. Further, brain volume at baseline does not predict the subsequent evolution to clinically definite MS, he stated.

The primary endpoint of the original ETOMS study was conversion to clinically definite MS. ETOMS included 309 patients with suspected MS with a single attack explainable by either a single lesion or multifocal lesions. Patients were randomized to receive either subcutaneous Rebif 22 mcg once weekly (n = 154) or placebo (n = 155) over a treatment period of 24 months. The mean age of patients was 28 years, and approximately two-thirds of patients had been treated with corticosteroids for their first attack suggestive of MS. Brain atrophy was measured by the SIENA method, which utilizes both cross-sectional and longitudinal volumes, Dr. Comi informed the audience.

Results of the original ETOMS study showed a 24% reduction for Rebif versus placebo in the proportion of patients converted to clinically definite MS, as well as a significant decrease in the median number of T2 active lesions as seen on MRI—two in the treated group versus three in the placebo group (P<0.001).

Patients who underwent analysis for brain atrophy included 131 in the Rebif treatment group and 132 in the placebo group. At entry, mean brain volume was comparable between the two groups (1503 mL vs 1496 mL). The mean percentage changes in brain volume from baseline to 24 months were significant for both treatment groups (P<0.001). However, the mean percentage reduction of brain volume over the 24-month study was significantly higher for the placebo treatment group (-1.68%) than for the Rebif treatment group (-1.18%)(P = 0.003). Over the entire study period, significant correlations were found between the brain volume percentage change and the number of enhancing lesions (r = -0.18, P = 0.006) and the number of new T2 lesions (r = -0.26, P<0.001). The number of enhancing lesions (r = -0.21, P = 0.003) and new T2 lesions (r = -0.29, P<0.001) formed during the first 12 months correlated significantly with brain volume changes during the second 12 months. No significant difference in brain volume was observed between patients who relapsed during the study and those who did not.

A weak correlation was observed between MRI-detected disease activity and brain tissue loss. This weak correlation suggests that, in patients at presentation with suspected MS, inflammation and neurodegeneration are, at least partially, dissociated, Dr. Comi stated.

Efficacy in Patients with High Risk MS—Results of the CHAMPS Subgroup Analysis

Frederick E. Munschauer III, MD, Professor of Clinical Neurology and Internal Medicine at the State University of New York at Buffalo, Buffalo, New York and the Jacobs Neurological Institute

The CHAMPS (Controlled High-Risk Avonex MS) study demonstrated the efficacy of interferon beta-1a (Avonex) in delaying the development of clinically definite MS in patients with a single demyelinating event and an abnormal MRI suggestive of MS.21 Results presented by Dr. Frederick Munschauer showed that the beneficial effect of Avonex in CHAMPS was even more robust in a subset of patients determined to be at highest risk of clinically definite MS (ie, ≥9 T2 lesions and at least 1 gadolinium-enhanced lesion on MRI at baseline).22

"Avonex had a treatment effect in all subgroups of patients with clinically isolated syndrome (ie, optic neuritis, partial transverse myelitis, or brainstem syndrome) suggestive of MS with abnormal MRI scan. The treatment effect was even more robust in a high-risk group of patients," Dr. Munschauer told the audience.

The placebo-controlled, double blind CHAMPS study included 383 patients from 50 North American MS centers who were randomized to receive either intramuscular Avonex 30 mcg once weekly or placebo injections once weekly. All patients had experienced a single demyelinating event: optic neuritis, spinal cord syndrome, or brainstem/cerebellar syndrome accompanied by abnormal MRI findings suggestive of MS (at least two T2 lesions, one of which was periventricular or ovoid on unenhanced MRI scan). Overall analysis of the CHAMPS study found that the risk of developing clinically definite MS at 2 years was 21% in the Avonex treatment group compared to 39% in the placebo treatment group; at 3 years, the risk was 35% and 50%, respectively.

Dr. Munschauer pointed out that the study population included patients with a wide range of MRI abnormalities suggestive of MS, with a median number of four T2 lesions. Patients were treated with intravenous steroids for 3 days, followed by oral prednisone for 15 days, and then randomized to treatment.

In the overall study population, Avonex reduced the time to conversion to clinically definite MS by 44% compared to placebo (rate ratio = 0.56, P = 0.002). At 18 months, a significant 67% reduction in the number of gadolinium-enhanced lesions was observed in patients who did not have a second MS attack (P<0.001). At 18 months, the T2 lesion volume was reduced by 91% in Avonex-treated patients compared to placebo-treated patients (P = 0.001).

Those primary results led the CHAMPS investigators to initiate a second analysis of the effects of Avonex in a subgroup of 91 patients from CHAMPS with a particularly high risk of clinically definite MS.22 In this high MRI lesion burden of disease patient subgroup, the 2-year Kaplan-Maier estimate of the cumulative risk of developing clinically definite MS was 21% for Avonex treatment group and 56% in the placebo treatment group. (see Figure 1) The overall risk of developing clinically definite MS was reduced by 66% in the Avonex-treated patients compared with the placebo treatment group (P = 0.002).

"These results are clinically relevant," Dr. Munschauer stated. "Evidence presented at this meeting shows that patients with a first demyelinating event already have irreversible central nervous system injury, and there is a correlation between the number of lesions at baseline and tissue damage. Further, we now know that brain atrophy occurs early in the MS process, within the first year. Clinically isolated syndrome may reflect the presence of a chronic inflammatory disease that has already resulted in central nervous system injury. MRI can stratify the risk of clinically definite MS in clinically isolated syndrome. Early treatment can have a major effect on disability in patients with clinically isolated syndrome at high risk of developing clinically definite MS."

Based on the CHAMPS findings, Avonex has recently been granted approval for treatment of clinically isolated syndrome in the European Union by the European Medicines Evaluation Agency.23

The Evidence of Interferon Dose-Response: European-North American Comparative Efficacy (EVIDENCE) Study: 48-Week Data

Douglas S. Goodin, MD, University of California at San Francisco, School of Medicine, San Francisco, California

Forty-eight-week data of the EVIDENCE trial presented at ENS compared two interferon beta-1a regimens: subcutaneous Rebif 44 mcg three times weekly versus intramuscular Avonex 30 mcg once weekly.11 The study enrolled 677 patients with relapsing-remitting MS from 56 multi-national centers and was conducted in two 24-week phases.

The primary outcome measure was the proportion of relapse-free patients. Secondary outcome measures included relapse rate, MRI active lesion count and T2 active lesion count. Baseline patient characteristics of both treatment groups were well matched. No significant differences were observed in age, duration of disease, percentage of women, EDSS score, and incidence of relapse within the previous 2 years. Baseline MRI characteristics were similar between treatment groups; however, the Avonex treatment group had 20% more combined unique lesions at baseline.

Both treatments were well tolerated and compliance was excellent. Ninety-three percent of the Rebif treatment group and 94% of the Avonex treatment group completed the entire 48 weeks of the study.

At 48 weeks, the cumulative probability of an MS attack was 38% in the Rebif treatment group and 48% in the Avonex treatment group, with an absolute difference of 10%, reported Douglas S. Goodin, MD, University of California at San Francisco, School of Medicine, San Francisco, California. The relative reduction in relapse rate compared to baseline was 26% for the Rebif treatment group and 16% for the Avonex treatment group and was not statistically significant. The relative risk of relapsing with Rebif treatment was calculated to be 0.81.

An analysis of these results revealed that most of the treatment benefit observed in this study occurred during the first 24 weeks of treatment, and that the differences between treatments became less pronounced over time. In the first 24-week phase, an 11.8% difference in relapses favored Rebif, but in the second 24-week phase, a 1% difference favoring Avonex was seen among the remaining cohort of relapse-free patients.

At 48 weeks, no statistically significant difference in the actual relapse rate was found between the Rebif and Avonex treatment groups. Additionally, no significant difference between the two treatment groups was found in sustained progression of disability as measured by the EDSS.

Monthly gadolinium-enhanced scans were performed for the first 6 months of the study, but the final scan at 48 weeks was not contrast enhanced (ie, PD/T2 only). The MRI outcome measure was the combined unique (CU) activity (T1 plus T2 abnormalities). Although Rebif was associated with less CU activity, the definition of disease activity in the study was inconsistent between the 24 and 48 week time points and, lacking a final gadolinium-enhancing scan, conclusions from the study are difficult to draw.

Importance of Neutralizing Antibodies

As with previous studies, there was a higher level of neutralizing antibodies detected in the Rebif-treated patients than in the Avonex-treated patients at all titers measured. Neutralizing antibodies were observed in 35% of Rebif-treated patients compared to 5% of Avonex-treated patients. Neutralizing antibody titers >20 NU/mL were observed in 25% and 2% of patients, respectively.


Injection-site reactions were common, with 44% of Rebif-treated patients experiencing inflammation and 35% demonstrating other injection side effects. These occurred in only 4% and 12%, respectively, of Avonex-treated patients (P<0.001) Elevated liver enzymes were seen in 18% and 19% of Rebif- and Avonex-treated patients, respectively (P<0.002); leukopenia in 11% and 5%, respectively (P<0.003); and flu-like symptoms in 42% and 49%, respectively (P<0.089).

Could Multiple Sclerosis Patients with a Prolonged MRI-Confirmed Absence of Disease Activity Benefit from the Reduction of Interferon Beta Dose?

Luca Durelli, MD, University of Turin, Turin, Italy

Administration of interferon beta-1b (Betaseron) requires injections every other day. Many patients find this a hardship and inconvenience, possibly resulting in non-compliance. "Several injections per week may be frustrating for patients and may lead to patients decreasing the dose and frequency of their drug without consulting their doctor," explained Luca Durelli, MD, University of Turin, Turin, Italy.

Dr. Durelli said that many patients who self-administer frequent injections and appear to be stabilized on interferon beta often ask about stopping or altering their treatment. In an attempt to answer whether this is advisable, Dr. Durelli and his colleagues conducted a small, prospective, unblinded study in relapsing-remitting MS patients (n = 27) who were receiving Betaseron.24 Patients were randomized to gradually switch from every-other-day Betaseron to once-weekly Avonex 30 mcg (n = 13) or to continue on Betaseron 8 million IU (n = 14). Before interferon dose reduction, patients had to have been on chronic Betaseron for at least 36 months and without clinical signs of disease and MRI activity during the previous 24 months.

No statistically significant differences in demographics, clinical and MRI parameters were observed between the two treatment groups, said Dr. Durelli. One year after interferon dose reduction, three patients in the Avonex treatment group were relapse-free compared to 11 patients in the Betaseron treatment group; three and nine patients, respectively, had no new T2 lesions. According to Dr. Durelli, the exacerbation rate, the proportion of patients with exacerbations, EDSS worsening, or with MRI activity were significantly lower (P = .05) for the patients who continued on Betaseron compared to those who switched to once-weekly Avonex.

Although the study was designed to evaluate correlations between disease activity and corresponding switches to Avonex therapy, investigators concluded that the results indicated that it is not advisable to reduce the interferon beta dose in patients who are stabilized on Betaseron even in patients with prolonged absence of disease activity. No further analysis was conducted beyond one year in this small patient group.

Provigil (modafinil): A Pilot, Single-Center, Double Blind, Placebo-Controlled Cross-Over Study in the Treatment of Fatigue in Multiple Sclerosis

Andrew Dowson, MD, London, Guilford, United Kingdom

A medication to treat the consistent fatigue suffered by many patients with MS showed promise in a single-center study from the United Kingdom reported by Dr. Andrew Dowson.25 While not statistically conclusive, a trend toward improvement in fatigue parameters was demonstrated by patients receiving modafinil (Provigil).

The double blind, placebo-controlled study included 35 patients whose mean age was 45 (± 7.9 years) years, mean time since diagnosis was 10.5 (± 7.7 years) years, mean EDSS was 3 (± 2.3), and mean MS-specific Fatigue Scale (MS-FS) was 4.6 (± 0.9). Patients were randomized to either modafinil 100 mg once daily for 3 weeks, followed by modafinil 100 mg twice a day for 3 weeks, or matching placebo. After a 2-week washout, patients crossed over to the other treatment arm. Twenty-nine patients completed the study and were included in the efficacy analysis. A power calculation using MS-FS as the primary efficacy parameter suggested enrolling 60 patients. Due to logistical problems, patient enrollment was terminated prematurely; however, the results were seen as sufficiently encouraging to propel further study of modafinil in MS patients.

Patients on modafinil experienced mean improvements from baseline in MS-FS score that were 0.5 points greater than on placebo, at both doses. This is the degree of difference the study had been powered to detect, however, due to the premature termination of patient enrollment; this difference did not reach statistical significance. The other fatigue parameters—Visual Analogue Scale of Fatigue and MS-Quality of Life Questionnaire—showed similar trends of improvement, but again, differences did not reach statistical significance. The Epworth Sleepiness Scale (ESS) showed a trend in favor of modafinil, but when a subset of patients with substantial sleepiness was analyzed (n = 19 with ESS = 10+), this trend was reduced or eliminated, principally due to a placebo response, Dr. Dowson reported.

No statistically significant differences between treatments were seen on the objective measures of sedation (Critical Flicker Fusion, CFF)(P = 0.128), although an initial placebo effect was noted. Some patients had normal baseline CFF values, despite being subjectively sleepy. No serious adverse events were seen; the most common side effects observed were headache and nausea, both occurring in 9% of modafinil-treated patients.

Dr. Dowson suggested that further studies appear warranted based upon these preliminary results. The differences between the fatigue and sleepiness parameter findings (baseline, efficacy, and placebo effects) strongly suggest that there are different features in this MS population that future studies must address.

Influence of Pulsed Methylprednisolone Therapy on Cognitive Functions in Patients with Multiple Sclerosis

Ingo Uttner, MD, Klinikum Grosshadern, Ludwig-Maximilians-Universitat, Munich, Germany

High-dose treatment with pulsed methylprednisolone can induce selective, but reversible, impairment of the declarative memory recall in MS patients, according to German investigators led by Ingo Uttner, MD, of the Klinikum Grosshadern, Ludwig-Maximilians-Universitat, Munich, Germany.

There is strong evidence that elevated glucocorticoid levels can cause cognitive impairment, but little data currently exist to define that association in MS patients treated with corticosteroids. This study addressed the question of whether high-dose corticosteroid treatment can cause such cognitive deficits and whether the effect on cognitive performance is dose-dependent.

The study included 16 patients (11 females, 5 males; mean age 33 years) with early-stage relapsing-remitting MS and 8 well-matched healthy controls (eg, age, gender). In a double-blind fashion, one half of the patients were randomized to receive methylprednisolone 500 mg daily for 5 days while the remaining patients received methylprednisolone 2000 mg daily for 5 days. Neuropsychological investigations were conducted at baseline (Day 0), on Day 6 and 60 days after treatment with methylprednisolone.

The results showed impairment of free and cued retrieval of declarative memory in the methylprednisolone-treated patients at Day 6 compared to Day 0 (P<0.05), which recovered completely by Day 60. All other functions were unaffected. In contrast, the untreated controls showed a slight improvement in their declarative memory at Day 6 compared to Day 0. No differences were found between the profile and severity of the cognitive impairment between the two dosing regimens of methylprednisolone.

The findings suggest that high-dose treatment with methylprednisolone can induce selective but reversible impairment of the declarative memory-recall in MS patients. This effect appears to be independent of the dose of methylprednisolone.


1. Clanet M. Sustained efficacy on relapsing multiple sclerosis: 4-year results of the European Dose-Comparison Study. 12th Meeting of the European Neurological Society, June 22-26, 2002, Berlin, Germany. Satellite Symposium: Make a difference-the importance of efficacy in RRMS. Presented June 25, 2002.
2. Clanet M, Kappos L, for the European Interferon Beta-1a Dose-Comparison Study Group. Sustained safety of interferon beta-1a in relapsing multiple sclerosis: results from the European Dose-Comparison Study. 12th Meeting of the European Neurological Society, June 22-26, 2002, Berlin, Germany. Abstract 211.
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