Introduction

The recent meeting of the 7th Annual Meeting of the Americas Committee for Treatment and Research in Multiple Sclerosis and 18th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS/ECTRIMS) held September 18-21, 2002 in Baltimore, Maryland, featured informative research presented by an esteemed international body of investigators.

Evidence was presented confirming that the three commercially available interferon beta agents (Avonex, Betaseron and Rebif) all reduce attack rates, disease severity, and brain lesion burden. The immunomodulatory agents were found to be equivalent in clinical efficacy in varying degrees—all producing significant reductions in relapse rates and affecting Expanded Disability Status Scale (EDSS) similarly (Avonex and Rebif), in several retrospective comparisons reported at this meeting.

Given confirmed efficacy, the question is not whether to treat multiple sclerosis (MS) patients with immunomodulatory agents—and to begin early in the disease course—but how to select the appropriate agent. Other factors, then, should be taken into consideration, such as the individual characteristics of the agents. One of these characteristics is the development of neutralizing antibodies, a topic of increasing concern.

At ACTRIMS/ECTRIMS 2002, a large Danish Study addressed the question that has been frequently asked most recently: do neutralizing antibodies actually matter? The Danish National Interferon Beta Project followed nearly 500 patients with MS taking interferon beta for up to 5 years and found significantly higher relapse rates and shorter time to first relapse among patients who developed neutralizing antibodies.¹

Dr. Per Soelberg Sorensen, principal investigator, encouraged clinicians to monitor for neutralizing antibodies, especially in patients not responding to interferon beta, and to consider the risk for developing neutralizing antibodies when selecting an agent. In the Danish study, Avonex was associated with the lowest rate of neutralizing antibodies; consistent with other studies of the interferon beta formulations.^2-4

The most important goal of the immunomodulatory agents is to prevent or delay long-term disability. In some cases, early positive results seen with immunomodulatory agents do not translate into long-term beneficial effects as was the case for a follow-up analysis of the Early Treatment of MS (ETOMS) study. Dr. Giancarlo Comi, principal investigator, reported here that the benefit of Rebif seen at 2 years was lost and no longer statistically significant at 4-5 years.⁵ The value of Rebif, therefore, may be limited to the early phase of treatment.

The debate continues on how early to begin immunomodulatory therapy. Dr. Frederick E. Munschauer III presented additional analyses from the Controlled High-Risk Subjects Avonex Multiple Sclerosis Prevention Study (CHAMPS) study that showed the presence of only two T2 lesions in patients with a clinically isolated syndrome, or even one gadolinium-enhancing lesions at baseline, should be indications for treatment.^6,7 The rate of conversion to clinically definite MS is practically double that of patients with clinically suggestive signs but without these lesions. Importantly, treatment with Avonex in the CHAMPS study significantly reduced the chances of having a second episode.⁷

This Multiple Sclerosis Forum Report reviews selected presentations from ACTRIMS/ECTRIMS 2002 to provide new insights into the current understanding of immunomodulatory therapies for multiple sclerosis.

Neutralizing Antibodies and Clinical Outcomes

Neutralizing Antibodies Against Interferon (IFN)-Beta Reduce the Clinical Effect in Relapsing-Remitting Multiple Sclerosis

Per Soelberg Sorensen, MD, Professor of Neurology, University of Copenhagen, and Director of the Copenhagen MS and Neuroscience Center, Copenhagen, Denmark

Neutralizing antibodies affect the long-term clinical efficacy of interferon beta treatment, and they occur least often with interferon beta-1a (Avonex), according to the results of a large Danish study presented by the study's principal investigator, Per Soelberg Sorensen, MD, Professor of Neurology, University of Copenhagen, and Director of the Copenhagen MS and Neuroscience Center, Copenhagen, Denmark.¹

"Neutralizing antibodies do matter in treatment efficacy", Dr. Sorensen stated. In fact, lack of response to interferon beta therapy should raise the suspicion of neutralizing antibodies, and if neutralizing antibodies are confirmed in non-responders to interferon beta therapy, patients should be considered for alternative therapy, he suggested.

The frequency with which immunomodulatory therapy for multiple sclerosis (MS) induces neutralizing antibodies has reportedly varied from 2% to 42% and has depended on the specific interferon beta formulation investigated and the dose administered.^2,8 There has been increasing interest in determining not only whether these neutralizing antibodies affect the therapeutic response to interferon beta therapy, but to what extent.

"For example, the 2-year data from the PRISMS study^[9] [in patients receiving subcutaneous interferon beta-1a (Rebif) 3 times weekly] showed no difference in annualized relapse rate for patients with or without neutralizing antibodies, but the data at 3 and 4 years showed a significant difference," he said. At 3-4 years^[3], annualized relapse rate was 0.50 for neutralizing antibody-negative patients and 0.87 for patients who developed neutralizing antibodies (P = 0.002), Dr. Sorensen noted.

To determine how neutralizing antibodies affect the long-term clinical course of interferon beta therapy, the Danish National Interferon Beta Project followed 467 patients with relapsing-remitting MS treated with the different interferon beta products for up to 5 years. Measurements of neutralizing antibodies were performed every 6 months in a blinded fashion with antiviral neutralization (A549/EMC) bioassays with high [3 LU/mL], medium [10 LU/mL] and low [100 LU/mL] sensitivity. Rather than antibody titers, the project used the more accurate "neutralizing capacities" as cut-off values for the definition of neutralizing antibody-positivity. The neutralizing capacity is defined as the extent of interferon beta neutralization by the neutralizing antibodies in a given sample.

The bioassay used in this study is currently employed only in investigational settings, but for reference, a high sensitivity bioassay is similar to a 1:20 titer, he explained. A 1:20 titer is the generally accepted level at which neutralizing antibodies have demonstrated the ability to attenuate clinical and magnetic resonance imaging (MRI) outcomes.^3,4,10 The percentage of neutralizing antibodies was dependent on the sensitivity of the specific bioassay utilized.

More Relapses in Neutralizing Antibody-Positive Patients

"We observed a significantly higher relapse rate during neutralizing antibody-positive periods compared with neutralizing antibody-negative periods," Dr. Sorensen reported. "The time to first relapse was significantly longer in neutralizing antibody-negative patients compared with neutralizing antibody-positive patients."

In neutralizing antibody-positive patients, the odds ratio for the higher relapse rate was 1.55 (range, 1.25-1.94; P<0.01) as determined by both the low- and medium-sensitivity bioassays. With the low-sensitivity bioassay, the yearly relapse rate was 0.73 for neutralizing antibody-positive and 0.48 for neutralizing antibody-negative patients; with the medium-sensitivity bioassay, the rates were 0.67 and 0.44, respectively.

Differences were less than with the high-sensitivity assay, which picked up inconsequential antibody loads, Dr. Sorensen explained. "Very low concentrations of neutralizing antibodies do not influence the odds ratio for relapses," he noted. Future investigations will use the lowest cut-off value for neutralizing capacity (≥20%) for the definition of neutralizing antibody positivity.

Patients treated with intramuscular Avonex 30 mcg once weekly demonstrated the lowest occurrence of neutralizing antibodies. The low incidence of neutralizing antibodies observed with Avonex was consistent over the entire course of the study, while the highest incidence was initially observed with interferon beta-1b (Betaferon). At 36 months, the highest incidence was observed with subcutaneous Rebif 22 mcg 3 times weekly, Dr. Sorensen reported.

Time to first relapse was also influenced by neutralizing antibody positivity. The time to first attack occurred an average of 177 days earlier in the neutralizing antibody-positive patients, he reported. There was no difference between the groups, however, in mean Expanded Disability Status Scale (EDSS) or time to sustained progression, although a clear trend was demonstrated beginning at year 3.

There were no pre-clinical features that were predictive of the development of neutralizing antibodies, although there was a trend for greater development of neutralizing antibodies in patients with a short duration of disease and a high progression index.

While some patients develop neutralizing antibodies that ultimately could disappear, Dr. Sorensen pointed out that neutralizing antibodies generally persist. "In our study, 80% of patients who were neutralizing antibody-positive at 12 months were still positive at 2 years; 70% were still positive at 3 years; and 60% were still positive at 4 years," he noted.

Dr. Sorensen emphasized the need to perform neutralizing antibody bioassays during treatment, "at a minimum" in patients with significant clinical activity. If the patient has clinical activity and is neutralizing antibody-positive, you should think of changing treatment, he advised. He further suggested, "Frequency of neutralizing antibodies is one factor to consider when choosing an interferon."

Interferon Beta Product Comparisons and Long-Term Observations: New Findings on Clinical Outcomes with Immunomodulatory Agents

Interferon Beta Treatment in Relapsing-Remitting Multiple Sclerosis: Results of an Observational Study in Southern Italy

Maria Trojano, MD, Neurological and Psychiatric Sciences, University of Bari, Bari, Italy

In a large observational study, three commercially available interferon beta formulations had similar effects on relapse rate and mean Expanded Disability Status Scale (EDSS) changes in 1,033 mildly disabled (EDSS 0-3.5) relapsing-remitting MS patients in southern Italy.¹¹ Maria Trojano, MD, of the University of Bari, Bari, Italy, reported the results. Relapse rate, EDSS, adverse events, presence of neutralizing antibodies, and treatment discontinuations were evaluated every 3 months. Twelve-month data were available for interferon beta-1b (Betaferon) (n = 234), interferon beta-1a (Avonex) (n = 219) and subcutaneous interferon beta-1a (Rebif) (n = 89), and 24-month data were available for Betaferon (n = 209) and Avonex (n = 169).

Each interferon beta formulation, independent of dose regimen, had similar effects on relapse rate, each reducing relapses at 12 and 24 months (P<0.001). At 12 months, relapse rates were equally reduced from baseline by 42% with Avonex (30 mcg intramuscularly once weekly), 43% with Rebif (22 mcg subcutaneously 3 times weekly), and 50% with Betaferon (250 mcg subcutaneously every other day) (P = 0.001). At 24 months, reductions in relapse rates were still statistically similar, 46% with Avonex and 54% with Betaferon, independent of dose and regimen, she reported.

Outcomes were also similar with regard to the proportion of patients who were relapse-free at 12 months (54.4 % for Avonex, 53.7% for Betaferon, and 49% for Rebif; P = 0.10) and 24 months (33% Avonex, 37% Betaferon, no 24-month data for Rebif). Changes in EDSS scores at 12 and 24 months were also comparable (P = 0.17) between the different interferon beta formulations, Dr. Trojano reported.

However, two significant differences were observed in this study: a higher rate of adverse events associated with Betaferon and a lower incidence of neutralizing antibodies with Avonex.

The side effect profile was better with Avonex, at least in the early period, Dr. Trojano stated. "In general, Betaferon patients had a higher incidence of adverse events during the first 3 months compared with Avonex patients (P<0.05), and more patients discontinued treatment with Betaferon≥10% vs 5% at 24 months." The cumulative numbers of patients discontinuing treatment were 10% with Betaferon, 7% with Rebif, and 5% with Avonex. Adverse events were given as the reasons for discontinuation in 41% with Betaferon, 28% with Rebif, and 16% with Avonex, she reported

The increase in adverse events with Betaferon was significant for arthralgias, asthenias, fevers, injection site reactions, leukopenia, anemia, and several laboratory parameters, such as elevated liver enzymes, primarily occurring in the early treatment period. Injection site reactions and anemia remained more frequent with Betaferon compared to the other formulations over the entire period of observation.

Dr. Trojano suggested that an improved side effect profile might influence patient adherence to interferon beta therapy. "The more favorable efficacy/safety ratio of Avonex versus Betaferon in relapsing-remitting [MS] patients with low disability may improve patient compliance during long-term treatment," she advised.

Consistent with studies from other investigators, the risk of developing neutralizing antibodies (titer ≥20 in at least two consecutive samples 3 months apart) was significantly less with Avonex (2.2%) compared to Betaferon (14.8%) and Rebif (6.7%) (P<0.00005).

Relapsing-Remitting MS Therapy Experience in Argentina

Adriana Carra, MD, Hospital Britanico de Buenos Aires, Buenos Aires, Argentina

The first Latin American study to evaluate all four commercially available immunomodulatory therapies found significant reductions in relapse rates for all therapies and no significant differences in EDSS changes.¹²

The retrospective, observational multicenter study evaluated 134 patients with relapsing-remitting MS with similar baseline characteristics who received Avonex (n = 26), Betaferon (n = 20), Rebif 44 mcg (n = 20), glatiramer acetate (Copaxone) (n = 30), or no immunomodulatory therapy (n = 38).

The results at 16 months follow-up revealed that treatment with immunomodulatory therapy significantly reduces relapses. Table 1 depicts the observed outcomes of the study.

The results are in accordance with those observed in the pivotal studies involving the four immunomodulatory agents after one year of therapy, Dr. Carra stated.

Effect of Interferon Treatment on Conversion to Definite MS: 4-Year Results from the ETOMS Study

Giancarlo Comi, MD, Professor of Neurology, Clinica Neurologica, Ospedale San Raffaele, Milan, Italy

The ETOMS (Early Treatment of MS) study¹³ showed a beneficial effect of subcutaneous interferon beta-1a (Rebif) 22 mcg once a week on conversion to clinically definite MS among patients with clinically isolated syndromes and MRI scans suggestive of MS. But this benefit was no longer statistically significant at 4-5 years, according to the results from an extension study reported at this meeting.⁵

In the ETOMS study, 308 patients were randomized to double blind treatment with subcutaneous Rebif 22 mcg once a week or placebo for 2 years, followed by a 2-year, open-label extension study with subcutaneous Rebif 22 mcg administered once a week. Patients who had reached the primary endpoint, conversion to clinically definite MS, could remain in the study or withdraw and start best available therapy at the physician's discretion.

At 2 years, fewer patients developed clinically definite MS in the Rebif treatment group than in the placebo treatment group, 34% versus 45%, respectively (P = 0.047).¹³ With long-term follow-up (n = 197 up to 5 years), the curves were still separate but the proportion of those converting was 62.9% with placebo and 55.4% with Rebif. The difference was no longer statistically significant (P = 0.224), Dr. Comi reported.

"There is clear and significant evidence of the benefit of interferon beta on the first 2 years of treatment, but there are no data [demonstrating this] long-term. The benefit of Rebif seems to be limited to the early phases of the disease," Dr. Comi said.

Role of Exacerbations in Persistent Impairment in MS

Fred Lublin, MD, Professor of Neurology and Director of the Corinne Goldsmith Dickinson Center for MS, Mount Sinai Medical Center, New York, New York

Exacerbations can leave residual deficits in patients with MS, and as such, are important therapeutic targets, according to Fred Lublin, MD, Professor of Neurology and Director of the Corinne Goldsmith Dickinson Center for MS, Mount Sinai Medical Center, New York, New York. His comments were based on an analysis of a database containing placebo patients from several completed clinical trials of relapsing forms of MS.¹⁴

Although it is intuitively obvious that repeated exacerbations may lead to step-wise worsening of neurological function, the actual role of exacerbations has not been quantified. This study evaluated pre- and post-exacerbation visits of placebo patients (n = 224) to assess changes that occurred during relapses and their resulting residual deficits. The analysis included a pre-exacerbation assessment of EDSS and Scripps score, intra-exacerbation scores, and follow-up evaluations.

The results of the study show that "exacerbations count," Dr. Lublin said. "This is consistent with what we see in clinical trials, and it's why we treat multiple sclerosis early."

The study found a stepwise worsening in EDSS after exacerbations, and found that "placebo groups don't catch up," he said. "Early recurrences produce long-term deficits that cannot be recovered from."

There was a mean worsening of 0.4 EDSS units that persisted when patients were assessed more than 30 days after an exacerbation, and there was an average worsening of two points on the Scripps score. At the first visit post-exacerbation, 50% of patients had residual deficits on the Scripps score and 43% on the EDSS; 39% of patients still had EDSS deficits after the second visit, an average of 150 days later, suggesting that the effect was permanent in many cases, he said. Some 45% of placebo patients who had experienced exacerbations had residual impairment.

Dr. Lublin said these findings speak to the need for early treatment. "If you treat in the inflammatory phase, you can make a difference, even in secondary progressive disease," he maintained.

Christian Confavreux, MD, Professor of Neurology, Hospital Neurologique, Lyon, France whose presentation¹⁵ followed Dr. Lublin's, agreed, "Relapses are an important cause of disability. We are perfectly aware of patients with relapses leading to complete deficits," he stated, but he maintained that the situation is complex and that relapses may be less influential in the accumulation of disability over time.

Relapses in MS are the clinical counterpart of acute focal inflammation of the central nervous system, whereas progression is the counterpart of chronic diffuse neurodegeneration. The classical view is that inflammation eventually causes the neurodegeneration, but whether inflammation is also the cause of the progression is not as clear, he said.

For example, interferon beta reduces the relapse rate by 30% and conventional MRI activity by more than 50%, indicating a strong effect by interferon beta on inflammation. Furthermore, potent immunosuppressive drugs administered to MS patients suppress clinical and MRI activity but progression of clinical disability and cerebral atrophy may still occur.

Studies of the natural history of MS from the Lyon MS Cohort¹⁶ also showed that relapsing-remitting patients take longer than secondary-progressive MS patients to reach an assignment of 4 on the Kurtzke Disability Status Scale (DSS) scale. However, the time to evolve from DSS 4 to DSS 6 is the same for both relapsing-remitting and secondary-progressive forms of MS, and is the same whether progression is superimposed by relapses or not.

In Dr. Confavreux's opinion, inflammation is not essential to the degenerative process, however, relapses and inflammation do deserve consideration. "It is urgent to administer immunomodulatory agents early to control inflammation, but keep in mind that even potent drugs do not necessarily prevent degeneration. Degeneration is a second player to inflammation and we need to develop strategies for protecting and repairing this system," he said.

MRI Response

Selecting High-Risk Patients for Early Treatment

Frederick E. Munschauer III, MD, Professor of Clinical Neurology and Internal Medicine and Interim Chairman of the Department of State University of New York at Buffalo School of Medicine and Biomedical Sciences, Buffalo, New York

The emergence of a clinically isolated syndrome (CIS) with an magnetic resonance imaging (MRI) scan showing at least two T2 weighted lesions suggestive of multiple sclerosis is an indication for treatment with disease-modifying agents, according to Frederick E. Munschauer III, MD, Professor of Clinical Neurology and Internal Medicine and Chairman of the Department of State University of New York at Buffalo School of Medicine and Biomedical Sciences, Buffalo, New York.⁶ His recommendation was based on a subgroup analysis of the CHAMPS study (Controlled High-Risk Subjects Avonex Multiple Sclerosis Prevention Study⁷) that examined the ability of baseline MRI parameters to predict the development of clinically definite MS.

Without treatment, patients with CIS in CHAMPS had a 90% chance of experiencing a second clinical attack or development of another T2 lesion during the study. Moreover, patients with further T2 lesion development were significantly likely to evolve to clinically definite MS.

As few as two T2 lesions typical of MS confer the risk of clinically definite MS. "Just the presence of two lesions should be a trigger to establish the patient as high risk. As few as two lesions are probably as predictive of a second event as 10 or more lesions," Dr. Munschauer said. "This is all I need to see in order to initiate therapy."

Gadolinium-enhancing lesions at baseline, however, confer an even greater risk for clinically definite MS, according to CHAMPS findings. In fact, only the presence of one or more gadolinium-enhancing lesions was predictive of developing clinically definite MS.

In the CHAMPS placebo group as a whole, 27% of patients developed clinically definite MS within the mean study time of 22 months. But the presence of two or more gadolinium-enhancing lesions at randomization was associated with a 52% conversion rate over the same study duration. In patients without gadolinium-enhancing lesions, the conversion rate was 23%.

In placebo patients with T2 lesions at baseline, conversions occurred in 39% with four or more T2 lesions and in 40% with over nine T2 lesions. The number of T2 lesions was not strongly associated to the magnitude of risk.

"The newer MRI data reinforce the idea that tissue injury is occurring very early. What we are seeing is evidence of inflammation with early irreversible loss," Dr. Munschauer maintained.

Patients with CIS and active MRI scans clearly derived a treatment effect from Avonex in the CHAMPS study. Patients with a high burden of disease on MRI—at least one gadolinium-enhancing lesion and nine or more T2 lesions—had a reduction of 66% in the development of clinically definite MS, compared with 44% for the CHAMPS cohort as a whole. This represented a 50% higher magnitude of treatment effect among patients with a high MRI lesion burden, he said.

"Significant treatment effects were seen, both in patients with total T2 lesion load >2050 mm³ and in patients with one or more gadolinium-enhancing lesions. While only gadolinium-enhancing lesions predicted clinically definite MS, the treatment effect was seen not only in these lesions but in a wide range of lesions," he emphasized.

Dr. Munschauer stressed the importance of MRI imaging in the high-risk population. "In the management of patients with CIS, MRI should be your yardstick for recommending therapy," he advised.

A 36-month Longitudinal Study on the Evaluation of the Effect of Interferon Beta in the Duration of Black Holes in Multiple Sclerosis

Francesca Bagnato, MD, Neuroimmunology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland

Treatment of relapsing-remitting MS with interferon beta-1b (Betaseron) appears to reduce the number of contrast-enhancing lesions (CELs), but does not prevent black hole formation, according to Francesca Bagnato, MD, Neuroimmunology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland.¹⁷

Dr. Bagnato's study followed 10 treatment-naпve patients (mean EDSS 3.0, mean age 34.4 years, MS duration 7.2 years) for 18 months pre- and post-treatment with Betaseron. Patients were evaluated by monthly MRI to determine the number and duration of CELs (reflecting inflammatory activity) and the number and duration of black holes (representing accumulated axonal loss). Patients underwent up to 36 monthly MRI scans to evaluate the probability of a CEL converting to a black hole before and during treatment.

Persisting black holes were defined as any hypo-intense regions visible on the T1-weighted scans with hyper-intensity on the T2-weighted image and without a CEL. Only persisting black holes with a previously identified CEL were considered for the analysis.

The study found a significant difference in total and new CELs in the pre-treatment versus post-treatment period (P<0.001), as well as the 6-month follow-up point during treatment (P<0.001). There was also a significant difference in cumulative or new black holes seen before and during treatment (P<0.002), Dr. Bagnato reported.

However, the proportion of CELs evolving to black holes over time was no different from natural history studies: about 30% versus 20%, she said. Also, the duration of lesions was similar before and during treatment for both CELs and black holes.

"Interferon beta-1b reduces inflammatory activity, as shown by a reduction in CELs, but once these lesions are formed, there is no way that the drug [interferon beta-1b] shortens their duration or reduces the proportion of CELs evolving to black holes," advised Dr. Bagnato.

Measuring Outcomes

Relationship between the MS Functional Composite and MRI in IMPACT

Jeffrey A. Cohen, MD, Director, Experimental Therapeutics Program, The Mellen Center, Cleveland Clinic, Cleveland, Ohio

A study by Cleveland Clinic investigators has validated the Multiple Sclerosis Functional Composite (MSFC) as an accurate clinical outcome measure.¹⁸ In this secondary-progressive multiple sclerosis (MS) cohort, T2 lesion volume, volume of T1 holes, and whole brain atrophy correlated substantially better with MSFC than did Expanded Disability Status Scale (EDSS), reported Jeffrey A. Cohen, MD, Director, Experimental Therapeutics Program, The Mellen Center, Cleveland Clinic, Cleveland, Ohio.

"Over the years, one of the things we have struggled with is the fact that magnetic resonance imaging (MRI), which we believe demonstrates underlying disease activity, correlates poorly with clinical measures [EDSS change]," he said. "This study suggests that much of that poor correlation is due to deficiencies in the EDSS. When you have better measures—measures more sensitive to change and reflecting other aspects of neurological dysfunction other than walking—then the correlations with MRI are greater."

The International Multiple Sclerosis Secondary Progressive Avonex Controlled Trial (IMPACT) study involved 436 subjects with secondary-progressive MS and EDSS 3.5-6.5 randomized to intramuscular interferon beta-1a (Avonex) 60 mcg once weekly or placebo for 2 years.¹⁹ A treatment benefit was shown on the primary endpoint, 2-year MSFC change. Benefit also was shown on relapse rate, MRI, and quality of life, but not on EDSS. The current study assessed the relationship between measures of neurological impairment and MRI parameters.

The analysis found that cross-sectional correlations of T2 volume, T1 volume, and brain parenchymal fraction (BPF) were stronger with the MSFC than with the EDSS, and the patterns of these correlations with clinical parameters were similar for the three measurements.

Baseline T2 volume and MSFC correlated moderately (r = -0.48), while EDSS correlated weakly (r = 0.20). Among the MSFC components, T2 volume correlated best with Paced Auditory Serial Addition Test (PASAT) (r = -0.47), compared to the 9-Hole Peg Test (r = -0.35) and Timed 25-foot Walk (r = -0.20), demonstrating the importance of including measures other than ambulation.

Baseline T1 volume also correlated better with baseline MSFC (r = -0.41) than EDSS (r = 0.20) with the same pattern among the MSFC components as for T2 volume. Baseline BPF showed similar correlations with clinical measures.

The strengths and patterns of cross-sectional MRI-clinical correlations at years 1 and 2 were similar to baseline. Two-year 9-Hole Peg Test change was the best correlate of T2 volume change (r = -0.26) and T1 volume change (r = -0.17), while 2-year BPF change correlated only with PASAT change.

"If you look cross-sectionally at the beginning of the study, for either 1 or 2 years, there are correlations between total MRI burden and the MSFC that are better than with EDSS," he summarized. "And you see the same pattern for the T1 black hole lesions, which are thought to be more destructive, and for brain atrophy, the total sum of tissue destruction. At each of these time points, the MSFC correlates more strongly than the EDSS."

"These are correlations at the beginning, middle and end of the study. If you look at change over 2 years, you see largely the same patterns but the correlations are weaker, largely because most patients typically do not change much in 2 years so it is hard to find a correlation. The pattern is the same but the strength of the correlation is weaker," he added.

References

1. Sorensen PS, Koch-Henriksen, Ross C, et al. Neutralizing antibodies against interferon (IFN)-beta reduce the clinical effect in relapsing-remitting multiple sclerosis. Presented at the 7th Annual Meeting of the Americas Committee for Treatment and Research in Multiple Sclerosis and the 18th Congress of the European Committee for Treatment and Research in Multiple Sclerosis, September 18-21, 2002, Baltimore, Maryland. Abstract 24.
2. Bertolotto A, Malucchi S, Sala A, et al. Differential effects of three interferon betas on neutralizing antibodies in patients with multiple sclerosis: a follow-up study in an independent laboratory. J Neurol Neurosurg Psychiatry. 2002;73:148-153.
3. PRISMS-4: Long-term efficacy of interferon beta-1a in relapsing MS. PRISMS Study Group. Neurology. 2001;56:1628-1636.
4. Neutralizing antibodies during treatment of multiple sclerosis with interferon beta-1b. The IFNB Multiple Sclerosis Study Group. Neurology. 1996;47:889-894.
5. Comi G, Filippi M, Barkhof, et al. Effect of early interferon treatment on conversion to definite multiple sclerosis: the ETOMS Study 4-year results. Presented at the 7th Annual Meeting of the Americas Committee for Treatment and Research in Multiple Sclerosis and the 18th Congress of the European Committee for Treatment and Research in Multiple Sclerosis, September 18-21, 2002, Baltimore, Maryland. Abstract 23.
6. Munschauer F. Selecting high-risk patients for early treatment. Presented at the Satellite Symposium "Defining Factors That Impact Efficacy in the Treatment of Relapsing-Remitting Multiple Sclerosis" held September 19, 2002 during the 7th Annual Meeting of the Americas Committee for Treatment and Research in Multiple Sclerosis and the 18th Congress of the European Committee for Treatment and Research in Multiple Sclerosis, Baltimore, Maryland.
7. Jacobs LD, Beck RW, Simon JH, et al. Intramuscular interferon beta-1a therapy initiated during a first demyelinating event in multiple sclerosis. N Engl J Med. 2000;343:898-904.
8. Ross C, Clemmesen KM, Svenson M, et al. Immunogenicity of interferon-beta in multiple sclerosis patents: influence of preparation, dosage, dose frequency, and route of administration. Danish Multiple Sclerosis Study Group. Ann Neurol. 2000;48:706-712.
9. Randomised double-blind placebo-controlled study of interferon b-1a in relapsing/remitting multiple sclerosis. PRISMS Study Group. Lancet. 1998;352:1498-1504.
10. Rice G for the PRISMS Study Group. Interferon-neutralizing antibodies reduce clinical and magnetic resonance imaging efficacy in multiple sclerosis patients treated with interferon b-1a (Rebif): observations from the PRISMS 4-year extension study [abstract]. Ann Neurol. 2000;48:477.
11. Trojano M, Paolicelli D, Ligouri M, et al. Interferon-b treatment in relapsing-remitting multiple sclerosis: results of an observational study in southern Italy. Presented at the 7th Annual Meeting of the Americas Committee for Treatment and Research in Multiple Sclerosis and the 18th Congress of the European Committee for Treatment and Research in Multiple Sclerosis, September 18-21, 2002, Baltimore, Maryland. Poster Presentation 311.
12. Carra AJ, Onaha P, Sinay V, et al. Relapsing-remitting multiple sclerosis therapy experience in Argentina. Presented at the 7th Annual Meeting of the Americas Committee for Treatment and Research in Multiple Sclerosis and the 18th Congress of the European Committee for Treatment and Research in Multiple Sclerosis, September 18-21, 2002, Baltimore, Maryland. Poster Presentation 152.
13. Comi G, Filippi M, Barkhof F, et al. Effect of early interferon treatment on conversion to definite multiple sclerosis: a randomised study. Lancet. 2001;357:1576-1582.
14. Lublin F, Cutter G, Baier M. The role of exacerbations in persistent impairment in MS. Presented at the 7th Annual Meeting of the Americas Committee for Treatment and Research in Multiple Sclerosis and the 18th Congress of the European Committee for Treatment and Research in Multiple Sclerosis, September 18-21, 2002, Baltimore, Maryland. Abstract 20.
15. Confavreux C. Relapses are not an important cause of disability. Presented at the 7th Annual Meeting of the Americas Committee for Treatment and Research in Multiple Sclerosis and the 18th Congress of the European Committee for Treatment and Research in Multiple Sclerosis, September 18-21, 2002, Baltimore, Maryland. Abstract 21.
16. Confavreux C, Vukusic S, Moreau T, Adeleine P. Relapses and progression of disability in multiple sclerosis. N Engl J Med. 2000;343:1430-1438.
17. Bagnato F, Jeffries N, Ohayon J, et al. A 36-month longitudinal study on the evaluation of the effect of interferon beta in the duration of black holes in multiple sclerosis. Presented at the 7th Annual Meeting of the Americas Committee for Treatment and Research in Multiple Sclerosis and the 18th Congress of the European Committee for Treatment and Research in Multiple Sclerosis, September 18-21, 2002, Baltimore, Maryland. Abstract 8.
18. Cohen JA, Goodman AD, Heidenreich FR, et al. Relationship between the MS functional composite and MRI in IMPACT. Presented at the 7th Annual Meeting of the Americas Committee for Treatment and Research in Multiple Sclerosis and the 18th Congress of the European Committee for Treatment and Research in Multiple Sclerosis, September 18-21, 2002, Baltimore, Maryland. Poster Presentation 5.
19. Cohen JA, Cutter GR, Fischer JS, et al. Use of the multiple sclerosis functional composite as an outcome measure in a phase 3 clinical trial. Arch Neurol. 2001;58:961-967.