Optimizing Treatment and Assessment of Clinical Outcomes in 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.
Donald E. Goodkin, MD, Medical Director UCSF/MT Zion Multiple Sclerosis Center and Associate Professor of Neurology, Department of Neurology, University of California, San Francisco
The combined meeting of ECTRIMS and ACTRIMS in Basel Switzerland convened multidisciplinary experts from around the globe to share data and thoughts relevant to tissue destruction and repair and new concepts of immune intervention for multiple sclerosis (MS). More than 2130 participants who attended 80 platform presentations, 340 posters, and 5 sponsored satellite symposia.
Dr. Emmanuelle Waubant reported serum levels of matrix metalloproteinase-9 (MMP-9) are higher and serum levels of tissue inhibitor of matrix proteinase-1 (TIMP-1) are lower the month before the appearance of new gadolinium enhancing (Gd+) MRI lesions in patients with relapsing-remitting MS [Neurology 1999;53:1397-1401]. In a pilot study of 7 patients with RRMS, monthly serum levels of MMP-9 were similar for 6 months before and during therapy with interferon beta-1a but serum levels of TIMP-1 were significantly increased after initiating therapy. If these provocative findings are confirmed by others, serum levels of MMP-9 and TIMP-1 may provide readily accessible surrogate markers of disease activity and a novel means of monitoring response to therapy.
The complexities involved in measuring T1- and T2-weighted MRI lesions were reviewed by Dr. Donald Paty. Despite these complexities, MRI remains a most sensitive measure of disease activity and is accepted as a secondary outcome measure for clinical trials of promising therapies. Measures of T1 contrast and magnetization transfer are more specific for axonal density and demyelination than T2 measures and this may ultimately persuade investigators that MRI may be used as a primary outcome in clinical trials of relapsing-remitting and secondary progressive MS. Several investigators have observed MTR and measures of T1 relaxation are reduced in new Gd+ lesions and recover gradually following resolution of enhancement in residual T2-weighted lesions. This is relevant because MTR and various measures of T1 relaxation provide relatively specific measures of axonal density and demyelination within new focal MRI lesions. Since interferon beta reduces the number of new Gd+ lesions, Dr. Nancy Richert compared monthly MTR in new Gd+ lesions before and after initiating therapy with interferon beta-1b. Dr Richert observed no difference in the monthly increase MTR after appearance of Gd+ before or during treatment. Dr. Peter Brex independently reported the proportion of new Gd+ lesions that evolved to T1 "black holes" was similar before and during treatment with interferon beta-1b.
Dr. Mariko Kita also observed no difference in monthly increase from baseline MTR in new Gd+ lesions that appeared before and during therapy with interferon beta-1a. However, Dr. Mariko Kita reported recovery of MTR was more rapid during treatment when recovery was measured by the slope of monthly MTRs across 2-5 months. Whether this observation reflects a treatment effect on remyelination or resolution of edema and inflammation is unknown. However, either treatment effect is desirable. Further studies comparing slopes of recovery of monthly MTR in new Gd+ lesions before and during treatment with approved and promising disease modifying therapies are needed.
Dr. Brian Weinshenker reported plasma exchange (PE) may reverse severe neurological disability in corticosteroid refractory attacks of MS and idiopathic inflammatory demyelination. Although only 12 patients with MS were evaluated, the careful design and conduct of this study argue PE is generally well tolerated and the benefits of this therapy were clinically significant. It is encouraging to have a "rescue" treatment for patients with severe attacks of MS who do not respond to intravenous methylprednisolone.
Data indicate the effect of glucocorticosteroids on the rate of new Gd+ MRI lesions is dose-dependent. These data support the use of high-dose intravenous methylprednisolone to treat acute exacerbations of MS but the optimal dose and duration of glucocorticosteroid therapy for acute exacerbations of MS are unknown. Dr. George Katsamkis reported his experience administering methylprednisolone intravenously at doses exceeding 1.5 g/day for 3-5 days for acute MS exacerbations. More than 75% of his patients experienced drug-related adverse events. Although this is worrisome, many will find it difficult to interpret these data because the numbers of patients who required hospitalization, the nature and timing of acute interventions for adverse events, and the number of patients who discontinued therapy were not presented.
Dr. Katsamakis cautioned methylprednisolone administered at doses above 1.5g/day should be administered in setting where complex medical intervention is available. He continues to favor this high-dose methylprednisolone for acute MS exacerbations but presented no data to justify use of this dose vs lower doses of intravenous or oral methylprednisolone.
Dr. Frederick Munschauer reported only 34% of patients enrolled in the Phase III trial of interferon beta-1a for relapsing forms of MS were within 2 standard deviations of normal performance in all spheres of cognition. This is a sobering statistic considering the EDSS scores in these patients at enrollment were less than 4.0. Importantly, interferon beta-1a slowed progression of cognitive impairment during this 2 year study. These observations are consistent treatment effects measured by time to onset of sustained progression of disability and change in the brain parenchymal fraction. These data offer support for the notion that we should routinely question our patients (and their significant others) for symptoms and signs suggestive of cognitive dysfunction, even in the absence of obvious neurological impairment and disability.
A review of clinical outcomes for MS clinical trials was presented by Dr. Christopher Polman. The proposed MS functional composite measure (MSFCM), derived from z-scores of performance on the 25-foot timed ambulation, 9-hole peg test, and paced auditory serial addition test is recognized as a more sensitive, multidimensional quantitative measure than the traditional Kurtzke Expanded Disability Status Scale (EDSS). In general, samples sizes to confidently detect a given treatment effect in MS clinical trials will be smaller with the MSFCM which is more sensitive to change in clinical status than the EDSS. This will be particularly appealing in future trials that compare active therapies.
Dr. Vermersch compared change in EDSS scores over 1 year in patients with mild (EDSS < 3.5) and moderate (EDSS > 3.5) disability. Approximately 33% of patients in each EDSS strata experienced progression of 0.5 or more EDSS points. The reader should interpret these results cautiously because the EDSS is not a linear scale and comparison of the rate of change across different EDSS strata is problematic.
Dr. Oscar Fernandez reported the results of a Phase IV study of weekly intramuscular interferon beta-1a 6.0 MIU. The drug was generally well tolerated for 1 year in this open-label study and 51 of 96 patients remained free of exacerbations. These observations are consistent with that reported in clinical practice.
Our search continues for improved disease modifying therapies. The design and preliminary data from promising pilot trials of combination therapies of interferon beta-1a and glatiramir acetate and interferon beta-1a and azathioprine were reviewed by Dr. Fred Lublin and Dr. Thibault Moreau. These combinations appear to be well tolerated. There is a pressing need to conduct rigorously controlled trials comparing approved, promising, and combination disease modifying therapies.
Although several investigators have reported diffuse atrophy of the corpus callosum correlates with cognitive dysfunction, Dr. Cecelia Borras reported atrophy of the mid-body region of the corpus callosum correlated most strongly with these measures. Surprisingly the correlation between atrophy of the mid- body of the corpus callosum and cognitive dysfunction was most robust in patients with primary progressive MS. However, the location of focal MRI lesions in these patients was not described and this may be relevant because, as noted by Dr. Jacqueline Palace, atrophy and axonal density in normal appearing white matter may reflect Wallerian degeneration resulting from distant focal lesions. A panel discussion on indications and practice of immunomodulating therapies for MS was highly interactive and informative. Surprisingly, not all panelists were comfortable discussing the risk of developing MS in patients who experience monosymptomatic episodes accompanied by 2 contrast enhancing MRI lesions. Most consider a discussion of prognosis to be most appropriate because data clearly indicate the majority patients will meet clinical criteria for definite MS within 10 years after experiencing a monosymptomatic episode [Brain 1988;121:495-503]. Moreover, the majority of those who experience a second attack will do so within 24 months of the monosymptomatic episode. Most panelists and more than two-thirds of the audience were reluctant to initiate a disease modifying therapy after a first monosymptomatic episode. This study and the CHAMPS study conducted in the United States should clarify whether interferon beta-1a delays time to onset of a second event following a monosymptomatic episode accompanied by MRI lesions. Hopefully the results of the Rebif monosymptomatic study will be presented and published as expeditiously as possible.
This forum provides a sample of the presentations made at the combined meeting of ECTRIMS/ACTRIMS. The complete abstracts from the meeting may be found in a Supplement to the September issue of Multiple Sclerosis. The organizers of the first combined meeting of ECTRIMS/ACTRIMS should be congratulated for creating an international meeting that effectively stimulates ideas and projects that will undoubtedly improve our understanding of disease mechanisms and how to most effectively treat MS.
Clinical Outcome Measures for MS
Christopher H. Polman, MD, Professor of Neurology, Free University Hospital, Amsterdam, The Netherlands
The Expanded Disability Status Scale (EDSS) is the most widely used instrument to measure neurologic impairment and disability. Yet it is acknowledged among experts that the instrument has limitations related to standardization, sensitivity, reliability, and inter-rater variability.
The EDSS is an ordinal scale that is heavily biased toward locomotor function, stated Christopher H. Polman, MD, Professor of Neurology, Free University Hospital, Amsterdam, The Netherlands. Impairment and disability are included in the same scale, but they are distinct, he added.
The National MS Society Task Force on Clinical Outcomes/Assessments in MS convened with the goal of developing a new multidimensional, quantitative outcome measure to be used in clinical trials. The Task Force analyzed large datasets and reviewed candidate measures that could show change over time. Measures that were chosen had to be present in at least two datasets.
The recommendation of the Task Force was that the new measure should include three tests: a timed 25-foot walk to measure ambulation (TTW), a nine-hole peg test to measure arm/hand function, and a paced auditory serial addition test (PASAT) to measure cognitive function. A functional composite score derived from these tests is converted into a z-score the MS Composite Score.
Dr. Polman defined a z-score as a standard score that represents the number of standard deviations from the mean of a given population. The z-score indicates how much better or worse a patient is compared with baseline, he observed.
In the retrospective study of the dataset, the MS Functional Composite Measure (MSFC) demonstrated a high reliability, clear correlation with disease duration, and predictive validity. The change in the composite score was predictive of the change in the EDSS in the year to come. In a study reported by Cutter et al. (Brain, 1999), half of the patients had a change in their composite score without any worsening on the EDSS, suggesting that the MSFC has the potential to be more sensitive than the EDSS, noted Dr. Polman.
Depending on how change is defined on a scale, the percentage of people who have a change varies. For example, a study by Schwid et al. showed that 18% of patients had a change on the EDSS over 6 months and 47% of patients had a concurrent change on a composite of TTW and nine-hole peg test, he explained.
Two studies have looked at the correlation between the EDSS and the nine-hole peg test, the PASAT, and the (TTW). Kalkers et al. (1999) studied the EDSS and the PASAT in 240 patients: 110 with relapsing-remitting MS (RRMS), 64 with secondary progressive MS (SPMS), and 66 with primary progressive MS (PPMS). Irrespective of MS phenotype and degree of disability on the EDSS, all measures included in the composite score correlated with the composite. However, discrepancies were found between the measures included in the composite score and the EDSS. Cutter et al. showed that the EDSS was not well correlated with any of the three tests included in the MSFC.
PASAT reflects dimensions that are not reflected by the EDSS. The time to walk (TTW) test correlates well with the EDSS for PPMS and SPMS, but not in RRMS, he said.
The Task Force members are enthusiastic about the MSFC and believe that this measure has the potential to be a more sensitive instrument than the EDSS. The composite score correlates with changes in the EDSS, and it measures additional dimensions. The MSFC needs to be studied prospectively to confirm its reliability, validity, and responsiveness. We can't introduce this score too soon, stated Dr. Polman.
Neuropsychologic Impairment in MS: Assessment and Treatment
Frederick Munschauer, MD, Associate Professor of Clinical Neurology and Internal Medicine, Department of Neurology, State University of New York at Buffalo and Buffalo General Hospital, Buffalo, New York
Neuropsychological dysfunction is present in 45% to 65% of MS patients. Language and short-term memory are relatively spared, however. The pattern and degree of involvement of the various dimensions of neuropsychological function are variable in MS patients. Further, physical impairment does not necessarily correlate with cognitive deficits.
We have all had patients who are relatively unimpaired physically, yet have cognitive deficits, explained Frederick Munschauer, MD, Associate Professor of Clinical Neurology and Internal Medicine, Department of Neurology, State University of New York at Buffalo and Buffalo General Hospital, Buffalo, New York.
The spectrum of neuropsychological function includes: cognitive function, personality, mood, behavior, quality of life, social function, visual/spatial function, and memory.
Cognitive abnormality may be an initial manifestation of MS, but the EDSS does not measure cognitive impairment well, continued Dr. Munschauer. I had a patient with progressive atrophy on MRI over a 6-year period but no change in EDSS. This patient was unable to work and now requires home care. She has cognitive impairment, he told the audience. The MRI may be a better predictor of cognitive impairment than the EDSS. The MSFC includes a sensitive measure of cognitive impairment the PASAT, he added.
Results of neuropsychological testing of patients in the Phase III pivotal Avonex® trial are instructive with regard to how widespread neuropsychological abnormalities are in MS. At baseline, extensive neuropsychological tests in 275 patients with relapsing-remitting MS (RRMS) revealed that only 34% of patients were within 2 standard deviations of normal in all spheres of cognition, and these were minimally impaired patients. Isolated deficits were found in executive functioning (12%) and visual/spatial functioning (27%). Multiple deficits were encountered in 25% of patients at baseline. Two percent would have qualified as having global cognitive impairment, noted Dr. Munschauer. Three sets of neuropsychiatric tests were administered at 6-month intervals throughout the 2-year Avonex® trial: memory/information processing (set A); visual/spatial/execution (set B); and verbal/attention span (set C). A statistically significant difference favoring treatment with Avonex® compared to placebo was seen for set A (p=0.038) and set B (p=0.043), but not for set C. These findings show that verbal ability is relatively spared in patients with MS, as Dr. Munschauer noted earlier, and they imply that Avonex® treatment slowed cognitive impairment in MS patients.
The curves between the treated group and placebo patients diverged at week 52 favoring the treated group for results on the brief cognitive battery of tests given every 6 weeks. On the PASAT, a treatment effect was seen at week 104: a 48% reduction in the ability to perform the tasks on the PASAT was seen in placebo patients compared to those treated with Avonex®. Dr. Munschauer commented that the PASAT is a difficult test for patients to take, and training personnel to administer the test properly can help patients' attitudes and performance.
Although depression was thought to be a side effect of treatment with interferon beta-1b, the Avonex® trial showed no difference between the treated and placebo groups on the Beck Depression Scale, and one patient with MS from the placebo group committed suicide.
In this trial, Avonex® slowed progression in domains of cognitive function known to be frequently compromised in MS. This trial showed that an immunomodulatory agent is effective in slowing neuropsychologic dysfunction as an independent measure of MS disease impact. The results showed internal validation without the EDSS, said Dr. Munschauer.
Dr. Munschauer emphasized the importance of a thorough work-up of cognitive function in MS patients and said that early treatment may have a favorable impact on preserving cognitive function.
Optimizing Treatment of MS with Immunomodulatory Agents
Fred D. Lublin, MD, Professor and Vice-Chairman of Neurology, MCP Hahnemann University, Philadelphia, Pennsylvania
Although we now have disease-modifying agents for the treatment of MS, there is still room for improvement. No major new agents for MS are in clinical trials at the current time, and the best opportunity for improving results rests with combination therapy. Currently available adjunctive agents for potential use with disease-modifying agents attack the inflammatory cascade at various sites. Current studies are evaluating the combination of beta interferon with intravenous (IV) cyclophosphamide, oral cyclophosphamide, methotrexate, mitoxantrone, IV immunoglobulin (IVIG), glatiramer acetate, prednisone, and azathioprine.
"When combining agents, we need to keep safety in mind. Additional toxicity could be induced by combination therapy and a new agent may interfere with the mechanism of action of a disease-modifying drug," said Fred D. Lublin, MD, Professor and Vice-Chairman of Neurology, MCP Hahnemann University, Philadelphia, Pennsylvania.
Dr. Lublin described a trial of combination therapy that is currently being conducted at the MS Center at MCP Hahnemann University, the Mayo Clinic, and Wayne State University to evaluate the safety of combining glatiramer acetate with Avonex®. The study has enrolled 32 MS patients who were treated with Avonex® for 6 months or longer, during which time they underwent three MRI scans. After the addition of Copaxone®, six more MRI scans are planned. MRI is the main measure of change in this study, with the end point being gadolinium- enhancing events.
"We hope to be able to combine these two agents safely," he said. "We know that Avonex® has a profound effect on the disease process. Our hypothesis is that if Copaxone® interferes with the action of Avonex®, a rise in gadolinium enhancement effects will be found," continued Dr. Lublin. If rationale for combination therapy is sound, and if safety is demonstrated, then perhaps there will be more progress in achieving better results, concluded Dr. Lublin.
Measurement of Atrophy
Elizabeth Fisher, PhD, Project Scientist, the Mellen Center for MS Treatment and Research, Cleveland Clinic Foundation, Cleveland, Ohio
Brain Parenchymal Fraction (BPF) has been previously validated as an accurate, reproducible, inter-individually consistent measure of brain atrophy, which is thought to reflect the pathological disease process of multiple sclerosis (MS).
A study presented here showed that measurable atrophy can be detected by BPF in early RRMS in the absence of severe disability, and that progression of brain atrophy can be measured over 1 to 2 years. These findings emerged in a re- analysis of data from the Phase III Avonex® pivotal trial, demonstrating that BPF could be correlated with: black holes (areas of the brain thought to reflect severe pathology), T2 lesions, and overall EDSS score. However, only a weak correlation was observed between BPF and small changes on the EDSS over time.
The Phase III trial included 140 patients with RRMS who were randomized to receive either Avonex® or placebo. Dr. Fisher and her colleagues found a mean decrease in BPF of 0.61% per year in the placebo group. No difference was seen during the first year between treated patients and those receiving placebo, but a difference in BPF was evident over a 2-year time period, with less atrophy in the treated group: a reduction of 0.527 units in placebo patients versus 0.236 in Avonex®-treated patients, a 55% difference (p < 0.00001).
This showed us that we could detect a difference in BPF over time and that this measurement could be a useful tool in clinical trials, explained Elizabeth Fisher, PhD, Project Scientist, the Mellen Center for MS Treatment and Research, Cleveland Clinic Foundation, Ohio.
In introducing Dr. Fisher, Richard Rudick, MD, explained why brain atrophy is important to assess. Although it was shown in the Avonex® data that 70% of placebo patients had a worsened BPF over time, no correlation was found between rate of brain atrophy and the number of relapses over the 2 years.
We had a number of patients with high rates of brain atrophy who did not have a relapse. Thus, the process of brain atrophy can continue without clinical manifestations and this is why it is an important area of focus, he commented. Dr. Rudick is Professor of Neurology, Director of the Mellen Center for MS Treatment and Research and Hazel Prior Hostetler Professor for Neurology, Cleveland Clinic Foundation, and Cleveland, Ohio.
Dr. Fisher said that atrophy can be measured by both regional and global measures. Regional measures are dependent on the physician to position the patient in exactly the same place for each measurement, while this is not true of global measures. Further, global measures reflect whole brain atrophy. BPF is a relative global measure that utilizes fully automated three-dimensional segmentation of the brain in T2-weighted images. The smooth contour of the outer surface of the brain is calculated, as is the total brain parenchymal tissue. Then the ratio of total brain parenchymal volume is divided by the total volume within the outer brain contour to determine the BPF.
Relative measures of atrophy, such as the BPF, offer a number of advantages, continued Dr. Fisher. In cross-sectional studies, normalization with a relative measure reduces variability due to non-disease related differences. In serial studies, normalization can reduce measurement errors due to patient positioning. BPF remains similar in scans and re-scans despite the positioning of the patient, she noted.
Measures of atrophy, however, cannot account for decreases in axonal density. Since MS is a diffuse disease, perhaps the BPF is best used along with Magnetic Transfer Ratio (MTR), she suggested. Further studies are needed to correlate the BPF with other measures of the MS disease process. Among issues for study are the effects of steroids and treatments on BPF and determining clinical correlates of BPF and the predictive value for clinical disability.
Quantitation of T1 and T2 Lesion Load
Donald Paty, MD, Division of Neurology and Department of Diagnostic Radiology, University of British Columbia, Vancouver, Canada
The complexities involved in measuring MS lesions detected by imaging techniques, including enhanced and unenhanced T1 lesions, T2 lesions, and so- called black holes, were elaborated by Donald Paty, MD, Division of Neurology and Department of Diagnostic Radiology, University of British Columbia, Vancouver, Canada. Understanding the interrelationship of these lesions will take a long time but will eventually help us understand the development of MS pathology, he told listeners.
MRI detects lesions that one would expect to be able to measure over time. The majority of the area of a new lesion comprises water. Over time, the lesion is reduced in size and becomes stable until it is reactivated at a later time. Black holes seen on MRI represent more severe pathology. MRI data does not tell the whole story about the pathological process. Information from Magnetic Transfer Ratio (MTR) is more specific in terms of actual pathology, he continued, and should increase understanding of the actual pathology. Axonal loss is a major part of the pathological process but is not measured on MRI. Peak measurements of NAA (N-acetyl aspartate) provide information about axonal loss and can be combined with MTR and MRI to face the challenge of understanding pathology, observed Dr. Paty.
One of the complicating factors is that active lesions do not all act the same way. The majority of lesions shrink over time and become stable, but other lesions are actively changing. A serious confounding factor is that 16% of lesions become confluent with their neighbor lesions over time, or they separate into two lesions. Following these lesions over time is quite complex, Dr. Paty emphasized.
Measurement of black holes on MRI is technically difficult, much more difficult than photon density, he continued. There are many variables. We don't know which ones to measure. Some lesions enhance and some don't. It is not clear whether one needs to measure the total extent of the black hole as seen on the pre- gadolinium scan. A problem in clinical trials is that when a treatment abolishes Gd enhancement it may cause unexpected changes in total measurement, elaborated Dr. Paty.
Proton density or T2 weighted images detect inflammatory components. T1 non- enhanced images are a good measure of severe pathology, including inflammatory acute black holes. It is much more difficult to measure these lesions in the chronic phase, because so many variables are superimposed on inflammatory changes, observed Dr. Paty.
"Interpretation of MRI is complex in terms of pathology. However, MRI does show treatment effects compared to placebo in various clinical trials. Even at 6 months, a proton density scan can reveal a massive decrease in total measurement of disease burden," Dr. Paty said.
Relationship of Regional Axonal Loss in Normal-Appearing White Matter to Distant Lesions
Jacqueline Palace, MD, Consulting Neurologist, Department of Clinical Neurology, Radcliff Infirmary, Oxford University, United Kingdom
An autopsy study of brains of patients with multiple sclerosis (MS) suggests that distant lesions of the hemispheric areas are responsible for axonal loss observed in the normal appearing white matter (NAWM) of the corresponding regions of the corpus callosum (CC). This group of researchers had formerly shown that the size, axonal density, and total number of axons in the CC were reduced in NAWM in brains from MS patients, but the cause of axonal loss was unknown, explained Jacqueline Palace, MD, Consulting Neurologist, Department of Clinical Neurology, Radcliff Infirmary, Oxford, United Kingdom.
Eight brains of MS patients (two with RRMS and six with primary progressive MS [PPMS]) from the Brain Bank at Oxford were studied and compared to eight brains from age- and sex-matched controls. The CC was divided into three sections and the area, axonal density, and total numbers of axons were measured using manual staining techniques.
Brains of MS patients had reduced area, axonal density, and total numbers of axons compared to brains of controls. A 33% decrease in area was found (p=0.004), which was fairly evenly distributed between the three areas of the CC, noted Dr. Palace. Axonal density was reduced in MS brains by about one-third in comparison with control brains, again with a similar distribution through the three areas of the CC. A 54% reduction in the total number of axons was found in MS brains compared to control brains, which was equally distributed between the thirds of the CC. The lesion volume was correlated significantly with the total numbers of axons (p = 0.001).
This study pathologically confirmed a significant reduction of axonal density in the NAWM in addition to tissue atrophy. Measures of atrophy alone underestimate the degree of axonal loss. We found that distant lesions cause axonal loss in NAWM. Our study and other papers are forcing us to think about the effect of Wallerian degeneration or demyelination of the axons, concluded Dr. Palace.
Nikos Evangelou, MD, a colleague of Dr. Palace's at Oxford University, was originally scheduled to deliver this talk, but he did not attend the meeting.
Improvement With Interferon Beta-1a Treatment Seen on Magnetic Transfer Imaging
Mariko Kita, MD, Clinical Instructor, Department of Neurology, University of California at San Francisco, Mt. Zion Multiple Sclerosis Center, San Francisco, California
A small pilot study provided encouraging evidence that treatment with interferon beta-1a (Avonex(r)) favorably influenced the rate of recovery of low-magnetic transfer ratio (MTR) following the appearance of new gadolinium-enhancing (Gd+) lesions. Recovery of low MTR is considered a favorable sign regarding resolution of a relapse.
This is the first indication that treatment with interferon beta-1a not only reduces the number of new focal lesions, as has been previously shown, but may also favorably affect the evolution of MTR abnormalities within these lesions, Mariko Kita, MD, told listeners. Dr. Kita is Clinical Instructor, Department of Neurology, University of California at San Francisco, Mt. Zion Multiple Sclerosis Center, San Francisco, California.
Interferon beta-1a is proven as an effective disease-modifying therapy for relapsing-remitting MS (RRMS), with a dramatic reduction in T2-weighted and Gd+ lesions on MRI. Dr. Kita explained that MTR was used in the pilot study because it provides a more specific imaging tissue marker for irreversible damage in MS lesions compared to T2-weighted sequences, which do not distinguish reversible from irreversible inflammation and edema and axonal loss.
The study reported by Dr. Kita included untreated patients with very early RRMS who participated in a previous natural history study. Patients included in the natural history study underwent monthly neurological exams and MRI scans for up to 5 months. New lesions were detected by T2-weighted and T1-weighted images. MTR was measured in all new Gd+ lesions that became visible before and during therapy. Lesions were monitored for up to 5 months.
Twenty-two untreated patients completed up to 14 monthly MRI scans. Eight of 22 exhibited> 3 lesions during the past six scanning sessions and elected to initiate treatment with interferon beta-1a (6 MIU given intramuscularly every week). Four of the eight patients developed one or more new Gd+ lesions during therapy. The eight patients developed 51 new lesions before therapy and 25 during therapy.
Lesions for three of these patients could be monitored for 2 to 5 months after becoming visible. These patients had a mean EDSS score of 1.5 and mean disease duration of 21.3 months.
The rate of recovery as measured by the slope of MTR was significantly faster during therapy than before therapy (p = 0.026), stated Dr. Kita. Using a crude estimation of median slopes before or after therapy for all patients, no correlation was seen between the slope and the lowest MTR, the slope and the lesion size, or the slope and Gd+ intensity.
She acknowledged several limitations of the study, including its small sample size and brief uneven period of observation, but added that none of these limitations invalidated the study.
To what extent the treatment effect seen with interferon beta-1a represents rapid resolution of microscopic edema versus early remyelination is uncertain. Either benefit could help explain why interferon beta-1a reduces the disease activity in relapsing-remitting forms of MS, she concluded.
The Effect of Interferon beta-1b on the Evolution of New Enhancing Lesions to Hypointense T1 Lesions in Secondary Progressive Multiple Sclerosis
Peter A Brex, MRCP, NMR Research, Queen Square Institute of Neurology, London, United Kingdom
Treatment with interferon beta-1b (Betaseron® [interferon beta-1b]) was found to reduce the number of new Gd+ lesions during the first 6 months of treatment and to reduce the number of hypointense lesions 18 months later. However, the proportion of enhancing lesions which become hypointense does not appear to be altered by interferon beta-1b, explained Peter A Brex, MRCP, NMR Research, Queen Square Institute of Neurology, London, United Kingdom.
Hypointense lesions, i.e. those lesions that become hypointense compared with surrounding white matter on T1-weighted MRI following the resolution of Gd enhancement, are thought to reflect more severe tissue damage, he explained.
Several studies have shown that treatment with interferon beta (1a and 1b) stabilize or reduce lesion load, but it is not clear how interferon beta exerts these effects. It was hypothesized that interferon beta reduces the proportion of hypointense lesions, and this was studied in 125 patients with RRMS at seven European sites in a double blind, placebo-controlled trial reported by Dr. Brex.
Patients treated with interferon beta-1b (n = 64) developed 179 new lesions over 6 months compared to 500 in placebo-treated patients' (n = 61). The active-treatment group developed fewer enhancing lesions per patient compared to placebo: 2.8 versus 8.2. At follow-up, fewer hypointense lesions were identified in the treated group per patient compared to the placebo group: a mean of 0.36 per patient versus 1.15 per patient, respectively. However, the mean percentage of enhancing lesions that developed into hypointense lesions was similar in the two groups: 23% in treated patients and 19% in controls.
The Rebif Monosymptomatic Study
Giancarlo Comi, MD, Professor of Neurology, University of Milan, Italy
Whether to initiate disease-modifying treatment for patients with a first episode suggestive of MS is an important question. Treatment with the three currently available disease-modifying agents is known to slow the progression of MS and reduce the relapse rate in patients with relapsing-remitting disease, but it is an open question whether treatment should be initiated at the very first sign of impending MS. Thus, attendees were eagerly anticipating results of the Rebif trial, which enrolled 311 patients within 3 months of a first attack suggestive of a demyelinating disease and a brain MRI with positive findings. However, results were not presented. Instead, the trial design and characteristics of enrolled patients were discussed by Giancarlo Comi, MD, Professor of Neurology, University of Milan, Italy.
Patients mean age at baseline was 28.7 years (range, 18 to 46 years). The most common symptoms at presentation were sensory (48.3%), motor (34.1%), and visual (31.5%). Clinical signs of multifocal central nervous system (CNS) involvement were observed in 27.1% of patients. Examination of cerebrospinal fluid showed intrathecal synthesis of immunoglobulin in 82% of patients.
The median numbers of total T2 brain MRI lesions was 25; infratentorial T2-weighted lesions, 1; and enhancing lesions, 1. One or more enhancing lesions were detected in 57.1% of patients. One or more areas of abnormal signals in T2-weighted images of the spinal cord were present in 84% of patients with spinal cord syndrome. Patients with multifocal disease tended to have a higher lesion load than those with unifocal presentation, and no major differences were seen in the site of lesions in patients with unifocal disease. Patients with two more enhancing lesions tended to have a higher number of T2 lesions.
Nine percent (28 patients) terminated the trial at 24 months. Of the total 311 patients, 83.3% experienced a second exacerbation by the end of the trial.
High-Dose Intravenous Methylprednisolone in MS
George Katsamakis, MD, MS Center, Rush Presbyterian St. Luke's Hospital, Chicago, Illinois
A prospective study found that high-dose methylprednisolone was associated with more frequent and severe adverse events than reported in previous studies by other investigators. The rate of adverse reactions (AR) was 77% among 204 patients with exacerbating MS. Fifty percent of patients reported insomnia, and 30% had psychiatric events. Three quarters of the patients with insomnia required interventions, as did 89% of those with psychiatric reactions. Cardiac events were reported in 11% of patients, greater than 50% of whom required some sort of interventions, including cardiac consultation, repeat EKG, or angiography. Other ARs were infection (19%), hyperglycemia (12%), and gastrointestinal problems (8%). H2 blockers were given prophylactically, which probably prevented some GI distress, according to Dr. Katsamakis. In previous studies of high-dose IV methylprednisolone, GI problems occurred in as many as 50% of patients.
Methylprednisolone at doses of 1.5 to 7.5g over 3 to 5 days is a well-accepted treatment for exacerbating MS. However, recent studies suggest that mega-doses (10 g over 5 days) are superior in reducing the rate of new MRI-enhancing lesions, which correlate with disability and brain atrophy, explained George Katsamakis, MD, MS Center, Rush Presbyterian St. Luke s Hospital, Chicago, Illinois.
Dr. Katsamakis said that in the study, each dose of IV methylprednisolone was administered over 20 to 30 minutes, with a 12-hour interval. There was some variation in dose, but >95% of patients received >1.5 g/day. Only a handful of patients received less, he noted.
At our institution, we favor high-dose methylprednisolone for patients with exacerbating MS, because it appears to be superior to standard doses of the drug. These results suggest that careful monitoring of high-dose IV methylprednisolone is warranted, and it would be prudent to use the high-dose treatment in settings where complex medical intervention is available, Dr. Katsamakis told the audience.
Plasma Exchange Reverses Severe Neurological Disability in Corticosteroid- Refractory Attacks of Idiopathic Inflammatory Demyelinating Disease of the CNS
Brian G. Weinshenker, MD, Mayo Clinic, Rochester, Minnesota
A study of 22 patients with acute, severe attacks of MS or other idiopathic inflammatory demyelinating diseases (IIDs) found that plasmapheresis (plasma exchange) can provide dramatic and rapid improvement as monotherapy in 42% of patients who failed fail to respond to corticosteroids.
"This study represents the culmination of 4 and one half years of work. MS patients rarely fail to respond to corticosteroids and experience permanent disability or death. There are no proven treatments in this setting," explained Brian G. Weinshenker, MD, Mayo Clinic, Rochester, Minnesota.
The study was a randomized, sham-controlled, crossover trial that included two groups of patients: those with clinically definite or lapsed secondary progressive MS (group A) or those with other IIDDs (group B) of 3 weeks to 3 months' duration. All patients had acute severe neurological deficits that included deficits in cognition, consciousness, language, or strength, and all failed to respond to a course of intravenous (IV) steroids (a minimum of 500 mg of methylprednisolone for 5 days).
Patients were randomized to active plasma exchange (n = 11) or sham exchange (n = 11) , comprising seven treatments over 14 days. If their treatment was considered successful, they went on to follow-up. If not, they were crossed over to the other treatment arm for 2 more weeks, and then evaluated. Follow-up was for 6 months. No or mild response was considered a failure. Moderate response included obvious impact on functions, and a marked response involved major functional improvement. The mean age was 42 years, and there were seven males and 15 females. Twelve patients had MS and 10 had other IIDDs.
Of the 11 patients who received active treatment first, five were deemed successful and six failed and crossed over to sham treatment, with no success.
Of the group randomized initially to sham treatment, one patient was considered a success, two patients died, and eight failures were crossed over to active treatment. Of those, three were successes and five failed. A total of nine of 22 patients were deemed successes, eight of whom had received active plasma exchange. Excluding three patients who died, the success or improvement rate was 8/19 (42%) compared to 1/17 (5.9%) in the sham group. Overall, plasma exchange was well tolerated and improvement was sustained. The only major side effect was anemia in eight patients who received active treatment. No predictor of success could be identified.
Dr. Weinshenker showed videotape of one of the successfully treated patient both before and after under-going plasma exchange. The difference in this responder was dramatic in terms of motor function.
Dr. Weinshenker was enthusiastic about the results in patients who suffered from severe neurological deficits and were able to regain function for whom there is no alternative treatment. He said that plasma exchange should be reserved for patients whose severe attacks do not respond to corticosteroids, and added that further study is needed.
Panel Discussion on Indication and Practice of Immunomodulatory Treatment in Europe and North America
A. J. Thompson, MD, Institute of Neurology, Queen Square, London, United Kingdom Michel Clanet, MD, Hopital Purpan, Toulouse, France
Giancarlo Comi, MD, Professor of Neurology, University of Milan, Milan, Italy Sten Frederikson, MD, Karolinska Institute, Division of Neurology, Stockholm, Sweden
D.W. Paty, MD, Division of Neurology, University of British Columbia, Vancouver, Canada
Chris Polman, MD, Professor of Neurology, Free University Hospital, Amsterdam, The Netherlands
George Rice, MD, London, Ontario, Canada
Richard Rudick, MD, Professor of Neurology, Director of the Mellen Center for MS Treatment and Research, Cleveland Clinic Foundation, Cleveland, Ohio
Jerry S. Wolinsky, MD, Professor of Neurology, University of Texas Southwestern Medical School, Houston, Texas
A panel of experts was presented with a hypothetical case history of a patient with MS. As the patient's disease progressed, the panel debated the timing of initiating immunomodulatory and other treatments.
Case: The hypothetical patient was a 26-year-old woman with sudden onset of blurred vision, decreased vision in her right eye, and an otherwise normal examination. MRI scan revealed two contrast-enhancing lesions. This episode represented the patient's first attack.
Several panelists agreed in this situation, they would initiate intravenous or oral methylprednisolone. Half of the panelists said they would discuss with the patient the probability that the attack was the first manifestation of MS, explain the progressive nature of the disease, and introduce the idea of using immunomodulatory therapies at this stage.
A few panelists felt it was too early and that a second episode was needed before starting this discussion. "The MRI indicates that the patient's disease may progress sooner than might be expected from her symptoms. I would discuss early treatment with her, even though we don't have good evidence for treatment at this early stage. It is disappointing that the results of the Rebif monosymptomatic trial were not presented here in Basel," stated Jerry S. Wolinsky, MD, Houston, Texas.
Panelists Michel Clanet, MD, Toulouse France, and George Rice, MD, London, Ontario, Canada, agreed that it was "deeply troubling" not to have data from the early intervention trial.
"My patients want a diagnosis. Two gadolinium-enhancing lesions plus optic neuritis strongly suggest that the patient has MS. Our patients come into our offices having read about the new treatments for MS, and I believe this is the time to discuss the disease and the availability of therapies," stated Richard Rudick, MD, Professor of Neurology, Director of the Mellen Center for MS Treatment and Research, Cleveland Clinic Foundation, Cleveland, Ohio.
Although the criteria for MS at present include at least two episodes, at least one panelist believes that there is no sense in waiting to treat this patient. "Why should we have to wait until this patient has a second attack. I would exclude other disease and consider disease-modifying therapy," said Giancarlo Comi, MD, Professor of Neurology, University of Milan, Italy.
"Deep in our hearts we realize this patient has a relatively poor prognosis. We would like to start disease-modifying therapy, but access to the drug in Canada depends on arbitrary criteria from clinical trials. If access were not a problem, theoretically we should probably begin treating as early and aggressively as we can," commented Donald W. Paty, MD, Division of Neurology, University of British Columbia, Vancouver, Canada.
"What is in our hearts and what is in the literature are two different things," A.J. Thompson, MD, reminded attendees. Dr. Thompson is from London, United Kingdom.
An informal poll of the audience showed that less than one-third would initiate a discussion of disease-modifying therapy at this time, and 95% said they would not encourage active immunomodulating therapy. The overwhelming majority voted to treat with steroids at this point. Six panelists said that they would tell the patient that MS is a probable diagnosis and the likelihood is high that she will be diagnosed with MS in the future, while four panelists said they would introduce the possibility that she has MS but not discuss probability.
"My experience is that at first, patients reject therapy and don't want to believe that the diagnosis of MS is correct until follow-up MRI scans show the patient that the lesions do not go away. Patients may come in to the doctor's office with information and want a diagnosis, but there is a discrepancy between what they say they want and what they actually believe," commented Dr. Wolinsky.
"Physicians' attitudes toward early treatment influences patients. The doctor/patient interaction is complex and important. I can't predict a course of disease for my patients. I have beliefs about early therapy, but no strong evidence yet. The patient should definitely be monitored at this stage," added Dr. Rudick.
Next, the panel considered the following developments: Nine months later, the patient has a second episode with numbness in the left leg and abnormal symptoms in the right eye. Several new T2 abnormalities are evident on MRI.
Sten Frederikson, MD, stated that with new evidence of active disease, he would definitely discuss disease-modifying therapy with the patient. He would also do a spinal tap. Other experts disagreed with him and said that a spinal tap provides no new information.
"In the optic neuritis trial, the strongest predictor of conversion was the number of lesions on MRI. A spinal tap did not add information. This case is clear-cut--the patient has both MRI evidence of new lesions and new symptoms. She is definitely a candidate for disease-modifying drugs," stated Dr. Rudick.
"In the optic neuritis trial, vague neurological symptoms that don't fulfill the diagnostic criteria for MS were as strong a predictor for eventual MS as MRI scan. Vague events many times are 'real'. I look for a second event that may be vague," added Dr. Paty. "If you wait too long to treat, the horse is out of the barn.
In early stages, the disease is inflammatory and we have disease-modifying therapies."
Next, the patient was started on interferon beta. Ten months later, she had evidence of transverse myelitis. Six months after that, the transverse myelitis is not completely resolved and a new INO is present.
"At this point, we are on thin ice or no ice about knowing what to do. The next step is combination therapy, and we need clinical trials to learn how best to combine the available drugs," stated Dr. Rudick.
Among the adjunctive drugs that panelists suggested were mitoxantrone, cyclophosphamide, and azathioprine. In general, the MS experts agreed that the present data are strongest for mitoxantrone as add-on therapy, but that further study is needed.
A new consideration for heroic treatment in patients with severe MS attacks that do not respond to treatment is plasma exchange, reported by Brian Weinshenker, MD, at this meeting. More data are needed to support use of plasmapheresis, but this is an approach for patients with severe, non-responding disease.
MRI Analysis of Corpus Callosum in MS: Association with Cognitive Impairment
Cecilia Borras, MD, Clinical Neurology and MS Unit, Hospital Vall d'Hebron, Barcelona, Spain
A MRI study comparing the corpus callosum (CC) of 21 MS patients and 21 age- and sex-matched controls showed that the mid-body region of the CC had the strongest correlation with cognitive impairment. It has previously been shown on MRI that global atrophy of the CC is associated with cognitive impairment, significant axonal loss, and a reduction in the area of the rostrum and the mid-body.
"The damage in the mid-body of the CC could reflect impairment in the transference of complex functions of the posterior-associated cortex temporal/parietal area," said Cecilia Borras, MD, Clinical Neurology and MS Unit, Hospital Vall d'Hebron, Barcelona, Spain.
Of the 21 MS patients, 11 had RRMS, 5 secondary progress were matched for education. Neuropsychiatric test were administered, and a cognitive performance standard was set at 2 standard deviations (SD) below the mean from the performance of controls. MRI scans were performed as well.
At baseline, mean EDSS was 4.2 (range, 0-8.5). Mean onset of disease was 10.5 years (range, 2-21 years). Eleven MS patients (54%) had cognitive impairment.
Significant differences were observed between unimpaired and cognitively impaired MS patients in the interior mid-body of the CC (p < 0.05), but no significant differences were seen in other CC regions. Among phenotypes of MS, significant atrophy in the mid-body of the CC was seen in PPMS patients compared to relapsing remitting MS (RRMS) patients.
Avonex® in MS: Comparison between Patients with Mild and Moderate Disability
P. Vermersch, MD, Department of Neurology, CHH University of Lille, Hopital St. Philibert, Lille and Region Nord-Pas de Calais-Picardie, France (on behalf of the Group for Study of MS)
One-year follow-up of 144 patients treated with Avonex® showed that patients with both mild and moderate disability, as reflected by EDSS scores, obtained similar treatment benefits. Most patients remained stable during therapy and early failures were not more common in the more disabled patients.
Patients were divided into two groups. Group 1 included 94 patients (designated as mild MS) with a baseline EDSS <3.5; Group 2 included 23 patients (designated as moderate MS) with baseline EDSS scores >3.5.
The mean EDSS in Group 1 was 2.2 and in Group 2, 4.6. There were six (7%) dropouts in Group 1 and five (10%) in Group 2. Dropouts were attributed to early failure, depression, deaths, flu-like symptoms, and unknown causes.
At 1-year follow-up there were no significant differences between Groups 1 and 2 for relapse rate, improvement in EDSS, and clinical response. At 1 year, relapse rates were 0.86 and 0.9. About half of both groups remained stable: 55% and 51%, respectively. The EDSS improved by at least .05 in 27 (31%) of Group 1 and 13 (29%) of Group 2. The EDSS decreased by at least .5 in 13 (15%) of Group 1 and 9 (20%) of Group 2. The EDSS increased by at least 1 point in 16 (18%) of patients in Group 1 and 6 (13%) of Group 2, and a 1-point decrease in EDSS was seen in 9 (10%) of patients and 4 (9%) of patients, respectively.
The author said that longer-term follow-up is needed with 2- and 3-year intervals, as well as analysis of sustained deterioration or improvement on EDSS persisting for at least 6 months.
"Comparing these two different groups in terms of change on EDSS remains questionable, because the groups were not matched by EDSS score and EDSS is not a linear scale. We don't know if a 1-point increase in EDSS has the same impact and influence on quality of life in patients with mild and moderate disability," said P. Vermersch, MD, Department of Neurology, CHH University of Lille, Hopital St. Philibert, Lille and Region Nord-Pas de Calais-Picardie, France.
Treatment of RRMS with Avonex(r): A Phase IV Open-Label, Multicenter Study
O. Fernandez, MD, Neurological Service, Hospital University Carlos-Haya, Malage, Spain
The safety and efficacy of Avonex® shown in a pivotal Phase III study was reproduced in a post-marketing, open-label study. "We used a prospective design with a common protocol and we verified the efficacy and safety of Avonex®. An open-label study is susceptible to bias, and our results should be interpreted with caution. Nevertheless, they are reassuring," said O. Fernandez, MD, Neurological Service, Hospital University Carlos-Haya, Malaga, Spain.
Ninety-six patients with RRMS were treated with weekly Avonex® 6 MUI intramuscularly (IM) during a period of 10.2 months. There were 37 males and 56 females. Forty patients were treated at a center in Malaga, 38 in Barcelona, and 18 in Sevilla. Mean age of onset of disease was 26.7 years. Mean age at the beginning of treatment was 35.6 years. Mean evolution time of disease was 9 years. The annualized rate of exacerbation the year before treatment was 1.64.
Following a year of treatment, this rate was reduced to 0.5, corresponding to a reduction of 57.1% in exacerbation rate. Fifty-one percent of patients remained exacerbation-free during treatment with Avonex®.
At the onset of the study, the mean EDSS was 2.9; at the end of the study, the mean EDSS remained at 2.9. "This shows that the disease stabilized during treatment," reported Dr. Fernandez.
Avonex(r) was well tolerated in the post-marketing trial. The most frequent adverse events were asthenia (45.1%), fever (42.9%), malaise (34.1%), fatigue (20%), and local pain (19.0 %). All patients remained on study, with no dropouts.
ERAZIMUS: A Pilot Study of Safety for the Combination of Azathioprine and Avonex®
Thibault Moreau, MD, Department of Neurology, Hopital de la Croix-Rouge, Lyon, France
An open-label pilot trial confirmed the biological and clinical safety and tolerance of the combination of interferon beta-1a (Avonex®) and azathioprine in RRMS. Both drugs have been proven effective in the treatment of RRMS, and the safety study paves the way for the study of efficacy of the combination.
Thirty patients already receiving azathioprine for at least 6 months were enrolled in the trial. Ten subjects were each assigned to one of three different dose groups: 50 mg, 100 mg, and 150 mg. After enrollment, patients received weekly injections of Avonex® 6 MIU for 4 months. At baseline, the three groups were comparable for age, gender, disease duration, and disability. The mean duration of azathioprine treatment at baseline was 4 months.
Major side effects were flu-like syndrome: 9 patients in Groups 1 and 2 (50 and 100 mg), 8 in Group 3 (150 mg). Minor viral infections were seen in some patients, especially those of the respiratory tract. One woman in Group 3 had probable cytomegalovirus infection, "but the relationship between this and the two drugs is questionable," noted Thibault Moreau, MD, Department of Neurology, Hopital de la Croix-Rouge, Lyon, France.
In Group 1, four relapses were treated with steroids; three were treated with steroids in Group 2, and none in Group 3. "The high relapse rates in Groups 1 and 2 may be related to the frequent follow-up, or to the decrease in azathioprine dose prior to inclusion in the study. The usual dose is 150 mg," observed Dr. Moreau.
No increase in disability was seen during the study, and there was no change in leukocyte levels, liver enzymes, neopterin levels (except for an increase on day 3), or 6-thioguanine nucleotide. "The levels of these markers of therapeutic activity were as expected if each therapy had been given separately," he said. (Neopterin level is a marker for Avonex® therapy and thioguanine is a marker for azathioprine.)
Magnetic Transfer Analysis of Contrast-Enhancing Lesions in RRMS: Effect of Interferon beta-1b and Intravenous Methylprednisolone
Nancy D. Richert, MD, Laboratory of Diagnostic Radiology Research, National Institute of Health, Bethesda, Maryland
A small study of eight subjects showed that the magnetic transfer ratio (MTR, a technique that quantitates demyelination in MS lesions) in the normal appearing white matter (NAWM) of RRMS patients did not differ significantly from the MTR of NAWM in healthy controls.
"It is possible that this reflects short disease duration in the patients with MS," noted Nancy D. Richert, MD, Laboratory of Diagnostic Radiology Research, National Institute of Health, Bethesda, Maryland.
The study found that a reduction in MTR occurred as early as 12 months prior to contrast enhancing in the region of interest in contrast-enhancing lesions (CEL) compared to NAWM. At the time of contrast enhancement, the reduction in MTR (28%) was similar in all three groups of CEL. No statistically significant difference in the rate of lesion recovery (as determined by an increase in MTR) was seen on monthly scans between baseline CEL and CEL that occurred on interferon treatment. Steroid treatment, however, significantly increased MTR at month 1 and month 2 after enhancement, and the difference remained statistically significant when the entire 12-month post-enhancement contrast period was considered (p=0.002).
Four healthy controls and four newly diagnosed MS patients were included in the study. Patients were treated with interferon beta-1b 8 MIU subcutaneously every other day. During baseline clinical relapses, patients were treated with intravenous methylprednisolone (IVMP) 1 gm/day for 5 days without oral taper. Contrast-enhancing lesions (CEL) that developed during a crossover trial with interferon beta-1b were followed in four newly diagnosed patients with RRMS. The MTR of 109 CEL at baseline, were compared to the MTR of 40 CEL that developed during interferon beta-1b treatment and to 76 CEL that occurred during baseline clinical relapses requiring IVMP.
"CEL which develop at the same time in the same location show considerable heterogeneity in MTR prior to and after contrast enhancement. The improved recovery toward normal MTR compared to untreated baseline CEL in those treated with IVMP may be due to suppression of the inflammatory response," observed Dr. Richert. "MTR may provide insight into the pathophysiology of MS lesions and be useful for evaluating therapeutic response," she added.
Measurements of MMP-9 and TIMP-1 in RRMS
Emmanuelle Waubant, MD, Mt. Zion MS Center, University of California, San Francisco, California
A study suggests that interferon beta 1-a (Avonex®) may exert its action in RRMS partially via an effect on matrix metalloproteinases (MMPs) enzymes which are thought to mediate transmembrane migration of active T-cells and macrophages into the central nervous system (CNS) compartment. During 6 months of Avonex® treatment, median levels of matrix metalloproteinase (MMP-9) did not change, while levels of tissue inhibitor of matrix proteinase-1 (TIMP-1) were more than 50% higher during treatment compared to baseline.
It has been shown that serum levels of MMP-9 are higher and levels of TIMP-1 are lower in RRMS the month before new gadolinium-enhanced (Gd+) lesions are evident on MRI Note: inadequate citation (Waubant, in press). In vivo, Avonex® dramatically decreases the formation of new Gd+ lesions on brain MRI; in vitro, Avonex® down-regulates short-term secretion of MMP-9 and migration of T-lymphocytes through basement membrane equivalents.
The study was conducted in seven patients with RRMS receiving weekly IM injections of Avonex® 30 mg. Patients underwent six monthly MRI scans before and during treatment. Patients had developed three or more gadolinium enhanced (Gd+) lesions on their last six monthly MRI scans. Patients were allowed to take IV methylprednisolone during clinically confirmed exacerbations.
Median MMP-9 levels were similar 6 months before Avonex® compared to treatment months 1 to 6 and months 3 to 6. However, median TIMP-1 levels were 50% higher during treatment months 1 to 6 compared to baseline and 67% higher during months 3 to 6.
"It is not clear whether the effect of Avonex® is a direct effect on TIMP-1 regulation or whether it is an indirect effect of lowering lesion formation that is associated with low TIMP-1," said Emmanuelle Waubant, MD, Mt. Zion MS Center, University of California, San Francisco, California. "Our study did not assess whether MMPs or TIMPs are modulated by interferon beta-1a therapy. In the future, it may be important to develop a ratio of MMP: TIMP activity that may better reflect the functional balance," she added.
Preliminary studies showed that short-term treatment with interferon beta-1b (Betaseron®) decreased IL-2-induced secretions in MMP-9 in lymphocytes and migration of these T-cells through basement membrane equivalents. It has been suggested that effects of interferon beta in MS may be partly related to these effects and to decreased migration of these inflammatory cells to the central nervous system compartment.
"Although our sample size was limited, our findings with Avonex® are different from the short-term, in vitro Betaseron® study. More studies are needed," said Dr. Waubant.
Concordance Between QOL Instruments and Disability
Didier Vernay, MD, Department of Neurology, Gabriel Montpied Hospital, Clermont- Ferrand, France
Multiple sclerosis (MS) has a dramatic effect on quality of life (QOL) compared to a healthy population and to people with other chronic diseases. Physical, psychological, and social dimensions of QOL suffer enormously, especially during the early stages of the disease. This study was undertaken to compare QOL before and after treatment with interferon beta-1a (Avonex®) in patients with a low to moderate EDSS <5. Data were presented at the meeting on the first 78 patients (a total of 106 were enrolled) for whom QOL data were available prior to the initiation of interferon beta-1a.
Preliminary data clearly showed a reduction in scales measuring all dimensions of QOL.As might be expected, the subgroup of patients with the higher EDSS scores (2.5 to 5) had a worse QOL compared to those with an EDSS score of 0 to 2.5 for mental, sleep, and social scales. Further, the study showed that patients with a higher EDSS score have pain more frequently and with more intensity than those with the lower scores. Also, those with the higher EDSS scores had a lower level of energy compared to the group with lower scores.
These findings are consistent with those of previous studies, including a Canadian study that showed an early decrease in QOL in patients with an EDSS score of <3. The study provides a benchmark for QOL before interferon treatment. Markers such as fatigue and pain are important to assess prior to treatment, because they are both potential side effects of interferon beta, said Jean- Francois Chermann, MD, Fondation St. Joseph, Paris, France for the MS interferon beta-1a (interferon b-1a) Avonex® Quality of Life French Study Group.
A second study on QOL showed that the Sclerose en Plaque (SEP) 59, the United Kingdom Neurological Disability Scale (UKNDS), and the EDSS had good concordance. "This study validates the tools that can be used to assess disability under long-term therapies," explained Didier Vernay, MD, Department of Neurology, Gabriel Montpied Hospital, Clermont-Ferrand, France.
A total of 104 patients with relapsing-remitting MS from 27 centers in France completed the SEP-59, which is a translation and adaptation of a scale used in the US (the MSQOL scale), and the UKNDS scale. Results showed that all patients declared a decrease in QOL, and results were concordant with the EDSS for most areas. Dr. Vernay said that a more precise definition for certain items on the UKNDS, like swallowing problems, would further improve correlation between scales.
Avonex®: The Lived Experience
Colleen Miller, DNS, RN, MS Center, State University of New York, Buffalo, New York
The experience of undergoing treatment with Avonex® was documented in extensive (1 to 3 hours) interviews with 20 relapsing patients (eight women, seven men, ages 28 to 55 years). "These people were selected for inclusion in the study because they were articulate, cognitively intact, and willing to share their experiences," explained Colleen Miller, DNS, RN, MS Center, State University of New York, Buffalo, New York.
Four major themes were identified from analysis of the interviews: learning and understanding symptoms and treatment, emotional experience about MS (uncertainty, hope, relief, fear), adaptation, and issues related to Avonex®. In general, patients were grateful and hopeful that there was a treatment available that would slow the progression of their disease. Taking Avonex® provided a sense of control over their illness.
Obstacles involved in taking Avonex® include financial limitations of insurance, the burden of self-injections, and overcoming side effects. Resources available to patients included injection training, financial assistance, and telephone support.
The interviews showed that patients progress through an adjustment to the medication as they learn to cope with self-injection. For the majority of patients, the side effects diminished over time. Social support was found to be extremely important to patients. Most patients expressed feeling improved since initiating Avonex®. All felt that their exacerbations had become less frequent and milder, and some patents reported less fatigue associated with exacerbations.
"Relapsing MS is a frightening diagnosis that carries with it uncertainty about the future. The symptoms are often vague, making the diagnosis difficult. The process of 'getting to know' what relapsing MS is and learning about the available treatments is complex and long-term. Most patients feel hopeful about the future, once they adjust to taking the medication," explained Ms. Miller.