Treat multiple sclerosis early to boost outcomes.
Early treatment also had a positive impact on other long-term outcomes such as disability, relapse rates, and the development of new active brain lesions.
"The early events are the driving events of disease activity. [Patients] are worse off by not protecting themselves early," Dr. Mark S. Freedman said after presenting a poster at the World Congress on Treatment and Research in Multiple Sclerosis.
'Any patient who meets the high-risk definition similar to the patients enrolled in this study deserves the option [of early treatment]. It's up to each patient to decide if they want to start injected treatment; not every patient will want that. But I would tell patients that the data suggest they could have several more episodes" of MS symptoms in the year after their initial event, Dr. Freedman, professor of neurology at the University of Ottawa and director of the MS Research Clinic at Ottawa General Hospital, said in an interview.
Patients enrolled in the study were aged between 18 and 45 years when they had a first neurologic event suggestive of MS that lasted for at least 24 hours, and at least two clinically silent lesions, 3 mm or larger, on a T2-weighted brain MRI scan.
Common first neurologic events that are suggestive of MS include optic neuritis or acute partial transverse myelitis. Patients with such presentations and who have not had a recent stroke or show no other identifiable cause are diagnosed with clinically isolated syndrome.
The Betaferon/Betaseron in Newly Emerging Multiple Sclerosis for Initial Treatment (BENEFIT) study randomized 468 patients with a first event suggestive of MS to treatment with 250 mcg interferon beta-lb subcutaneously every other day or placebo. The study was sponsored by Bayer Schering Pharma, which markets interferon beta- lb (Betaseron in the United States and Canada; Betaferon elsewhere). Dr. Freedman is a consultant to and advisory board member for Bayer Schering as well as for other drug companies.
Initial findings from this study, published in 2006, showed that after 2 years of treatment, 45% of the 176 patients in the placebo group and 28% of the 292 patients in the interferon group developed clinically definite MS (according to the Poser criteria), an absolute reduction in cases of 17%, and a relative risk reduction of 50%, a statistically significant difference (Neurology 2006;67:1242-9).
According to the McDonald MS criteria that were introduced in 2001, the rate of progression to MS after 2 years was 85% in the placebo arm and 69% in the interferon arm, a 16% absolute reduction in conversion rate and a 46% relative risk reduction, also statistically significant.
The rate of serious adverse effects was similar in the interferon and placebo arms, and the safety results with this formulation of interferon were consistent with results from previous studies. Based on these findings, the Food and Drug Administration expanded the indication for Betaseron in 2006 to include treatment for a first clinical event suggestive of MS.
Patients in the placebo arm were switched to interferon treatment after they developed clinically definite MS (based on Poser criteria) or after the end of 2 years of blinded treatment. The 5-year outcome data in the new report by Dr. Freedman are from 358 of the original 468 patients (76%), including about 80% of the patients who began the study on interferon treatment and remained on interferon for 5 years, and about 70% of the patients who began the study on placebo and then crossed over to interferon treatment and received interferon for at least 3 years.
The 5-year results showed that over time and with crossover of the placebo patients, the patients who began interferon early continued to have a lower overall rate of progression to definite MS, although the difference between the placebo and active treatment groups fell to a 37% relative reduction, still a significantly significant difference.
The relative rate of progression to MS was reduced 45% in patients who began interferon at their first clinical event.
The long-term follow-up phase also introduced a measure of disability linked to MS development, the expanded disability status score (EDSS). Three-year follow-up data reported last year showed that confirmed EDSS progression occurred in 24% of placebo patients and in 16% of patients treated with interferon up front, an 8% absolute difference and a 40% relative risk reduction that was statistically significant (Lancet 2007;370:389-97).
After 5 years, the relative risk reduction of the EDSS from early interferon treatment dropped to 24%, a difference that was not statistically significant. That reduction was not unexpected because "all the disability was driven in the placebo group by the first year of disease," Dr. Freedman said.
A better indicator of the long-term impact of early interferon treatment was the Paced Auditory Serial Addition Test (PASAT) score, a measure of intellectual function and cognitive ability. A new finding in the 5-year follow-up was that patients who received interferon early on had significantly better average PASAT scores than did patients who started interferon later.
"Early treatment is critical for patients, and we now have evidence for long-term benefits in the cognitive test," Dr. Freedman said in an interview. "There is no explanation for the better cognitive scores other than early treatment." He added that this benefit alone is a compelling reason for patients to start on interferon early.
Other benefits from early interferon treatment reported by Dr. Freeman were a significantly better reduction in the relapse rate and a significantly reduced development of newly active brain lesions.
Dr. Freeman estimated that about two-thirds of patients in the United States are now choosing to begin treatment after the first clinical event suggestive of MS.
BY MITCHEL L. ZOLER
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|Author:||Zoler, Mitchel L.|
|Publication:||Internal Medicine News|
|Date:||Nov 15, 2008|
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