Research supports quick initiation of MS care

The challenge now is to determine how to detect the disease accurately at early stages.

By Victoria Stagg Elliott — Posted Aug. 27, 2007

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When it comes to multiple sclerosis, early initiation of therapy, when possible, appears to be very effective. Also, researchers have discovered two genes that confer additional risk for the development of MS. These alleles have a role in other autoimmune diseases and are expected to open the door to new treatment targets, according to a handful of papers published in July and August.

"It's a very exciting time for MS research," said Stephen Hauser, MD, professor and chair of neurology at the University of California, San Francisco.

A paper in the Aug. 4 Lancet found that patients who started every-other-day injections of interferon beta-1b soon after the first signs of the disease were less likely to progress to full-blown MS or to develop additional disability within three years.

"Early treatment ... at the time of the first event highly suggestive of MS makes a difference for patients who have additional evidence of clinically silent lesions in the initial MRI," said Dr. Ludwig Kappos, lead author and acting chair of neurology at University Hospital in Basel, Switzerland.

This study is the latest to suggest that sooner is better, but experts say there are many barriers to starting treatment at the disease's earliest stages. Patients who may not feel that sick may be hesitant to begin an injectable medication, particularly since the course of MS can be unpredictable and vary widely from crippling to benign.

"It really depends very much on the patient," said Elizabeth Morrison, MD, MSEd, associate professor of clinical family medicine at the University of California, Irvine, who has researched wellness issues for those with this disease. "Some patients have one attack with a symptom that is very concerning to them, such as temporary or permanent loss of vision. Then they're willing to consider treatment. Some want to wait until they've had other symptoms. We need to respect how patients feel about that."

Early diagnosis is also far from clear-cut. In the beginning, MS can look like many other conditions, and diagnosis is a combination of eliminating other possibilities, clinical judgment and an MRI. Misdiagnosis is not uncommon. Several papers have suggested that 5% to 10% of patients who have such a diagnosis most likely have something else. Also, a study published in the April 2005 Archives of Neurology found that 30% of patients referred by a physician to an MS center to confirm diagnosis did not have any symptoms suggestive of this disorder.

"There can be a certain delay factor and confusion about the diagnosis," said Elliot Frohman, MD, PhD, professor of neurology and ophthalmology and director of the MS program at the University of Texas Southwestern Medical Center. "We have to exclude things that can mimic MS, and we still don't have a specific diagnostic test for it."

While some researchers are examining the use of these drugs to modify the course of MS, others are focused on better understanding its genetic underpinnings. According to several papers published online in July in the New England Journal of Medicine and Nature Genetics, variations of the interleukin 2 receptor alpha, interleukin 7 receptor alpha and human leukocyte antigen locus are associated with an increased risk of MS.

This finding is notable for several reasons. HLA genes have been implicated since the 1970s, but IL2RA and IL7RA are the first new genetic suspects discovered in a couple decades. This accomplishment required the completion of the Human Genome Project and the analysis of the genetics of more than 12,000 MS patients and their relatives in Europe and North America.

"We have been working hard for 20 years to try to find genes outside of the HLA region that influence susceptibility to MS," said Dr. Hauser, one of the leaders of the International Multiple Sclerosis Genetics Consortium, the group responsible for this research. "It's been a long and arduous process."

These papers also further link MS to other medical conditions with an autoimmune component. For example, the IL2RA allele has also been implicated in type 1 diabetes and Graves disease.

"This study will likely spur further research into the connection between these seemingly separate conditions," said David Hafler, MD, another consortium leader and professor of neurology at Harvard Medical School and Brigham and Women's Hospital in Boston.

These genes exert a very small influence and also may be present in those who don't have MS, but experts say these discoveries are extremely important. These genes govern a different part of the immune system than the ones suggested by previous research. This advance could lead researchers to a better understanding of the inflammatory and regulatory structure of how MS works as well as novel ways to treat it.

"This brings us into a brand new pathway that could be the central, fundamental cause of MS," Dr. Hauser said.

These genes are unlikely to be the last connected to MS, but experts said these studies also suggest that drug research under way likely is on the right track.

Researchers are in the midst of a phase II trial investigating whether daclizumab, a drug used to suppress the immune system of transplant recipients that acts on the receptor coded by the IL2RA allele, will be effective against multiple sclerosis.

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Impact of early MS treatment

Objective: Determine if initiation of interferon beta-1b therapy soon after a first event suggesting multiple sclerosis has an impact on disability related to the disease.

Methods: In the first phase, 468 patients who had experienced one MS-like event and had two clinically silent lesions found by MRI were randomized to inject either interferon or placebo every other day for two years or until they received a diagnosis of clinically definite MS. Of this group, 418 moved into an open-label phase. Those who were treated early were compared to those who delayed treatment until after a confirmed MS diagnosis or at least two years into the study.

Results: Three years into the follow-up period, 37% of those who received early treatment developed confirmed MS compared with 51% who delayed treatment. Approximately 16% of the early group became more disabled compared with 24% of those who initially received placebo. Early treatment reduced the risk of MS by 41% and cut the chance of worsening disability by 40%.

Conclusions: Early treatment with interferon beta-1b reduces the onset of disability and should be used at the first sign of relapsing-remitting MS.

Source: The Lancet, Aug. 4

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External links

"Effect of early versus delayed interferon beta-1b treatment on disability after a first clinical event suggestive of multiple sclerosis: a 3-year follow-up analysis of the BENEFIT study," abstract, The Lancet, Aug. 4 (link)

"Risk Alleles for Multiple Sclerosis Identified by a Genomewide Study," abstract, New England Journal of Medicine, online July 29, in print Aug. 30 (link)

"Old Suspects Found Guilty -- The First Genome Profile of Multiple Sclerosis," New England Journal of Medicine, online July 29, in print Aug. 30 (link)

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