All About Multiple Sclerosis

More MS news articles for October 2002

Solving the MS puzzle

In multiple sclerosis, new drugs and new insights are giving rise to new hopes

October 7, 2002
BY Katherine Hobson
U.S. News & World Report

Lawrence Vail knew something was terribly wrong. More than a year ago, he was walking across a busy street in Boston when his leg went numb. Then came double vision and a mental fog that was so bad the 44-year-old thought he'd have to quit his job. But almost as quickly as he was diagnosed with multiple sclerosis, his doctor at Boston's Brigham and Women's Hospital put him on Avonex, one of several MS drugs approved over the past decade. After the disease changed his life, the medicine has changed it back. He can talk and express himself again. "The drug meant you go from the edge of the cliff to about 30 feet before the edge," he says.

Tanya Pugliano, another MS patient at Brigham, also tried Avonex. But it didn't stop her legs from giving out or her hands from going numb. Neither did another MS drug, Copaxone. Now the 29-year-old is undergoing monthly chemotherapy treatments, like a cancer patient, trying yet another way of fighting back against the disease.

Had either patient developed MS 15 years ago, even doctors at renowned medical centers like Brigham would have had little to offer them. They would have been powerless to stop the basic disaster of MS: a patient's immune system that savagely assaults the nerves in the brain and spinal cord. Now, thanks to a handful of recently developed drugs--one just approved a few months ago--physicians can blunt this attack. "It's not a cure, but it's a far cry from what we had before," says neurologist Fred Lublin, director of the Corinne Goldsmith Dickinson Center for Multiple Sclerosis at Mount Sinai Hospital in New York.

Researchers are even beginning--just beginning--to suspect why Vail and Pugliano responded so differently to treatment. The theory: MS, which affects 350,000 people in the United States, may be more than one disease. "I've given speeches where I call it multiple scleroses, not multiple sclerosis," says Stephen Hauser, chair of the neurology department at the University of California-San Francisco. Genes and individual immune reactions may drive the ailment in different directions. "We're very hopeful that through new imaging or immune assays we can begin to stratify people," says Hauser. "I'd hope that in the foreseeable future, maybe five to 10 years from now, someone with the symptoms of MS will be able to have a swab for genetic analysis, a drop of blood for an antibody/cell study, and we'll be able to say she has MS Type 2B" and give her a drug tuned to that type.

Self-destruction. Still, there are commonalities to the disease, or diseases. In a patient, T cells, which normally attack foreign invaders like bacteria, instead turn upon myelin, the sheath covering nerves in the brain and spinal cord. When the myelin is destroyed, leaving scar tissue behind, the nerves' ability to communicate with the rest of the body is damaged. That's what causes the disease's disabling symptoms.

Most people initially experience a relapsing-remitting course of the disease, in which these T cell attacks cause temporary problems but then relent for months or even years at a time. Eventually, many experience more lasting disability. A smaller fraction of people see a steady decline from the onset of the disease, either with or without periodic flare-ups.

Even within those types, though, there is variation. Some relapser-remitters, for instance, have one attack and then go years without another. Others have attack after attack and quickly become disabled.

Why? Because, it turns out, some attacks are "silent." Doctors knew from autopsies that the inflammatory attacks scar the brain, but they couldn't observe the lesions come and go in living patients. Recently, brain scans like the MRI allowed neurologists to do exactly that, and what they found was startling. The waxing and waning of lesions in the brain didn't mirror the external waxing and waning of symptoms. Patients who felt perfectly fine might actually be experiencing significant damage. "An attack in 2002 may not hurt until 2005," explains Marco Rizzo, a neurologist at Yale.

With brain scans, doctors can now count these lesions to see how well drugs are working. MRI evidence showing fewer active lesions among patients on the drug Betaseron was crucial for its approval in 1993 by the Food and Drug Administration. The drug is a synthetic version of a protein called an interferon, naturally produced by cells to help the body fight off viruses. Since researchers once suspected a virus might cause MS, interferons seemed like a good way to fight back. Scientists no longer believe in a single viral cause for the disease (though a host of viruses may trigger the first overactive immune response in susceptible people), but certain types of interferons do slow down a hyperactive immune system. Interferon beta 1a was approved by the Food and Drug Administration in 1996; it's marketed as Avonex, the drug that gave Vail his life back. Rebif, a medication similar in action to Avonex, can be taken more frequently and thus can interfere with more immune-system attacks. It won approval just this spring.

New defenses. But interferons often don't slow down enough rogue T cells to stop the disease. They reduce the number of annual attacks by about 30 percent when compared with patients who aren't taking the medications. To improve on that number, other drugs have taken different tacks. One, Copaxone, approved in 1996, is believed to act like a myelin decoy. It lures the T cells that cause damage; their absence seems to stimulate other kinds of T cells that don't attack inappropriate targets. Chemotherapy drugs that are used for cancer, like Cytoxan and Novantrone, are also used to suppress the damaging T cells in MS. So is a technique called plasma exchange, which physically filters out many of the marauding cells. And Biogen and Elan, two biopharmaceutical companies, are now conducting Phase 3 trials on yet another drug, Antegren. For immune cells to make their move out of a blood vessel and into the brain, they need to travel through a cellular channel in a vessel wall. Antegren blocks those channels before the T cells can get in.

Now, often the question is: Which treatment for which patient? Currently, doctors try treatments until they find one that works, but they hope to be able to play matchmaker, dovetailing one treatment with one of MS's many faces. Claudia Lucchinetti, a neurologist at the Mayo Clinic, is leading a five-year project to analyze MS lesions in brain tissues from autopsies or biopsies. So far, her group has identified four different patterns, based on which proteins in the myelin are damaged, where the areas of inflammation appear, whether there are attacks on the cells that make myelin instead of the myelin itself, and whether antibodies (another arm of the immune system) are involved as well as the usual T cells.

There's some evidence that specific clinical symptoms--like a certain kind of eye problem--show up only in patients with a given pattern. Lucchinetti's preliminary findings have shown that plasma exchange works only in patients who fall into one of her lesion-pattern groups.

Other studies suggest that 50 percent of MS patients with a certain gene respond better to Copaxone than do those without it, says Hauser. He's also studying how genetic differences might affect the response to interferons.

A genetic connection. The genetics of MS are complex--just having a gene associated with the disease does not mean someone will get it, for instance--but there's strong evidence that genes have a lot to do with it. An identical twin of an MS patient has about a 1-in-3 chance of getting sick; a sibling has about a 1-in-20 chance. But outside the nuclear family of an MS patient, the risk falls off sharply. It's possible that genes may also influence the severity of the disease along with its occurrence.

Finding stronger links among genes, drug effectiveness, and particular patterns of MS calls for less intrusive ways of identifying those patterns than taking repeated samples of brain tissue. That might take the form of a blood test or MRI scan. Charles Guttmann, director of Brigham's Center for Neurological Imaging, works with Howard Weiner, director of the hospital's MS center, to tie clinical data--like the presence of certain immunological proteins in the blood--to the ways in which lesions appear on an MRI. The group is trying to develop even more-precise brain-imaging techniques that could further classify lesions--and patients--into distinct groups.

Even if such techniques make drug-patient matchmaking possible, they won't solve one pressing problem. Many current MS patients have lost a lot of their myelin already, and none of the existing treatment can replace myelin once it's gone. So there's a lot of interest in making the nerve covering. In a very early trial, physicians at Yale are transplanting certain myelin-producing cells from the ankles of five patients and injecting them into the patients' brains in the hope they will survive and restore myelin to stripped nerve fibers. Timothy Vollmer, who is leading the trials and has since become the chairman of neuroimmunology at the Barrow Neurological Institute in Phoenix, says his team takes small biopsies months later to see if the cells have survived or made myelin. Results will be released after all the surgeries have been completed.

If these projects bear fruit, the many faces of MS--Vail, Pugliano, the patients who thrive on Copaxone and those who don't, and more--may prove to have one thing in common: a future even farther away from the edge of a cliff.

© 2002 U.S. News & World Report, L.P.