ADVANCES IN INCLUSION-BODY MYOSITIS

The least understood inflammatory myopathy
is finally yielding to researchers' probes

On winter mornings in icy Prescott, Wis., Ed Bankston gets up early, and, as he has done for many years, drives to his office in St. Paul, Minn. Bankston, 55, has been an attorney with the St. Paul District of the U.S. Army Corps of Engineers since 1988, and he now heads the district's legal department.

But getting to his desk requires a little more planning than it once did. Nowadays, Bankston drives an adapted Dodge Caravan with hand as well as foot controls to an underground garage, where a staff member meets him with a power wheelchair. In the evening, he drives the chair back down to the garage and transfers into his van.

Walking is something Bankston has all but given up, except to get into the shower, which requires two forearm crutches. His arms and hands are weak, making it hard to hold onto objects or to open containers.

The trouble started in his late 40s, when Bankston began feeling that his muscles were no longer as strong as they once were. "If I was trying to play tennis or bicycling and tried to stop, my knee would buckle, and I would fall," he recalls. "And I couldn't walk as fast as I used to. At first, I thought I was just getting older."

But in 1994, at age 49, he grew concerned enough to consult his internist. The doctor told him his strength was within normal limits for his age, but the weakness continued — and progressed.

A year or so later, Bankston and his wife, Pam, went to a neurologist, who did an electromyogram and made a diagnosis of amyotrophic lateral sclerosis (ALS, or Lou Gehrig's disease), a devastating disease of muscle-controlling nerve cells that usually leads to death within a few years.

The Bankstons decided to get a second opinion and made an appointment with the Mayo Clinic in Rochester, Minn. Fortunately, they received a lesser sentence: Bankston was told he either had polymyositis (PM), a disorder involving an immune system attack on muscle; or inclusion-body myositis — IBM — a muscle disorder that major medical centers were just beginning to recognize.

How Rare Is It?

Until recently, IBM was considered a rare disease, but experts now say it's the most common form of inflammatory muscle disease in men over age 50. Some even say it may be the most common muscle disease of any kind that begins in either men or women over 50.

IBM is more common in men but affects both sexes. The slowly progressive disease produces severe weakness and muscle atrophy (shrinkage) in the forearms, including the muscles controlling finger movements. It typically affects the muscles of the arms and legs, particularly the thigh (quadriceps) muscle and muscles in the lower legs that move the feet. The weakness isn't necessarily the same on both sides of the body. About one-third of those affected have weak throat muscles and difficulty swallowing.

The usual type of IBM isn't considered a genetic disorder (although genetic risk factors may be involved) and is called sporadic IBM. There are also genetic forms, which present a slightly different picture (see "When It Runs in the Family,").

"They started treating me with Imuran and prednisone because they thought that would differentiate which disease it was," Bankston says. Both medications suppress the immune system. "If it was polymyositis, they thought it would respond. After three or four months, we discontinued the treatments, because it didn't respond, so they pretty much figured it was inclusion-body myositis."

About a year later, the Bankstons traveled to the National Institutes of Health in Bethesda, Md., where the diagnosis of IBM was confirmed. (Last year, MDA began covering the disease in its services program.)

Curious Inclusions

None of Bankston's story is a great surprise to Valerie Askanas, an MDA-supported researcher and clinic director at the University of Southern California in Los Angeles.

Askanas is among a handful of scientists now mapping the territory of sporadic and hereditary forms of IBM and separating it from other types of inflammatory myopathies (muscle disorders involving an immune-system reaction known as inflammation), muscular dystrophies and diseases of the nervous system, like ALS.

The name itself is a mouthful, as Askanas is the first to admit. An inclusion, or inclusion body, she says, is "a cluster of material, anything that doesn't belong inside a cell. It has a broad meaning. In IBM, we're constantly discovering new proteins in the inclusions."

The "myositis" part of the name carries the prefix myo, which means muscle, and the suffix itis, which means inflammation.

When muscle biopsy samples from people with IBM are examined under a microscope, trained eyes can see strange-looking inclusions; bubblelike spaces called vacuoles that are sometimes empty and sometimes contain inclusions; and inflammatory cells invading like enemy troops around the borders of muscle fibers. It's largely what's inside the inclusions that intrigues Askanas. Until recently, nobody was sure what they were.

"Without special staining," she says, "it was not possible to see what we see now. It was only possible to see that within the vacuoles there was some material. A few years ago, it was becoming apparent that those inclusions contained clusters of filaments. That was all that was known for many years."

Researchers also observed that the disease wasn't very treatable. "It differs from polymyositis, and that always puzzled us," Askanas says, "why polymyositis is so well treatable in many patients and why inclusion-body myositis is not."

An Alzheimer's Connection?

Ed Bankston drives an adapted van to his office where he heads a legal department.

Then, in 1990, Askanas attended a meeting in Birmingham, England, to probe the mysteries of ALS, another baffling disease. In that disorder, muscle-controlling nerve cells (motor neurons) degenerate for reasons that remain obscure. "Someone was showing inclusions in neurons, and they were staining positively for ubiquitin," Askanas recalls.

Shortly before leaving for Birmingham, Askanas had been studying a muscle biopsy sample from a patient with suspected IBM. "I remembered how they looked," she says of the IBM inclusion bodies she'd seen there. At the meeting, she says, "they were still very much in my eyes."

Ed Bankston

Askanas began wondering if the muscle inclusions might also be positive for ubiquitin, a protein that tags other proteins for cellular degradation. Ubiquitin had also shown up in brain tissue in another degenerative disorder, Alzheimer's disease. "When I came back from the meeting, I did the staining — and the IBM inclusions were incredibly positive."

About the same time, neuromuscular disease specialist and MDA research grantee Jerry Mendell at Ohio State University in Columbus was also becoming intrigued with IBM pathology. In 1991, Mendell and colleagues published a paper showing that amyloid, a compound composed of malformed protein pieces that take up a special stain, could also be found inside the muscle fibers of people with inclusion-body myositis.

Amyloid had by then been associated with brain degeneration in Alzheimer's and had been seen in some other conditions, but it had never before been shown to exist inside muscle fibers. "When Jerry showed this in 1991, many people didn't believe it," Askanas says. "But we looked, and indeed it was there."

Later, she and neurologist W. King Engel, her husband and colleague, identified amyloid beta, a protein fragment cleaved off from a larger protein known as amyloid beta precursor protein, as a major component of the amyloid deposits in IBM. This same protein has been implicated in the abnormal deposits in Alzheimer's brain tissue (where it's outside, not inside, brain cells).

Askanas' team went on to identify several more proteins found in the mysterious inclusion bodies in the muscle fibers of people with IBM. Curiously, many of these proteins — for example, amyloid beta, apolipoprotein E, ubiquitin, and possibly a toxic form of a protein known as tau (one with too many phosphate groups) — are also found in the brains of people with Alzheimer's, leading the investigators to suspect there might be some biochemical pathway common to the two disorders.

But here Askanas wants to clear up what she fears has become a frightening rumor: "We personally have never seen IBM patients with Alzheimer's disease; nor have our colleagues I have talked to. That's very important. I'm not so brave as to say that IBM protects against Alzheimer's disease, but I can say that IBM does not predispose one to Alzheimer's.

"In regard to IBM, I'm developing a hypothesis now that there are predisposing genes to different diseases, not disease-causing genes but disease-predisposing genes, and that there's one set that predisposes people to IBM and a different set that predisposes them to Alzheimer's disease. What I think is happening is that some genes direct a disease process to occur in aging muscles, and another set of genes directs a disease process to occur in the aging brain."

normal muscle IBM-affected muscle In inclusion-body myositis, bubblelike spaces called vacuoles and clumps of proteins form, while inflammatory cells invade the muscle tissue.

In fact, the mysteries of IBM aren't limited to its similarities to Alzheimer's brain tissue, Askanas notes. Another clue to the disease may lie in what she and Engel have called junctionalization. Normally, Askanas notes, the proteins produced at the neuromuscular junction — the place on each muscle cell that receives contact from a nerve cell — are unique to that cellular domain and aren't made elsewhere in the mature muscle fiber (cell). In IBM muscle samples, such "junctional" proteins appear all over the cell, not just at the junctions. That, Askanas believes, represents some sort of cellular process run amok.

Searching Upstream

While amyloid beta, tau and various mislocated proteins are clearly key parts of the picture in IBM, they probably appear "midstream" in the development of the disease, says Engel, who has worked closely with Askanas for a decade on IBM research and also sees many patients with the disease. "There's something upstream that leads to the accumulations of these proteins — and that's what is now being sought by the Askanas team."

That upstream something, Engel says, could well be a virus. "We've proposed that a virus is the real trigger. Viruses have a way of putting themselves into the cell, such that their RNA or DNA [genetic material] can be there but not in the shape of viral particles," which makes them hard to find, Engel says. A virus hasn't been detected in IBM, he notes, perhaps because the techniques being used to find it aren't sufficiently sensitive, or perhaps because it isn't there at all.

Askanas and her colleagues are also looking at another phenomenon that could play a role in IBM — the aging process itself. "There may be something about the aging muscle fiber environment that's not ordinarily a problem, but that could allow a virus contracted decades before to become detrimental," Engel says.

'Itis' Not Forgotten

W. King Engel and Valerie Askanas are studying inclusion bodies in IBM.

While Askanas and Engel have focused on aging and inclusions, other investigators have looked closely at the myositis part of IBM.

Neurologist and MDA research grantee Rabi Tawil, who co-directs the MDA clinic at the University of Rochester Medical Center in upstate New York, believes treating the inflammatory component of IBM still holds promise.

Tawil admits that attempts to treat IBM with various anti-inflammatory and immunosuppressant drugs have been far from successful. Corticosteroids (the prednisone family of drugs) allow some people to "transiently improve," he says, "but they don't sustain the improvement." Other treatments aimed at the immune system, including intravenous immunoglobulins — a cumbersome and somewhat risky way of changing the behavior of the immune system — have likewise failed, Tawil notes.

But he and several researchers are far from giving up on the idea that the immune system is a key player in sporadic IBM.

"Some investigators believe IBM is a degenerative myopathy [muscle disorder] and that the inflammation that's present is a kind of nonspecific inflammation but not the primary insult. But there's also some pretty significant evidence that IBM is an immune-mediated [immunologically caused] myopathy," he says.

While Askanas and Engel have focused on the parallels between IBM and Alzheimer's, Tawil and colleagues have chosen to look at the similarities that may exist between IBM and multiple sclerosis, a disorder in which it's believed that the immune system mistakenly attacks the myelin coating that forms a sheath around nerves. "In parallel to MS," Tawil notes, "IBM does not seem to respond to the typical immunosuppressive agents."

One new type of agent to which MS has responded, however, is a class of drugs called interferons, which are naturally produced cellular proteins that have regulatory effects on the immune system. Tawil has chosen to investigate interferon beta-1a, marketed as a treatment for MS by Biogen under the trade name Avonex. The drug is given by intramuscular injection once a week.

With help from MDA, the National Institutes of Health and Biogen, Tawil and colleagues have recently completed a small trial of Avonex in IBM. "There was concern about whether giving something intramuscularly to somebody with atrophic muscle might be a limitation," he says. "But we've been able to work around that by having patients give injections in a different limb every week and choose only the best-suited muscles."

Although no one showed dramatic improvement, the drug was safe and well tolerated. The research team now plans to move on to a seven-center study and to give the drug at double the dose. "There's some evidence that higher doses of interferon beta may have additional beneficial effects," Tawil says, noting that recruitment for the trial will begin when all the regulatory matters have been settled.

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