Ellie Glasgow, left, and Allison McClusky, who takes methotrexate for arthritis, take off their shoes after ballet class. (By James A. Parcell / The Post) In This Report JRA at a Glance Changes in Treatment Philosophy Resources

By Sally Squires
Tuesday, March 10, 1998; Page Z12

Every Wednesday afternoon, Allison McCluskey, 4, of Vienna, pulls on her white leotard and tights and takes her place in ballet class with a bevy of other little girls. She goes through the usual exercises then performs plies, battement tendu and port de bras -- movements that last year would have been impossible for Allison, who was diagnosed with juvenile rheumatoid arthritis at age 2.

The fact that Allison can walk, let alone dance, amazes her parents, who once watched in despair as arthritis reduced their healthy, active daughter to crawling. Megadoses of nonsteroidal anti-inflammatory drugs, such as Advil and Naprosyn, failed to relieve her painful, swollen joints. Steroids tamed the arthritis but also stunted Allison's growth and produced serious side effects, including bone loss. "There was a time when we began to think about how we could manage a child in a wheelchair," said Allison's mother, Karen.

But then the doctor recommended methotrexate, a powerful anti-cancer drug that is increasingly being used as an effective therapy for some children with juvenile rheumatoid arthritis, although it is not yet approved by the U.S. Food and Drug Administration for this purpose. Estimates are that 40 to 60 percent of children with moderate to severe forms of the disease now take methotrexate, according to Daniel J. Lovell, a pediatric rheumatologist at Children's Hospital in Cincinnati. No one knows what the long-term effects may be.

That left an agonizing decision for the McCluskeys: Should they try methotrexate with the uncertainty over its long-term effects or let arthritis continue to ravage Allison's joints? "We chose methotrexate," Karen McCluskey said. "And have not regretted the decision."

Allison's symptoms began to abate a few months after starting the drug. "Now she is running, jumping, trying to skip, hopping on one leg and doing ballet," noted Karen McCluskey. "Methotrexate has been a godsend for her and for us."

The cancer drug is one of several potent medications being recommended for the treatment of juvenile rheumatoid arthritis. For children with severe forms of the disease, the new therapies are the first real hope that they can manage their illness and prevent permanent disabilities. But the track record of using these drugs in children with arthritis is so limited that many questions remain.

"To say that we are not worried about long-term effects would be silly," said Edward Giannini, part of the National Institute of Health's National Arthritis Data Work Group. "There is always the possibility that a rare side effect will appear when you increase the number of children taking this drug. But undoubtedly methotrexate has kept children off crutches, out of wheelchairs and made them more ambulatory, self-sufficient and increased their quality of life. Nobody would debate that."

A Common Childhood Illness

Arthritis of all types strikes an estimated 100,000 children annually in the United States and as many as half of those youngsters have rheumatoid arthritis, according to figures to be published later this year by the NIH's National Arthritis Data Work Group. Juvenile rheumatoid arthritis is second only to asthma as a leading cause of chronic illness in those 16 years of age and younger. More children suffer from arthritis than from such other well-known chronic diseases as cystic fibrosis, muscular dystrophy, sickle cell anemia and hemophilia.

Arthritis is a disease in which the immune system runs amok and attacks the body it is designed to protect. White blood cells, which normally defend against such invaders as bacteria and viruses, unaccountably begin to strike the cells lining the joints, producing swelling and pain.

Juvenile arthritis is different from the osteoarthritis that usually develops in older adults from wear and tear on the joints. The illness can surface before a child's first birthday, or it can remain hidden until the mid-teens.

In its mildest form, the disease swells a joint or two, perhaps a few fingers, a knee or a hip, making them stiff and painful to move. The swelling may subside over a few months with minimal treatment. Children with the mildest cases usually "have no permanent impairment," said Edward Sills, director of pediatric and adolescent rheumatology at the Johns Hopkins Children's Center in Baltimore. "Their lifestyle and other activities should not be interfered with, and the impact on their families should be minimized."

But for up to two-thirds of children with the disease, juvenile rheumatoid arthritis will be a chronic disorder with repeated flare-ups that can be debilitating and lead to permanent damage of joints. These youngsters are often sidelined by joint pain that makes the simplest activities excruciating to perform. And at its very worst, juvenile rheumatoid arthritis assaults the skin and key organs, producing irreversible damage that can cause permanent disability and, in very rare cases, even death.

What causes the immune system to suddenly veer out of control is still a matter of debate and scientific investigation. "As of right now, we cannot tell you that we know exactly how the disease starts," said Giannini, who is also part of the pediatric rheumatology collaborative study group at Children's Hospital Medical Center in Cincinnati.

Few believe that there is one inherited genetic defect that causes arthritis, however. The suspicion is that "there are probably substantial numbers of genes involved, like in asthma and high blood pressure," said David Glass, director of pediatric rheumatology at Children's Hospital in Cincinnati. Yet, it is rare for more than one child in a family to have rheumatoid arthritis.

It may be that children are born with several genetic errors that make them prone to arthritis and then perhaps something else triggers the disease. Experts have investigated whether an infection could also be responsible for the more chronic and severe forms of the disease in children, but they have found little evidence to support that theory.

What is clear is that prompt treatment of juvenile rheumatoid disease is essential to minimize permanent joint damage.

There is a growing recognition of the "seriousness of juvenile rheumatoid arthritis and that the most rapid joint destruction occurs in its very earliest stages," said John Klippel, clinical director of the National Institute of Arthritis and Musculoskeletal Diseases in Bethesda, Md. "If one wants to make a difference, one has a very short window of time in which to act."

Low Doses of Methotrexate

For this reason, doctors have become much more aggressive in controlling symptoms as quickly as possible. The new approach is to "hit the disease hard and hit it early," said Sills of Johns Hopkins -- the reason why methotrexate has become so popular in recent years.

In a 10-year review of juvenile arthritis treatments, Lovell of Children's Hospital in Cincinnati reported last year that methotrexate "was the second most commonly prescribed medication," ranking only behind the drug naproxyn (Naprosyn).

Some doctors are pushing the envelope even further by using methotrexate as the first line of therapy. At a scientific meeting next week in Park City, Utah, the Pediatric Rheumatology Database Research Group is scheduled to report the latest results of a four-year study of medication choices in 5,221 children with juvenile rheumatoid arthritis. The study, of which Lovell is a co-investigator, found that doctors prescribed methotrexate at the initial visit in 13 percent of children with five or more affected joints and in 8 percent of those with severe disease affecting both joints and organs in the body. Methotrexate was recommended in only 2 percent of children who had four or fewer joints affected.

The classic way of treating juvenile rheumatoid arthritis first with non-steroidal anti-inflammatory drugs "is coming under scrutiny," said Norman Ilowite, chief of the division of rheumatology at the Schneider Children's Hospital in New Hyde Park, N.Y. "The desired goal is to put these kids into remission."

For this reason, methotrexate moved center stage in arthritis treatment about a decade ago after doctors watched their dermatologist colleagues successfully use very low doses of the drug to treat severe psoriasis in children. This painful skin disorder occurs along with arthritis in some children.

Methotrexate is given in tiny doses that are 1/1,000th to 1/10,000th of what is normally prescribed to treat cancer. The drug is administered weekly and can be given by pill or by injection. It costs anywhere from $20 to $100 a month, depending on the dosage, and is often covered by health insurance.

Children usually take the drug for a number of years as doctors attempt to quiet the arthritis symptoms. Kevin Hale, 6, of the District, first started taking weekly doses of methotrexate in 1995 after he was diagnosed with arthritis in his knees, ankles and wrist. His father, Kevin Sockwell, ground up pills and put them in the boy's juice.

Taking methotrexate has enabled doctors to reduce the amount of prednisone that Hale takes, and improved his movement. "He didn't want to move or do anything before," Sockwell said. "It was sad."

Earlier this year, doctors switched Kevin from pills to weekly injections of methotrexate -- a form of the medication that is less toxic and more effective in some children. That change enabled another reduction in prednisone, which reduces inflammation but stunts growth and causes bone loss. "The goal is to get him completely off the prednisone," said Kevin Sockwell as his son raced around the clinic at Children's National Medical Center in Washington.

Methotrexate decreases the inflammation in arthritis so much that it enables the body's immune system to quiet down completely, thereby reducing the need for other drugs. Doctors believe that if children remain symptom-free for a number of years, they may be considered "cured" and can then go off methotrexate. The idea is to put the arthritis permanently in remission.

"We are able to get complete clinical control with the medication, which means that there is no evidence of the disease at all," said Carol Wallace, associate professor of pediatrics at Children's Hospital and Regional Medical Center in Seattle, who has used methotrexate to treat 200 children with arthritis. "The hope is that the disease will go away altogether, and that has happened in some children, although we can't promise that for everybody."

A number of studies have shown how effective the drug can be. The most pivotal was a 1992 trial published in the New England Journal of Medicine that followed 127 children for six months. The study found that a dose of 10 milligrams a week improved symptoms in 63 percent of juvenile arthritis patients compared with 36 percent of those who got a placebo. Since that study, the use of methotrexate has risen steadily and "is now galloping along as a treatment for juvenile rheumatoid arthritis," Glass said.

The drug works by interfering with folic acid, one of the essential B vitamins that is instrumental in cell division and protein synthesis throughout the body. So important is this B vitamin that without it, cells die. In cancer, the drug selectively kills malignant cells, which grow and divide faster than normal cells. Without enough folic acid, the cancer cells quickly die. To help protect the slower-growing normal cells, doctors often "rescue" them by providing supplements of folic acid. "By then, the cancer cells are already goners," said Klippel of the NIAMS.

In arthritis, methotrexate appears to target cells that are overactive and produce the inflammation that makes joints so tender and swollen. The doses used in arthritis are generally low enough that "rescue" with folic acid is not necessary.

Concern About Side Effects

While methotrexate is well tolerated in up to 70 percent of children, it can still produce significant side effects. Eight studies of nearly 300 young arthritis patients treated with methotrexate found that about 13 percent suffered gastrointestinal problems and 15 percent experienced liver problems. Two percent or less of children in the studies reported headaches and skin rashes. Mouth sores and a general feeling of fatigue are another common side effect; many doctors schedule administration of the drug on Saturdays to enable children to recover by Monday.

"Most of the side effects can be resolved by adjusting to lower doses," said Robert Lipnick, a pediatric rheumatologist who practices in Bethesda and often prescribes methotrexate for his young patients.

But doctors must take particular care in choosing the patients for whom methotrexate will be used. Many physicians require adolescent female patients to be on birth control before they give methotrexate, because of the possibility of birth defects. "I discuss this at length with my teenage patients and their parents; if I have any worries that they will not go on birth control, then they don't go on methotrexate," said Wallace.

The consequences of not doing so are underscored by a recent case reported by Lenore Buckley and her colleagues at the University of Virginia in Charlottesville. A 20-year-old woman who had been taking methotrexate to control her juvenile arthritis became pregnant. Her son was born with multiple congenital problems and died shortly after birth.

Doctors are also concerned about the long-range effects of methotrexate. Studies of the chronic use of methotrexate in young arthritis patients are just now getting underway. Results won't be available for a number of years. Most of the research to date on this drug has been in cancer patients, who take the drug as part of their chemotherapy. While the dosages are extremely low for arthritis patients, no one knows if the cumulative effect of being on the drug for many years may lead to unforeseen consequences.

One fear is an increased risk of lymphoma, a cancer of the lymph nodes that already is slightly more common in adults who have arthritis. Studies of adult arthritis patients who took methotrexate showed no greater risk of lymphoma than in arthritis patients who had not taken the drug, according to Ilowite of the Schneider Children's Hospital.

But there have also been a few reports in the scientific literature of a lymphoma-like disease that occurs in arthritis patients who took methotrexate. "There is some evidence that the perhaps methotrexate is causing the lymphoma-like condition, because it goes away when the drug is stopped," said Ilowite of Schneider Children's Hospital.

Even so, Ilowite and many other experts believe that the other alternatives -- irreversible damage to joints and disabling side effects from drugs such as prednisone -- are worth any unknown risks of methotrexate. "The advantages of methotrexate far outweigh the disadvantages," Ilowite said.

It is the uncertainty about the future, however, that led Susan Hurwitch and her husband to reject methotrexate as a treatment for their daughter Beryl a couple of years ago. Beryl had tried NSAIDs, prednisone and half a dozen other drugs during the past decade to control her symptoms with mixed success. Gold injections worked well for about seven years, but then her symptoms suddenly flared again.

A month ago, Beryl, 17, woke feeling very stiff and tender. When she tried to get up, she collapsed on the floor in great pain, unable to walk.

Her doctor prescribed a four-month course of prednisone and asked the family to reconsider methotrexate when the steroid is stopped. The flare-up was severe enough that Susan Hurwitch said she is now willing to try methotrexate for her daughter.

"It's going to be a matter of seeing how she does when she comes off the other medication," she said. "It looks like the next best option is methotrexate."

Doctors are hoping that methotrexate can completely shut down juvenile arthritis and prevent the irreversible damage that cripples children for a lifetime. "We want to make the young person functional and without pain," said Patience White, of Children's National Medical Center in the District. "Even if we don't wipe away the arthritis, we want to keep them moving their joints so that they will develop better. Then we will have an adult who is an active part of society -- that is the major hope of this drug."

For many parents, including the McCluskeys, that promise is enough to justify the risk. "I don't know what we will discover when Allison is 30," said Karen McCluskey, who said that she spent a week crying when her daughter first started taking methotrexate. "I do know that it works today, the toxicity is controlled in her and her body is managing it well. For her, it seems that we have made the right decision."

Resources

Numerous resources are available to help children and their parents live with juvenile rheumatoid arthritis. Among them are:

National Arthritis and Musculoskeletal and Skin Diseases Information Clearinghouse, National Institutes of Health, 1 AMS Circle, Bethesda, MD 20892-3675 Phone: 301-495-4484. TTY: 301-565-2966. Fax: 301-587-4352.

American Juvenile Arthritis Organization, 1330 West Peachtree Street, Atlanta, GA 30309. Phone: 404-872-9559.

Pediatric Rheumatology Home Page

Finally, the National Institutes of Health is sponsoring a registry of families who have two or more children with juvenile rheumatoid arthritis. For information, contact the registry, which is located at the Children's Hospital of Cincinnati, at 800-636-7011 or by fax at 513-636-5990.