Elisheva Frankel started to get the kind of joint pain most people associate with the elderly when she was only six years old. By the time she reached her teens, her joint pain had become severe, and she was diagnosed with juvenile rheumatoid arthritis. By then the damage to the joints in her left wrist was permanent. The disease would flare up painfully at times. “I had to miss my junior year of high school because I couldn’t get out of the house,” she said. “I was in a lot of pain.”

As many as 50,000 children in the United States are afflicted with a childhood version of rheumatoid arthritis. Some children grow out of their arthritis to lead normal lives, while others, like Frankel, continue to suffer the cumulative effects of joint damage. She had tried a variety of drugs like steroids and disease modifying anti-rheumatic drugs (DMARDs)—with side effects including weight gain, anxiety and the jitters. The drugs were not completely effective in stopping the progression of her illness, and her doctors had begun to consider surgery for her wrist. As a last resort, they decided to try a new drug called Enbrel that had just been released a year earlier.

“Enbrel changed my life,” said Frankel, who can now enjoy running and other activities without pain.

Enbrel is part of a new class of arthritis medications that appears to be revolutionizing the treatment of some kinds of arthritis with fewer perceptible side effects than other drugs. Because how effective these drugs are, and the lower level of patient discomfort, this class of drugs has become widely used—and not just for rheumatoid arthritis, but also for other inflammatory diseases like psoriasis, and Crohn’s disease. But the popularity of these drugs is raising issues in experts’ minds about what the long-term side effects might be, and whether those risks are worth it for patients with less debilitating diseases than arthritis. As more and more of these drugs gain Food and Drug Administration acceptance for use in milder disease, their availability and acceptance increases. A recent study found that this type of drug carries a bigger risk of cancer than was originally thought—and some experts are worried that patients might not be aware of the potentially serious consequences they could face.

If the “hot new drug with surprisingly few side effects” title sounds familiar, that’s because it is: That’s how Vioxx was described after it was approved in 1999. The drug was initially approved for treating pain associated with several kinds of arthritis, and later the Food and Drug Administration approved it for milder indications such as migraines and acute pain in adults. Vioxx and other Cox-2 inhibitors were hailed as a revolution in the treatment of pain—gone were the uncomfortable side effects associated with the older generation anti-inflammatory drugs, like gastric upset. Soon Vioxx was used across the globe and had become one of Merck’s blockbuster drugs. But long-term studies, conducted after the drug was released, revealed that Vioxx increased its users’ risk of heart attack and stroke. Suddenly the risks were no longer worth the benefit for people using the drug for milder conditions. In September 2004, Merck withdrew the drug from the market, although some patients with severe arthritic pain might have accepted the higher risks if it meant relief from daily pain.

A difficulty that continually faces drug makers and consumers is that long-term effects of a drug are often not known until a new drug is released to the general public and used for a number of years. Enbrel has been on the market for just over seven years—not long enough for doctors to extrapolate long-term side effects like cancer, which can take a longer time to develop.

But a study published in last month’s Journal of the American Medical Association (JAMA) extrapolated those long-term side effects by combining data from many past trials, rather than waiting decades to evaluate the consequences of the widespread use of Enbrel and related drugs. Tim Bongartz of the Mayo Clinic and his colleagues compiled data from nine different early clinical trials of two of the three TNF-alpha inhibitors, which prevent inflammation by blocking the chemical TNF-alpha, part of the immune system. The study looked at trials of Remicade, made by Centocor (owned by Johnson and Johnson) and Humira, made by Abbott. Enbrel, made by Wyeth and Amgen, was excluded.

With data from such a large pool of rheumatoid arthritis patients, researchers were able to examine how rare some of the side effects really were. The study concluded that patients using TNF-alpha inhibitors are 3.3 times as likely to get cancer and 2 times as likely to get a serious infection as a group of patients who used standard treatment or nothing.

While these risks may be acceptable for patients with diseases like rheumatoid arthritis, which in some cases painfully cripples and disfigures the joints of the body, the risk might not be worth it for less severe diseases. Enbrel is also being used for psoriasis, in which raised splotches of red flaky skin appear on the body and cause itchiness. The disease is not physically debilitating, but can be socially and emotionally damaging in severe cases when the red patches cover large and externally visible areas of the body.

Enbrel was the only TNF-alpha inhibitor approved for treating moderate to severe psoriasis, until September of this year when the FDA approved Remicade. But regardless of FDA approval, many doctors were already prescribing TNF-alpha inhibitors to their patients with psoriasis. This practice, known as “off-label prescribing,” is perfectly legal and common with all types of drugs. And although drug companies are not allowed to advertise their drugs for off-label uses, all three makers of TNF-alpha inhibitors continue to gain immensely from the considerable number of psoriasis patients looking for effective treatment.

There are about 6.6 million people in the U.S with psoriasis. But patients are eligible for TNF-alpha inhibitors only when they have moderate to severe cases of psoriasis, in which three percent or more of the body is covered with the disease (one percent is about a palm-sized patch of skin). If the entire population of eligible psoriasis patients were to take this drug—about 1.5 million people—the U.S. could see roughly 11,000 more cases of cancer for every year the drugs were taken. The longer the drugs are used, the more new cancers are likely to occur.

These results weren’t a huge surprise to some doctors. The package inserts for this class of drugs warn of the risk of serious infections and the possibility of cancer. TNF-alpha inhibitors block part of the body’s natural inflammation process, which is overactive in psoriasis and rheumatoid arthritis. These diseases arise when the body’s TNF-alpha mistakenly recruits the immune system to fight against healthy parts of the body—a condition called autoimmunity. The immune system attacks and causes inflammation in the joints in rheumatoid arthritis, or the skin in psoriasis.

But inflammation also helps fight infection, and can help keep cancer in check, according to Jan Geliebter, a professor of immunology at New York Medical College. “We’d be in big trouble if we got rid of all of the TNF-alpha in our bodies,” he said.

While it may not have been surprising, the JAMA study was important because it gave an actual estimate of risk in concrete numbers, showing that serious side effects may be more common than doctors realized.

After a few years on Enbrel, Elisheva Frankel experienced one of these side effects first hand. She came down with cellulitis, a potentially life threatening bacterial skin infection, which began to spread rapidly on her arm. She was treated with antibiotics at the hospital and recovered, but these types of infections can be deadly for people taking TNF-alpha inhibitors if they are not treated quickly and appropriately.

People faced with a choice of surgery or permanent joint damage might choose a higher risk of cancer if it helps them live their lives more fully. Eric Matteson from the Mayo Clinic, another researcher on the TNF-alpha study, said it’s important to remember that “these drugs have made people’s lives immensely better.” But would a person with psoriasis make the same decision to take the drug if they understood the risk?

There are still a number of questions the study does not answer. Are the risks the same for Enbrel, the drug that Frankel uses, as they are for the two drugs included in the study? According to the authors, Enbrel was excluded because it blocks TNF-alpha slightly differently than do Humira and Remicade. However, Matteson, a key investigator in the study, conceded that all three drugs have about the same effect in the patient, and the FDA considers all three drugs to have similar side effects.

Another question unaddressed by the study is whether the risks for patients with rheumatoid arthritis are the same as the risks for patients with psoriasis. Mark Lebwohl, a member of the Medical Advisory Board of the National Psoriasis Foundation, says he thinks both sets of patients face the same risks. However, Matteson from the Mayo Clinic disagrees. He said patients with rheumatoid arthritis start out with a higher risk of some kinds of cancer, which could make them more susceptible to that particular side effect of immunosuppressive drugs like TNF-alpha inhibitors.

What is clear is that the pharmaceutical companies that sell TNF-alpha inhibitors stand to gain huge sales from the psoriasis market, even in the U.S. alone. Enbrel is the number one prescribed non-topical drug for psoriasis, despite being also being one of the most expensive. According to Med Ad News, part of the Biotech Communications Group, Enbrel was ranked 10th of all pharmaceutical products sold around the globe.

Potentially muddying the issue is the fact that the two organizations that serve as a resource for doctors who treat psoriasis accept large grants from the major manufacturers of Enbrel, Humira and Remicade. Both the National Psoriasis Foundation and the American Academy of Dermatology link to articles and educational sites that extol the benefits of TNF-inhibitors, offering a disclaimer that their sites are funded in part by the drug makers.

In general, doctors treating psoriasis and those treating rheumatoid arthritis agree that TNF-alpha inhibitors are serious drugs, not to be given to people with mild disease. Practicing dermatologist David Cohen, an associate professor in the dermatology department of New York University’s medical school, often treats psoriasis patients. He said he wouldn’t prescribe Enbrel to a patient who came to him with psoriasis because of its considerable side effects. “I would send them to a rheumatologist,” he said, or to another specialist who could monitor their reaction to the drug more carefully.

But how severe a patient’s disease must be before a TNF-alpha inhibitor is prescribeed is left to each doctor’s discretion. Lebwohl, a practicing dermatologist, says that insurance companies often require patients to fail the cheaper and more widely used alternative therapies before they will cover the cost of these drugs. However, he added that TNF-alpha inhibitors could be useful for people who “can’t make it in three times a week for UV treatment,” which is one of the safest and most effective dermatologists have for psoriasis.

The reputation and undeniable effectiveness of TNF-alpha inhibitors means these drugs have the potential to be over-prescribed to psoriasis patients who want to see results, but don’t fully realize the extent of the risks.

Despite the side effects, this class of drugs is filling an important therapeutic hole. They improve the lives of patients who have failed every other arthritis treatment and they’ve let children suffering from rheumatoid arthritis return to the playgrounds. Elisheva Frankel, who has temporarily gone off Enbrel to have her first child, says that when she goes back on medication she will try other rheumatoid arthritis drugs first. But because of the advent of drugs like Enbrel, she says she can foresee a time when rheumatoid arthritis will no longer be considered the crippling disease it is today.