Government debates risks of powerful arthritis drugs

WASHINGTON -- Increasing reports of major side effects -- cancer and liver failure -- are spurring the government to reassess the safety of rheumatoid arthritis drugs that gave patients unprecedented hope when they began hitting the market four years ago.

"These drugs have shown tremendous benefit, but they ... all have pros and cons," said Dr. Karen Weiss of the Food and Drug Administration.

Of the 2 million rheumatoid arthritis sufferers, thousands try one of the four drugs each year. Tuesday, the FDA's scientific advisers began two days of debate over how big a risk each medication poses and whether stronger warnings or restrictions are needed.

The consumer advocacy group Public Citizen is pushing for one of the medicines, Arava, to be banned. Reaction within FDA is mixed. An agency analysis posted on the FDA's Web site Tuesday recommends a ban -- citing 54 U.S. cases of liver failure or damage and eight deaths linked to the drug.

"People should not use this," said Public Citizen's Dr. Sidney Wolfe, who contends Arava is far riskier than an equally effective, older alternative.

Higher-ranking FDA officials will tell agency advisers Wednesday that they disagree, citing additional analyses that argue there's no proof Arava is more dangerous than competing treatments.

"There are cases of liver injury that are possibly or probably related to use of Arava, but we also think it continues to have a place," said FDA drug chief Dr. John Jenkins. He said the FDA might find, however, that more safety restrictions were needed.

The FDA also is struggling to determine if three other medicines -- Enbrel, Remicade and Humira -- are linked to 170 cases of lymphoma, a hard-to-treat immune system cancer, reported since 1998.

Manufacturers argue patients already are adequately warned about possible side effects, and there's no proof the drugs are to blame.

"Causality is not easy to determine," said Dr. Francois Nader of Aventis Pharmaceuticals, Arava's maker. Meanwhile, "the physicians need choices, and the patients need choices."

Rheumatoid arthritis, which affects mostly women, is not the wear-and-tear joint damage that plagues the elderly. Instead, the immune system goes awry and attacks patients' own cartilage, causing pain and swelling and eventually destroying the joint. It typically strikes between ages 25 and 50, and within 10 years about half of patients are too disabled to work.

Standard treatment is a cancer drug called methotrexate. For years, few options existed for patients who failed methotrexate or couldn't tolerate its side effects, including liver damage.

In 1998, new-generation treatments started selling. First came Arava, a chemical that blocks the overproduction of immune cells that inflame joints, similar to how methotrexate works.

Then came Enbrel and Remicade, biologically engineered drugs that sop up a different inflammation-causing protein, tumor necrosis factor or TNF. A third TNF inhibitor, Humira, won FDA approval last December.

From the start, FDA warned of serious risks. It urged doctors to check Arava patients regularly for liver damage, and stressed use of birth control because Arava could cause birth defects. All three TNF inhibitors carry warnings that they suppress the immune system enough to cause severe, even deadly, infections and theoretically could increase the risk of cancer.

Now, after four years of sales, the FDA has reports of 170 cases of lymphoma among users of the three TNF inhibitors.

It's hard to prove if the drugs play any role, Weiss cautioned. Rheumatoid arthritis itself increases lymphoma risk -- RA patients get that cancer at two- to threefold higher rates than the general population. Plus, only 29 of the cases occurred during formal studies that allow full investigation.

"You can make a case that the incidence of lymphomas is in the range you would expect to see in rheumatoid arthritis," said Tom Schaible of Centocor Inc., Remicade's maker.

Dr. John Klippel of the Arthritis Foundation hopes the FDA meeting will help doctors and patients better compare each drug's different risks before choosing one. "These remain very important drugs," he said.