WASHINGTON (AP) -- Patients taking Remicade for rheumatoid arthritis suffered a type of cancer, lymphoma, at three times the rate of the general public, manufacturer Centocor warned doctors on Thursday.

Centocor, a subsidiary of Johnson & Johnson, said the lymphoma incidence rate was six times higher among all patients who took the monoclonal antibody in completed clinical trials.

Experts said such toxic outcomes, however, are still rare, and that the new drugs, on balance, work markedly better than older medications, without such side effects as nausea and fatigue.

The Malvern, Pa.-based company, working with the federal drug regulatory agency, revised its label to reflect the lymphoma risk. According to NDCHealth, Remicade was the 28th top selling drug in 2003, with $1.5 billion in U.S. sales.

The label change is the drug's second in six weeks. In late August, Centocor warned that people taking Remicade for rheumatoid arthritis and Crohn's disease can sometimes experience fatal blood and central nervous system disorders. At least 12 people taking Remicade -- in combination with other drugs -- died worldwide.

The Food and Drug Administration said then that those deaths could not be linked definitively to Remicade use.

The company's new warning letter to doctors, released Thursday, said patients receiving Remicade suffered higher rates of lymphoma than seen in the general population. Lymphoma is cancer of the cells of the lymphatic system, tissues and organs involved in fighting infection.

Centocor said the label change is in line with warnings recently added to others drugs, such as Enbrel and Humira, in the new class that block overproduction of TNF, an inflammation-regulating protein thought to lie at the heart of rheumatoid arthritis and other autoimmune disorders.

Rheumatoid arthritis is a disease in which the body's immune system rebels, treating its own tissues as enemies to attack. Some 2.1 million Americans suffer from this illness, which ultimately deteriorates cartilage and destroys joints.

Centocor found that three people developed lymphoma among 2,410 patients taking Remicade to treat Crohn's disease or rheumatoid arthritis. That was six times higher than the lymphoma rate among healthy individuals.

But such autoimmune diseases up the odds of suffering lymphoma, making it difficult to determine whether to blame the drugs or the underlying disease.

"That's the issue here," said Dr. Tom Schaible, Centocor vice president of medical affairs. "There's not enough signal coming out of the population of patients receiving TNF blockers to distinguish it from what the underlying risk is in those diseases."

By neutralizing the overproduced protein, the new class of biologically engineered drugs relieves painful symptoms.

But an FDA advisory panel last year debated whether Amgen and Wyeth's Enbrel, Abbott Laboratories' Humira and Centocor's Remicade were also linked to 170 cases of lymphoma reported among the drugs' recipients since 1998.

"The drugs that we use are powerful because they do affect the immune system. And that's how they work in arthritis," said Steven Abramson, who was acting chairman during that March 2003 advisory committee session that scrutinized the increase in adverse events, including lymphoma.

"The good news is that you don't feel rotten taking the drug every day," said Abramson, chairman of rheumatology at New York University Hospital for Joint Diseases.

Last week, the agency approved using a combination of Remicade and methotrexate as a first-line treatment for patients with rheumatoid arthritis.

Phase three clinical trials indicated one in three patients taking the drug showed marked improvement in their psoriatic arthritis. Later this year, the company will ask the FDA to expand the drug's usage.

Copyright 2004 The Associated Press. All rights reserved.