WASHINGTON – The Food and Drug Administration ordered stronger warnings Thursday on four medications widely used to treat rheumatoid arthritis and other serious illnesses, saying they can raise the risk of possibly fatal fungal infections.

The drugs – Enbrel, Remicade, Humira and Cimzia – work by suppressing the immune system to keep it from attacking the body. For patients with rheumatoid arthritis, the treatment provides relief from swollen and painful joints, but it's “a double-edged sword,” said the FDA's Dr. Jeffrey Siegel. That's because the drugs also lower the body's defenses to various kinds of infections.

Siegel, who heads the office that oversees arthritis drugs, said the FDA became concerned after discovering information that doctors appeared to be overlooking a particular kind of fungal infection called histoplasmosis. Of 240 cases of the infection reported to the FDA, a total of 45 patients died – about 20 percent.

The infection, which mimics the flu, is prevalent in much of the middle part of the country. It can have particularly grave consequences if it isn't caught early and spreads beyond the respiratory system to other organs of the body.

Siegel said the investigation began with a single case of a woman taking one of the drugs who died of histoplasmosis. Delving into the case, doctors at the FDA found that the woman had been sick with the fungal infection for a long time. “This case led us to be concerned that there may be other situations in which physicians may not recognize histoplasmosis,” said Siegel.

FDA officials searched the agency's database and found the 240 cases of patients taking the medications who had also developed the fungal infection. Of those, at least 21 appeared to involve a late diagnosis. And 12 of these patients – more than half – ultimately died.

Siegel said the FDA's order Thursday means that the risk of histoplasmosis will be flagged in a “black box,” the strongest warning information in a drug's prescribing literature. The four medications already have black box warnings about the risk of infections, but the language varies from drug to drug.

Patients will be alerted to call their doctors if they develop persistent fever, cough, shortness of breath or fatigue, which can be signs of the fungal infection.

And the FDA is also urging doctors to consider aggressive use of antifungal drugs in patients who develop such symptoms, even if the infection has not been confirmed by a laboratory test. Siegel said such a decision should not be taken lightly, since antifungal drugs can also have dangerous side effects. Doctors should also consider stopping treatment with the immune-suppressing drugs, he said.

The four drugs belong to a class known as TNF-alpha blockers, and are also used to treat Crohn's disease, juvenile arthritis, certain types of psoriasis, and other conditions. Three of the drugs, Enbrel, Humira and Remicade, are considered blockbusters, with sales of over $1 billion annually for each. Cimzia is newer and less widely used. All are delivered by injection.

Humira is made by North Chicago, Ill.-based Abbott Laboratories Inc; Cimzia by Belgium-based UCB; Enbrel by Thousand Oaks, Calif.-based Amgen Inc. and Madison, N.J.-based Wyeth; and Remicade by Horsham, Pa.-based Centocor.

Abbott shares fell 91 cents to $57.02 Thursday afternoon; Amgen fell $1.69, or 2.7 percent, to $61.41; and Wyeth fell 95 cents, or 2.2 percent to $41.64. Centocor is privately held.