The Food and Drug Administration ordered stronger warnings about the risk of potentially deadly fungal infections on four medications widely used to treat rheumatoid arthritis and other serious illnesses. The FDA has received 240 reports of patients taking such drugs as Cimzia, Enbrel, Humira, and Remicade, known as TNF-alpha blockers, who said the drug lowered the body’s defence to infections. Overall, 45 patients died. They developed histoplasmosis, a fungal infection which spreads throughout the body. TNF-alpha blockers carry black-box warnings that mention fungal infection.

The drugs work by suppressing the immune system to keep it from attacking the body and they are approved to treat rheumatoid arthritis, juvenile idiopathic arthritis, psoriatic arthritis, plaque psoriasis, ankylosing spondylitis and Crohn’s disease. But the treatment can leave patients vulnerable to other complications, or diseases.

“FDA has asked the manufacturers of these four drug products to highlight existing warnings of fungal infections,” Dr. Jeffrey Siegel, clinical team leader in the division of anesthesia, analgesia and rheumatology products at the FDA’s Center for Drug Evaluation and Research, said a news conference. He added that the box warning must be upgraded to “strongly warn doctors to consider the occurrence of histoplasmosis and other fungal infections.” No TNF blockers single out histoplasmosis in their black box warning. These infections need to be identified early enough so that treatment is not delayed, Siegel said.  

Histoplasmosis is a disease caused by the fungus Histoplasma capsulatum. The disease primarily affects the lungs. Occasionally, other organs are affected. Disseminated histoplasmosis can be fatal if untreated. The acute respiratory disease is characterized by respiratory symptoms, a general ill feeling, fever, chest pains, and a dry or nonproductive cough, according to the CDC. Antifungal medications are used to treat severe cases of acute histoplasmosis and all cases of chronic and disseminated disease. Infants, young children, and older persons, in particular those with chronic lung disease are at increased risk for severe disease. People with cancer, AIDS or other forms of immunosuppression are also at risk for hystoplasmosis.

The FDA warns patients and doctors to watch for any simptoms of histoplasmosis, including persistent fever, cough, chest pains and general ill feeling. Strengthened warnings will also encourage doctors to identify at-risk patients who live in certain areas of the United States where H. capsulatum is endemic. Most of the infected patients lived in the middle part of the United States, neat the Ohio River and Mississippi River valleys.

The agency is also investigating a possible link between the four medications and cancer in young patients. The FDA had received 30 reports of cancers, mainly lymphomas, in patients who began taking the medications when they were 18 or younger. The agency said it has a six-month timeline for the review. “We intend to meet that timeline,” Siegel said.

The drugmakers said they are working with the agency to make the required changes. Humira is made by the drug company Abbott. Cimzia is made by the drug company UCB. Remicade is made by the drug company Centocor. Enbrel is marketed by the drug companies Amgen and Wyeth.