The FD in 2008 ordered stronger warnings about the risks of fungal infections in patients who take biologic drugs known as TNF blockers for treatment of rheumatoid arthritis and Crohn’s disease, with an eye to Remicade side effects and other potential problems with biologics.
Though TNF blockers, which suppress the immune system, already carry warnings about increased risk of serious infections, Food and Drug Administration officials said that infliximab (Remicade), etanercept (Enbrel), adalimumab (Humira) and certolizumab pegol (Cimzia) – a drug approved to treat Crohn’s disease that is expected to soon win approval as a rheumatoid arthritis medication – need “more uniform” boxed warnings because doctors don’t seem to be recognizing these infections when they strike.
Of particular concern, officials said, is an infection called histoplasmosis, an invasive respiratory disease that is spread by spores that live in soil and that thrive in bird droppings, including chicken litter, and in bat guano.
The FDA said problems with histoplasmosis and TNF blockers were noted when the agency began investigating whether these drugs, which suppress compounds that help the body kill cancer cells, could increase cancer risk in children.
Officials said they reviewed 240 reports of histoplasmosis in patients being treated with Enbrel, Humira or Remicade. There was one case of the disease in a patient taking Cimzia, which has only been on the market for a short time.
In 21 cases, clinicians didn’t recognize the disease, leading to delayed treatment. Twelve of those patients died. Another 33 patients whose treatment had not been delayed also died.
But experts say it is important to note that even in patients who take TNF blockers, histoplasmosis appears to be a relatively rare.
“We’ve seen two cases of histoplasmosis in patients taking TNF blockers,” said George Deepe, M. D., chief of the division of infectious diseases at University Hospital, in Cincinnati. “Two weeks to a month before they really became ill they were cleaning out barns. They probably shouldn’t have done that. They probably got a really big exposure.”
Dr. Deepe, who published a study on the association between TNF blockers and histoplasmosis infections last year, said the spores seemed to be confined to specific geographic areas, particularly the Ohio River Valley in the Midwest, and the southeastern states, excluding Florida. But he also cautioned, “We don’t know where it all is.”
Once exposed, a healthy person may carry histoplasmosis spores around for a lifetime and never get sick. Drugs that suppress the immune system like TNF blockers may give the infection an opportunity to take hold.
“The problem with histoplasmosis is that there are no clinical signs or symptoms that are specific to this infection,” Dr. Deepe said. “People get fever and chills, and they can have a cough,” symptoms that could easily be mistaken for the flu or another viral complaint, he added.
Physicians who are unfamiliar with the infection, or who live in areas where it hasn’t historically been a problem, would be less likely to suspect it, Dr. Deepe said.
“If some of these patients had been from the Midwest, but now lived in these areas where it is not common, the doctor may also be less familiar with it,” Dr. Deepe said.
Patients taking TNF blockers, then, should see their doctor at the first sign of any illness.
And Dr. Deepe said he hoped the new FDA warning would spur doctors prescribing TNF blockers to closely question patients about any history of living in areas where the spores are found.
Histoplasmosis can be treated with antifungal agents if it is caught before it overwhelms the body.