The U.S. Food and Drug Administration (FDA) have issued stronger warning about four rheumatoid arthritis drugs after these have been said to be linked to the deaths of 45 patients. The prescription drugs Cimzia, Enbrel, Humira, and Remicade, which are jointly called TNF blockers, are used to treat rheumatoid arthritis, Crohn's disease and other conditions.

The FDA received reports of these drugs causing histoplasmosis, a fungal infection that starts as a respiratory infection and spreads throughout the body.

Web MD reported that out of the 45 patients who died at least 12 had not been diagnosed with histoplasmosis immediately. The patients varied in age from 8-86 years though none of the deaths involved children. More deaths were reported from other fungal infections though the FDA did not say how many.

Jeffrey Siegel, a clinical team leader in the FDA's Division of Anesthesia, Analgesia and Rheumatology Products said, “Current warnings must be upgraded to strongly warn doctors to consider the chances of fungal infections in patients especially those who are seriously ill or who are not responding to current antibiotics. These infections need to be identified early enough so that treatment is not delayed."

The four medications target diseases like rheumatoid arthritis, Crohn's disease and other diseases which are caused in part by inflammation. The drugs suppress the immune system to try to combat flare-ups, but often that can leave patients vulnerable to other complications. TNF blockers are approved to treat a variety of conditions, including rheumatoid arthritis, juvenile idiopathic arthritis, psoriasis and Crohn's disease. This is not the first time the TNF blockers are under scrutiny. The federal agency is still reviewing the possibility of a link between the drugs and increased cancer risks in children and ypung adults. Although strong “black box” warnings are carried on some of the drug labels, listing the serious risk for fungal and other infections, the FDA wants them to be consistent for all products and to be highlighted in an attempt to draw more attention to histoplasmosis risks, Siegel said.

The FDA has asked patients and doctors to be alert for symptoms of histoplasmosis, which include a persistent fever, cough, shortness of breath, and fatigue. The problem partly could be that patients and doctors do not immediately recognize the infection, thereby delaying treatment that could help prevent hospitalizations or deaths, Siegel said. In at least 21 of the 240 cases, the infection was not caught in time by doctors and 12 of those 21 patients died, the FDA said.  The reason diagnosis can be tricky is as histoplasmosis targets the respiratory system and has common flu-like symptoms, such as a fever and cough it rarely causes  alarm, Siegel said.

The FDA has given the companies 30 days to submit new warning language for approval or give a reason to oppose the changes. Laureen Cassidy, spokeswoman for Abbott said Humira's label already notes histoplasmosis risk but the company would comply with the agency's request while representatives for UCB and Amgen also said their companies would cooperate with the FDA.