Since their introduction more than ten years ago, concerns have been raised by some about safety. As a result, multiple studies evaluating the potential side-effects of this group of medicines have been published.

During clinical trials, most adverse events have been mild and short-lived. Side effects such as injection site reactions, headache and nausea were generally weel-tolerated.

Once these drugs reach the general marketplace, though, then a larger population of patients with more significant co-morbid conditions (other medical problems) is exposed.

Two large studies comparing patients treated with TNF-α inhibitors and those treated with methotrexate and other standard disease modifying medicines showed an increased likelihood for hospitalization with infection in one study and an overall increased risk for skin and soft tissue infection in another. (Curtis JR, et al. Arthritis Rheum. 2007; 65: 178-181; Dixon WG, et al. Arthritis Rheum. 2006; 54: 2368-2376)

More recently, there has been documentation of an increased risk for fungal infections such as histoplasmosis and coccidiomycosis in patients taking TNF- α inhibitors. This data prompted the FDA to order a strengthening of warnings regarding the risk of serious infections for patients taking these medicines.

Another study looked at the combination of abatacept (Orencia) and TNF inhibition and there was a significant increase in adverse events. (Weinblatt M, et al. Ann Rheum Dis. 2007; 66: 228-234). In the same vein, a study evaluating the combination of TNF-α inhibition and IL-1 inhibition demonstrated an increase in infections and other adverse events. (Genovese M, et al. Arthritis Rheum. 2004; 50: 1412-1419)

Another concern has been malignancy. There have been two large studies published. One study failed to show an increased incidence of lymphoma. Another study- a meta-analysis of 9 randomized studies- showed an increased risk of malignancy in patient receiving TNF-α inhibitors compared with placebo. (Wolfe F, et al. Arthritis Rheum. 2007; 56: 1433-1439; Bongartz T, et al. JAMA. 2006; 259: 2275-2285). Other smaller studies have failed to demonstrate this association.

So what do you do? Rheumatologists and patients must be aware of the relative risks and benefits regarding this set of drugs. Close supervision is mandatory.

Prior to starting patients on these drugs, a careful evaluation for risk factors such as active infections, shingles, hepatitis B and C, and fungal infections should be done. During the course of therapy, patients need to be followed closely.

More recently, concerns have been raised regarding the occurrence of a rare but fatal neurologic illness, progressive multifocal leukoencephalopathy, occurring in patients treated with rituximab (Rituxan.) While extremely rare in RA patients, this is an issue to be discussed.

Prior to surgery, patients should probably withhold their biologic therapy until at least one to two weeks following the procedure. TNF inhibitors probably should not be used in patients with a history of lymphoproliferative disease until at least five years have elapsed.

Unfortunately, there are no set guidelines to help in determining when non-biologic disease-modifying drugs or biologic therapies can be used in patients with a history of solid malignancies. Risk benefit analysis should be individualized.

Yes… I realize that's a cop-out but when the firm data is not available, looking at a single patient's clinical course, talking with them, and coming up with a decision they feel comfortable with is the best option.