Starting a tumor necrosis factor-alpha inhibitor, or anti-TNF, doesn’t increase a patient’s risk of serious infections requiring hospitalization any more than starting a non-biologic disease modifying drug, according to a study published online in November in the Journal of the American Medical Association.

The side-effect profile of anti-TNFs, biologic drugs used to treat rheumatoid arthritis, or RA, and other autoimmune conditions, has been a concern to doctors, researchers and patients alike since the first one was introduced about 13 years ago. Because anti-TNFs suppress the immune system, the drugs increase the risk of infections. And because they are relatively new, the long-term risk of side effects isn’t yet known. Anti-TNF drugs include infliximab, or Remicade; etanercept, or Enbrel; adalimumab, or Humira; certolizumab pegol, or Cimzia; and golimumab, or Simponi.

“We hope [the research] provides some clarification and some reassurance for patients and providers,” says lead study author Carlos G. Grijalva, MD, an assistant professor of preventive medicine at Vanderbilt University in Nashville, Tenn.

Previous studies of the severity of anti-TNF side effects have had mixed results, with the worry extending beyond infections to cancer. The cancer risk was put into perspective by several recent studies, including a meta-analysis published online in September in the Annals of Rheumatic Diseases, which found anti-TNFs slightly elevated the risk of skin cancer but not other cancers.

But in that same month, the U.S. Food and Drug Administration strengthened the warning label on the drugs to include an elevated risk of infection from two additional types of bacteria, Legionella and Listeria. And a British study published in June in the journal Rheumatology found the risk of infections associated with anti-TNFs is “highest during the first six months of therapy.”

“Some previous studies have suggested most of the potential increased risk would be concentrated right after initiation, so we set up our study to look at the frequency of infection in the first year, with that idea in mind,” Dr. Grijalva explains.

He and his team collected and analyzed 10 years’ worth of records on more than 32,000 patients with RA, inflammatory bowel disease, or IBD, psoriasis and spondyloarthropathies from several large databases – national Medicaid and Medicare, Tennessee Medicaid, Kaiser Permanente Northern California and pharmaceutical assistance programs in New Jersey and Pennsylvania.

The researchers identified more than 1,100 serious infections requiring hospitalization within the first 12 months of starting any kind of therapy; 53 percent involved skin or soft tissue infections or pneumonia.

But when researchers compared the infection rate of anti-TNF users to the infection rate of those who used non-biologic medications, such as hydroxychloroquine, or Plaquenil, and leflunomide, or Arava, they found no significant difference.

There was one exception: RA patients taking infliximab, or Remicade, had a higher infection rate than those on etanercept, or Enbrel, and adalimumab, or Humira. “Remicade had a significant association between risk of infection, but we didn’t see anything with other anti-TNF drugs,” says Dr. Grijalva, noting that they don’t know why.  

Additionally, among patients with RA and psoriasis/spondyloarthropathies, the simultaneous use of corticosteroids at the start of therapy was associated with an increased risk of serious infection, regardless of the treatment regimen (anti-TNF vs. non-biologic); the higher the corticosteroid dose, the higher the risk of infection.

“I think these results should reassure patients and providers that we did not observe that these biologics increase the risk of serious infections when compared with other, non-biologic regimens,” Dr. Grijalva explains.

But some researchers say the study isn’t the final word on anti-TNF infection risk because of the high drop-out rate of study patients.

“I think the study was well done, but a lot of people starting on anti-TNFs dropped out of treatment, so the follow-up was not comprehensive,” says David T. Felson, MD, a professor of medicine and epidemiology at the Boston University School of Medicine, who wrote an editorial accompanying the study. “They might have missed a heightened infection risk because those people weren’t taking the drugs for long enough.”

Dr. Felson says it’s important to figure out why there is conflicting research on this topic, but he thinks that’s more of a research matter than a clinical one at this point.

“I do think some people are scared to start [biologics] and I think the message isn’t all black and white. There is a risk to starting them,” Dr. Felson says. “I would say it’s right to be concerned – but not right to be overwhelmed with concern.”

Dr. Felson says patients who have previously had infections or are at a higher risk because of their age might want to be particularly mindful of this issue. But for most patients, he says, “Being so scared you don’t feel comfortable starting medicine that might help you is not good. I have a lot of patients on anti-TNFs. They are very effective and the infection risk in most patients is by no means overwhelming.”