Biologic drugs were a game changer for rheumatoid arthritis treatment; the first, etanercept (Enbrel), was approved in 1998. Since then, eight more have been developed (nine if you count the latest drug, tofacitinib (Xeljanz), a synthetic oral drug that acts a bit differently and isn’t exactly categorized with other biologics).

Genetically engineered proteins originating from human genes, biologic drugs target specific parts of the immune system that fuel inflammation. Non-biologic rugs, like methotrexate, offer a more scattershot approach.

“If you are fighting a war, biologic drugs are the snipers,” explains Jeffrey Curtis, MD, MS, MPH, director, University of Alabama (UAB) Arthritis Clinical Intervention Program and do-director, UAB Center for Education and Research on Therapeutics in Birmingham. “They take out one target.  And if the target is the [Army] General, you will do well. ”

The problem is that no one knows which target is the right one for which patient, says Curtis: “There are probably genetic determinants, but there’s no diagnostic test [telling] who will respond to a given biologic.”

Making drug selection more difficult is that RA is often driven by several factors, not just the one a biologic targets. “But combining biologics has minimal difference in effect and significantly higher safety risk,” says Jasvinder Singh, MD, MPH, a staff physician at Birmingham VA Medical Center and associate professor of Medicine and Epidemiology at the University of Alabama at Birmingham. 

In a six-month 2004 study at Stanford University of 244 patients with RA, for instance, researchers gave one group etanercept only, another group etanercept plus anakinra (Kineret), and a third group a half dose of etanercept plus anakinra.  The researchers found no benefit from combined therapy and saw increased risks such as serious infections, injection-site reactions, and lowered white blood cell counts.

So, for now, biologics are used singly, or in combination with other non-biologics. What also distinguishes biologics, besides how they work and what they target, is their makeup, how they are delivered, and some risks – although all of them share a risk of infection.

Below is a breakdown of biologics, how they vary – or are alike:

Tumor necrosis factor inhibitors (TNF-Inhibitors)

How They Work. The five tumor necrosis factor inhibitors work by blocking tumor necrosis factor, which Curtis calls “the chemical messenger of inflammation that drives joint inflammation and destruction.”

“The TNF-inhibitors are often the first biologics tried for rheumatoid arthritis, not because they work so much better but because we have the most experience with them,” he says.

They include: certolizumab (Cimzia); etanercept; Golimumab (Simponi); adalimumab (Humira); and infliximab (Remicade).

Makeup. Adalimumab, golimumab, and certolizumab are human monoclonal antibodies –antibodies made from a single group of cells – like our bodies make, explains rheumatologist Nathan Wei, MD, director of the Arthritis Treatment Center in Frederick, Md., who has been involved in clinical trials with all of the biologics.

Another, infliximab is created from part human, part mouse antibodies.  

Etanercept is a fusion protein, says Wei: “That means that an antibody called IgG is fused to a TNF receptor [where] it acts like a sponge for TNF.”  Most of the antibodies in our blood are some type of IgG.

Delivery. Infliximab is given intravenously over two hours in a doctor’s office, clinic, or hospital three times in the first six weeks, then every eight weeks.  The other four are given by self-injection but at varying schedules: adalimumab, usually every two weeks; certolizumab every two to four weeks; etanercept once or twice a week; golimumab, once a month.

Risks. The risk from taking TNF-inhibitors is the same for all the biologics, says Curtis, one for serious infections. “On average, about two to three people out of 100 have a serious infection like pneumonia or a skin infection after taking a TNF inhibitor.”

For a pregnant woman the only choice of TNF inhibitor is certolizumab, says Wei: “All the others cross the placenta. Certolizumab does not.”