A decade or so ago biologics were “game-changers” in the treatment of rheumatoid arthritis. Now they’re the first line of defense. Learn more about how they work.
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.”
A Sniper for Interleukin-6
How it works. Tocilizumab (Actemra) is an antibody that blocks the spot when interleukin-6 (IL-6) attaches to cells. IL-6 is an immune system protein that stokes inflammation, says Wei.
Makeup. Tocilizumab is a human monoclonal antibody.
Delivery. Tocilizumab is given intravenously for about an hour once a month. “Its manufacturer [Genentech] is now working on an [injected] formulation,” says Wei.
In 2012, Genentech released results of SUMMACTA, a multicenter two-year study that found similar results between injections every two weeks compared with monthly intravenous forms of the drug.
Risks. Like other biologics, tocilizumab carries a risk of infection. In some patients, it raises liver enzymes and cholesterol, says Curtis. High liver enzymes may indicate liver damage or inflammation.
A Biologic Targeting B Cells
How it works. Rituximab (Rituxan) was first used to treat Non-Hodgkin's lymphoma, says Wei: “It wipes out B-lymphocytes, [a type of white blood cell] involved in inflammation.”
Makeup. Rituximab is a mix of mouse and human monoclonal antibodies.
Delivery. Rituximab requires two 4- to 6-hour infusions two weeks apart every six to 12 months, says Curtis: “That [schedule] is a convenience.”
Risks. A risk of infection. “It also carries a higher risk for an infusion reaction like itching, a rash, or wheezing,” says Curtis.
How it works. Abatacept works by acting on T-cells [a type of white blood cell], says Wei. It attaches to the surface of inflammatory cells, blocking any communication between them.
Make-up. Abatacept is a fusion protein.
Delivery. Abatacept is given by a 30-minute infusion every two weeks for three doses, then every four weeks.
Risks. It carries the risk of infection.
Interleukin-1 (IL-1) Blocker
How it works. “Interleukin -1 is a protein that is a major player in inflammation,” says Wei. Anakinra (Kineret) blocks the action of IL-1. However, says Wei, results from other drugs are stronger, so it isn’t used as frequently.
Makeup. Anakinra is a man-made form of a specific kind of protein secreted by the immune cells called Il-1 receptor antagonist, or IL-1Ra, which blocks IL-1.
Delivery. It’s self-injected once a day.
Risks. Anakinra carries the usual risk of infection.
A Novel Class of Drug
How it works. Tofacitinib (Xeljanz) is one in a new class of drugs that inhibits Janus kinases, enzymes key to inflammation. It differs from other biologics because it targets RA from inside, not outside, the cells. But like biologics, it has a single target, the Janus kinases.*
Makeup. “Unlike other biologics, it’s a small molecule drug, which enables it to be taken orally,” says Wei.
Delivery. The excitement: it’s a pill taken twice a day..
Risks. Along with a risk for infection, tofacitinib can increase liver enzymes and cholesterol, and raise the risk of shingles, a viral infection that causes a painful rash, says Curtis. “It’s quite different in that regard than the others.”