Dr. Joan M. Bathon, medical editor of The Johns Hopkins Arthritis Bulletin explains how TNF inhibitors such as Enbrel, Humira, and Remicade have improved life for patients with rheumatoid arthritis.
The arsenal of rheumatoid arthritis drugs was given a big boost in 1998 when the first Tumor Necrosis Factor (TNF) inhibitor received FDA approval. While extremely effective, both patients and doctors alike have many questions and concerns about which of the three current drugs to use, dosing regimens, and possible side effects.
TNF is part of the immune system. It is a protein produced by white blood cells. Discovered in 1975, it was originally named for its ability to trigger the death of transplanted tumor cells in mice. Although TNF has been shown experimentally to be capable of attacking and destroying some cancerous tumors, it may stimulate the growth of others. Therefore, the name “tumor necrosis factor” may be a bit of a misnomer.
What is certain, however, is that TNF plays a key role in rheumatoid arthritis. Although TNF does not actually cause the disease, it is one of the primary causes of the sustained inflammation that results in the pain, inflexibility, and joint destruction associated with rheumatoid arthritis.
Initial studies reported that mice with collagen- induced arthritis -- an animal model of rheumatoid arthritis -- had elevated levels of TNF in their joints. To block its effects, scientists created genetically-engineered proteins and antibodies, or TNF inhibitors, and found that these drugs could either prevent collagen-induced arthritis or halt its progression in mice.
After the safety of TNF inhibitors was established, the drugs were tested in adults
with early rheumatoid arthritis and in children with juvenile rheumatoid arthritis. The treatment response in these patients was just as robust as it was in patients with advanced disease. The year 1998 marked an important turning point in rheumatoid arthritis treatment with the introduction of Enbrel (etanercept), a soluble TNF-receptor that inhibits TNF. Enbrel is administered by self-injection.
Since then, two other TNF inhibitors have also been approved by the FDA to treat rheumatoid arthritis: Remicade (infliximab), a human/mouse monoclonal antibody that attacks and destroys TNF is administered by intravenous infusion; and Humira (adalimumab), a fully human monoclonal anti-TNF antibody is administered by self-injection. In just eight years, TNF inhibitors have become an important therapeutic option in the treatment of rheumatoid arthritis. An estimated 20% of rheumatoid arthritis patients in the United States are currently being treated with TNF inhibitors.
Here are some common questions and answers about TNF inhibitors:
Q. How do you rate the effectiveness of TNF inhibitors?
A. They’re very effective. About 50% of rheumatoid arthritis patients who are treated with TNF inhibitors get a very good response. Because TNF inhibitors reduce signs and symptoms of rheumatoid arthritis as well as alter the natural progression of the disease they make people feel better. Patients have less joint swelling, stiffness, and pain. By reducing inflammation, TNF inhibitors also reduce damage to the joints. If you take X-rays of rheumatoid arthritis patients before and after they’re treated with these drugs, you see very little additional damage. TNF inhibitors almost completely halt the damage in many rheumatoid arthritis patients. While methotrexate, a common rheumatoid arthritis therapy can do the same it’s not quite as potent.
Q. How soon do rheumatoid arthritis patients typically notice an improvement in symptoms with TNF inhibitors?
A. Improvement can be very rapid. Some people feel better after the very first dose, although people with very severe disease might take longer to respond. On average, however, patients usually see improvements in a matter of days or weeks, which is one of the big advantages of TNF inhibitors. By comparison, in patients treated with methotrexate, improvements may not be seen for several months.
Q. How are TNF inhibitors administered?
A. Humira is self-injected subcutaneously, usually every other week. If there’s no response, we can switch the patient to a weekly injection. Enbrel is also self-injected subcutaneously, usually once per week. Remicade is administered by intravenous infusion at a doctor’s office. Two weeks after the first dose, patients receive a second dose. A month after that, they receive a third dose. They then receive subsequent doses every eight weeks, although this schedule can be adjusted. The big plus with Remicade is that it’s the TNF inhibitor with the biggest dosing variability. The dose can be increased from 3 mg per kilogram of body weight up to 10 mg per kilogram of body weight.
Q. If rheumatoid arthritis patients respond to TNF inhibitors, do they have to take keeping them indefinitely?
A. In general, their arthritis will tend to flare if they go off the TNF inhibitor. Rheumatoid arthritis is a chronic disease, just like high blood pressure and diabetes. If you stop treatment, the disease worsens.
Another factor to consider is how early in the disease the treatment was started. In a person with very early disease that is brought under control by the drug, you can stop treatment and flaring may not occur for 6 to 12 months. However, in people with very advanced rheumatoid arthritis that is brought under control, stopping treatment usually results in immediate flaring.
Unfortunately, there’s no cure for rheumatoid arthritis. Although TNF inhibitors can effectively reduce inflammation and relieve symptoms, many patients don’t understand that the treatment is only controlling their disease, not curing it. The rebound of disease activity after TNF inhibitors are stopped is a sobering reminder that we still don’t know the underlying cause of rheumatoid arthritis or have any way to address it effectively.
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