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Harvard Commentaries
Harvard Commentaries
Reviewed by the Faculty of Harvard Medical School

Combining The Old And New To Treat Rheumatoid Arthritis

April 03, 2009

Rheumatoid Arthritis
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Combining The Old And New To Treat Rheumatoid Arthritis
Combining The Old And New To Treat Rheumatoid Arthritis
In the past five years or so, the biologic agents have revolutionized the treatment of rheumatoid arthritis.
Harvard Medical School

Harvard Medical School

Combining The Old And New To Treat Rheumatoid Arthritis
By Robert H. Shmerling, M.D.
Beth Israel Deaconess Medical Center
Arthritis of any kind can be terribly painful. But rheumatoid arthritis is among the most destructive forms of arthritis, frequently associated with disabling symptoms, affecting multiple joints, and striking most commonly during early adulthood and middle age. It's also remarkably common, affecting an estimated 1 percent of the population and 3 percent to 5 percent of women. Despite decades of research and major advances in understanding and treatment, the cause remains unknown and a cure remains elusive.
In the past five years or so, the "biologic agents" have revolutionized the treatment of rheumatoid arthritis. These medicines attack the chemicals produced by cells (called cytokines) thought to play an important, and possibly direct, role in the joint inflammation so typical of this illness. Tumor necrosis factor (TNF) is one such cytokine that may be at the heart of joint inflammation in rheumatoid arthritis. The U.S. Food and Drug Administration (FDA) has approved three agents that target TNF, including adalimumab (Humira), etanercept (Enbrel) and infliximab (Remicade). While there are minor differences in how they work, their dosing schedules (varying from twice a week to every eight weeks) and side effects (especially allergic reactions and infections) are more alike than different. All three tend to be much more effective than previously available treatments for people with the most severe arthritis (especially when other treatments fail). They must be injected (either under the skin or into a vein) and are quite expensive.
Rheumatologists, the arthritis specialists who most often prescribe these medicines, must decide if and when to recommend them and whether to prescribe them along with other, older drugs. Infliximab in particular was studied (and approved) in combination with methotrexate, the standard treatment for rheumatoid arthritis, because methotrexate was thought to prevent the formation of antibodies that could reduce the potency of infliximab. However, many people with rheumatoid arthritis continue to receive methotrexate during biologic therapy with adalimumab, and etanercept as well, because their arthritis worsens when methotrexate is taken away. Recent research not only confirms that combining the old and new medicines improves joint symptoms more than either alone, but it also suggests that combination therapy of this sort can promote repair of past joint damage, something thought impossible with previous treatment options.
Two newer injectable therapies were approved in 2006 for the treatment of rheumatoid arthritis: rituximab (Rituxan) and abatacept (Orencia). Rituximab targets B-cells, immune cells that make antibodies; abatacept prevents immune cells called T-cells from becoming fully active. It's expected that more biologic treatments will soon be approved.
Biologicals Not for Everyone
Because studies tend to select patients with the worst disease and because direct advertisements promote these new medicines, it may seem as though everyone with rheumatoid arthritis should be taking biologic therapy. Although that may someday become standard practice, there is no evidence yet that patients with mild rheumatoid arthritis that is well-controlled with other medicines must be switched to anti-TNF therapy. Other treatments, such as methotrexate, sulfasalazine, hydroxychloroquine and leflunomide, work well for many people. So if you have mild rheumatoid arthritis, without evidence of joint damage on X-rays, your physician may not recommend anti-TNF treatment.
On the other hand, there is convincing evidence that among persons with aggressive, severe rheumatoid arthritis, joint damage may occur in the first few months, and effective treatment is best started as soon as possible. If you have significant joint pain, especially if you have joint swelling, see your doctor for evaluation. There are more than 100 types of arthritis, and early diagnosis and treatment can make a big difference in your function and quality of life.
If you are taking methotrexate or a biologic agent alone for rheumatoid arthritis, you may wonder if you would be better off taking both together. However, some people, such as those with liver problems, cannot take methotrexate, so talk with your doctors about the advisability of taking these two medicines together.
Regardless of your current treatment, talk with your doctors about all of your options for treatment, including anti-TNF treatment and be sure to keep up with regular monitoring. Blood tests are recommended every eight weeks for people taking methotrexate. If you are taking anti-TNF treatment, see your doctor regularly, report any reactions or side effects and stop the medication in the event of significant infection or fever.
What's Next?
Researchers will continue to assess the role of single medications compared with combinations in the treatment of rheumatoid arthritis. Treatment of early rheumatoid arthritis, diagnosed after only a month or two of symptoms, will be a topic of intense research in the coming years. New treatments will be developed that target TNF and other cytokines that perpetuate the joint inflammation of rheumatoid arthritis; for example, another newly approved biologic agent, anakinra (Kineret), targets the cytokine interleukin-1, though this drug's effectiveness has been disappointing..
Rheumatoid arthritis is a heterogeneous disease, meaning that although it has a single name, it can vary widely in severity and how it responds to treatment. There is not a single best treatment, so good studies that evaluate early arthritis (comparing it to arthritis that's been present for a while), severe arthritis (comparing it to milder disease) and other subsets of rheumatoid arthritis are important in sorting out the best treatment. One promising approach, called pharmacogenomics, uses information about one's genetic makeup to choose a drug that is most likely to help without causing problems. Many experts believe this is how much of medicine will be practiced in the not so distant future.
At the present time, most insurance companies will not cover anti-TNF drugs unless other, older (and cheaper) medications have been tried first. If early and aggressive treatment of rheumatoid arthritis with biologic agents is to take hold, as recommended by many experts, health insurers will need to cover these treatments even before other drugs have been tried. For that to happen, we'll need convincing proof of how much better these drugs are when started at the start of arthritis.




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