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Medical advances have transformed the treatment of rheumatoid arthritis (RA), a chronic inflammatory condition in which the immune system attacks the synovium (a thin layer of soft tissue) that lines the joints, causing swelling, pain and, in severe cases, immobility and deterioration of the joints. While many mysteries remain (some scientists question whether RA is a single disease or many different diseases with one name), progress is being made. “We know much more about the biology of inflammation, tissue destruction and repair,” says Nortin Hadler, M.D., professor of medicine and microbiology/immunology at the University of North Carolina at Chapel Hill and spokesperson for the American College of Rheumatology. “As that knowledge advances, more and better treatments for rheumatoid arthritis are becoming available.” Here, the biggest breakthroughs in the past 20 years, and what lies ahead.
Saving joints. Up through the 1980s, the only treatments available for rheumatoid arthritis were medications that could relieve the symptoms, including gold salts, antimalaria drugs like hydroxychloroquine, anti-inflammatory steroidal medications (such as prednisone and methylprednisolone) and nonsteroidal anti-inflammatory medications (NSAIDs) like indomethacin and aspirin. Some are still used today, mostly for treating the pain and inflammation of acute flares, and as adjuvant therapies in the long-term management of RA.
In the mid-1980s, doctors began using methotrexate, the first of a new category of medications called disease-modifying antirheumatic drugs (DMARDs), to treat rheumatoid arthritis. In studies, methotrexate relieved RA symptoms and stopped progression of the disease, protecting the joints from damage. “Methotrexate does a very good job of controlling rheumatoid arthritis in at least half of people who are severely affected by it,” says John Hardin, M.D., chief science officer for the Arthritis Foundation. Methotrexate is still a first-line treatment for severe RA, but there are several other DMARDs now available, so if one doesn’t work for a particular patient, another of this category of drug may be the answer.
Blocking messages. The 1990s saw the development of drugs that addressed RA at its source, thanks to the discovery of molecules that play a part in inflammation. One of the first such molecules was tumor necrosis factor, or TNF alpha, a type of immune system protein called a cytokine that acts as a messenger, triggering inflammation in the body. Scientists began developing drugs that could block TNF and stop those messages from being received. These TNF-alpha blockers belong to a class of genetically engineered drugs called biologics, designed to interrupt the inflammation process. Today there are several TNF-alpha blockers on the market, including etanercept (Enbrel), adalimumab (Humira) and infliximab (Remicade). “They’re not a home run for every patient, but in a significant percentage of people they do work and sometimes even induce remission of the disease,” says Dr. Hadler.
The biologic boom. Since the introduction of TNF-alpha inhibitors, many immune system cells and other cytokines that play major roles in rheumatoid arthritis have been identified. These include T cells, which, when activated by an infection, injury or other threat to the body, multiply and produce cytokines such as TNF, interleukins (proteins known to increase swelling, pain and stiffness in the joints) and other messenger cells that lead to inflammation. The understanding of T-cell properties led to the development of additional biologics designed to target T cells and thereby stop the immune process in its tracks. In late 2005, the FDA approved abatacept (Orencia), the first drug for RA that decreases symptoms by blocking T cells.
Shortly after abatacept was approved, another drug came on the RA market called rituximab (Rituxan), which reduces a type of white blood cell known as B cells that fuel the immune response that leads to rheumatoid arthritis symptoms. When given together with methotrexate, studies show these biologics can provide long-lasting relief from RA symptoms.
Not surprisingly, people with rheumatoid arthritis have higher than normal levels of several types of interleukins, leading to the development of medications that block them directly, including anakinra (Kineret) and tocilizumab (Actemra). Research shows that these medications can work in certain people who do not respond well to DMARDs. More interleukin blockers are in the research pipeline.
A bright future. The National Institutes of Health lists more than 1,000 clinical trials pertaining to rheumatoid arthritis currently taking place, but not all RA research is focused on drugs. Some studies are examining environmental factors that might contribute to whether a person develops the condition; smoking, exposure to air pollution and obesity have all been identified as possible factors that make someone more likely to develop the disease. In addition, thanks to the human genome project, doctors are fast discovering ways to determine which medications are going to work best for individuals, so that in the future, RA patients may require less trial and error to find the drug that works best for them.
“We may soon have the ability to look at the genetic profile of an individual and identify traits that say that they will respond best to certain drugs, and get patients on the right drug at the right time,” says Dr. Hardin. “The second thing that is beginning to emerge as an exciting possibility is that these drugs might be used in combination very early in the disease, really with the goal of achieving a complete remission, and then in a year or so people could taper off those drugs and be drug-free and disease-free.”