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Rheumatoid arthritis (RA) is an autoimmune disease that can cause chronic inflammation of the joints and other areas of the body. Rheumatoid arthritis can affect persons of all ages. Its cause is unknown. Rheumatoid arthritis is a chronic disease that is characterized by periods of disease flares and remissions. In RA, multiple joints are usually, but not always, affected in a symmetrical pattern (affecting both sides of the body). The chronic inflammation of RA can cause permanent joint destruction and deformity. The "rheumatoid factor" is an antibody blood test that can be found in 80 percent of patients with RA.
Rheumatoid arthritis is a common rheumatic disease, affecting more than two million people in the United States. The disease is three times more common in women than in men. It afflicts people of all races equally. The disease can begin at any age, but most often starts after age forty and before sixty. In some families, multiple members can be affected, suggesting a genetic basis for the disorder.
There is no known cure for RA. The treatment of RA optimally involves a combination of patient education, rest and exercise, joint protection, medications, and occasionally, surgery. Currently, doctors feel that the earlier patients with RA receive aggressive treatment, the better their long-term outcome.
Below are perspectives on key reports presented at the recent national meeting of the American College of Rheumatology:
Remicade (infliximab) is an antibody that blocks the effects of tumor necrosis factor alpha (TNF-alpha). TNF-alpha is a substance made by cells of the body that has an important role in promoting inflammation. TNF promotes the inflammation and its associated fever and signs (pain, tenderness, and swelling) in several inflammatory conditions, including rheumatoid arthritis. By blocking the action of TNF-alpha, infliximab reduces the signs and symptoms of inflammation and stops the progression of joint damage. Remicade is used to treat rheumatoid arthritis, Crohn's disease, and other serious forms of inflammation such as uveitis, psoriatic arthritis, and ankylosing spondylitis. Remicade is given by intravenous infusion over approximately 2 hours, usually every 4-8 weeks.
Dr. Shiel's Perspective: Rheumatologists have known that a small percentage of patients using Remicade treatment will develop autoantibodies (antibodies directed against the body's own tissues). Rarely, patients can develop features of lupus and patients are monitored for signs of this condition while taking Remicade.
French researchers found that Remicade treatment raised the blood levels of beneficial "good" cholesterol.
Dr. Shiel's Perspective: The relationship between blood vessel disease (atherosclerosis) and rheumatoid arthritis was highlighted by a number of papers reported at this meeting. The fact that aggressive treatment of the inflammatory disease, rheumatoid arthritis, can improve the cholesterol profile is very encouraging.
Researchers from Texas reported that Remicade with methotrexate was more beneficial than methotrexate alone in sustaining work employment.
Dr. Shiel's Perspective: We know that employment is directly associated with physical function. So this outcome measure of the effectiveness of Remicade is reassuring.
A multicenter study found that patients treated with Remicade had a diminished rate of bone density loss.
Dr. Shiel's Perspective: Patients with rheumatoid arthritis are at risk for the development of osteoporosis. This is felt to be due factors such as cortisone-related medication use, but also simply due to the effects of chronic inflammation. This is good news, though not surprising.
Enbrel is an injectable blocker of tumor necrosis factor for treating rheumatoid arthritis and psoriatic arthritis. Tumor necrosis factor (TNF) is a protein that the body produces during the inflammatory response, which is the body's reaction to injury. TNF promotes the inflammation and its associated fever and signs (pain, tenderness, and swelling) in several inflammatory conditions, including rheumatoid arthritis. Enbrel is a synthetic (man-made) protein that binds to TNF. Enbrel thereby acts like a sponge to remove most of the TNF molecules from the joints and blood. This prevents TNF from promoting inflammation and the fever, pain, tenderness, and swelling of joints in patients with rheumatoid arthritis (and apparently other forms of inflammatory arthritis, such as psoriatic arthritis, ankylosing spondylitis, and juvenile arthritis-see below). Enbrel is given by subcutaneous injection with a needle and syringe twice weekly.
Enbrel was found to be effective in a once weekly, 50 mg, dose!
Dr. Shiel's Perspective: This is big news for Enbrel users. Enbrel is now given by two 25 mg doses each week. Look for once weekly 50 mg dosing soon (next 2 months). Also, the new form of Enbrel will not require mixing powdered drug with sterile liquid as it is already premixed in a liquid solution! Obviously, far more convenient for patients using Enbrel.
Researchers again reported at this meeting, similar to last year, that patients whose rheumatoid arthritis is not controlled with Remicade can respond successfully to Enbrel.
Dr. Shiel's Perspective: Well this is very interesting. Since both Remicade and Enbrel block TNF as a key method of action, one might expect that switching from one drug to the other might not be effective. Wrong. The researchers point out that the reason for the benefit from switching might be related to the fact that they do differ slightly in their targets (Remicade binds to both a soluble form of TNF-alpha and to TNF-alpha bound to membranes of cells, while Enbrel binds to soluble TNF-alpha and to another chemical messenger lymphotoxin-alpha). Big words! They simply mean that if one fails on one TNF-blocking drug, it is rational to try another.
Enbrel for adults with rheumatoid arthritis was reported to have sustained benefit and safety after 7 years of treatment and for 4 years in children with rheumatoid arthritis.
Dr. Shiel's Perspective: Great news to have long-term data that supports the concept that this drug actually safely stops rheumatoid arthritis in its tracks!
Humira (adalimumab) is an antibody that blocks the effects of tumor necrosis factor alpha (TNF-alpha). TNF-alpha is a substance made by cells of the body that has an important role in promoting inflammation. TNF promotes the inflammation and its associated fever and signs (pain, tenderness, and swelling) in several inflammatory conditions, including rheumatoid arthritis. By blocking the action of TNF-alpha, adalimumab reduces the signs and symptoms of inflammation and stops the progression of joint damage. Humira is given by subcutaneous injection with a needle and syringe weekly or every other week.
In a study of 799 patients, researchers from a number of centers reported that Humira combined with methotrexate was extremely effective, and more effective than either drug alone, in treating very early rheumatoid arthritis.
Dr. Shiel's Perspective: This work is important for several reasons. We are finding that if we can turn off rheumatoid arthritis quickly and early we have a better chance of ultimately stopping the disease. Moreover, it seems that if we hit rheumatoid arthritis hard (such as with the combination of drugs as above), we significantly increase the chances of stopping the disease.
Humira was reported as effective in treating patients with rheumatoid arthritis who had already failed to improve with other biologic medications, such as Enbrel, Remicade, and Kineret.
Dr. Shiel's Perspective: These reports are welcome news for patients with rheumatoid arthritis. We need to have options available when we do not get the expected results from medications we use. It is interesting that Humira can work even when biologic medications that act similarly (Enbrel and Remicade) are not effective.
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Researchers from Germany reported that Humira is effective and safe for at least 6 years of study.
Dr. Shiel's Perspective: This report is encouraging as we are now accumulating more and more longterm data that suggests that the effectiveness of the drug is sustained.
Rituxan (rituximab) is an antibody that is used to treat lymphoma, cancer of the lymph nodes. It seems to be effective in treating autoimmune diseases like rheumatoid arthritis because it depletes B-cells, which are important cells of inflammation and in producing antibodies.
Rituxan was found to be beneficial in treating rheumatoid arthritis.
Dr. Shiel's Perspective: Rituxan would represent a novel approach as a treatment alternative in rheumatoid arthritis. This report is one of many suggesting that Rituxan may offer an alternative in treating rheumatoid arthritis. An interesting aspect of this reports treatment is that in the 2 years of the study, patients received Rituxan infusion only on days 1 and 15 they did fine without further infusions for the 2 year period while continuing with methotrexate treatment. It is not yet clear which patients would be the best candidates for Rituxan treatment.
Abatacept is a potential new treatment for rheumatoid arthritis on the horizon. It is unique in its method of action, which involves blocking the function of specialized immune cells called T-cells. Abatacept is given by intravenous infusion.
Abatacept was reported as effective and safe in treating patients with rheumatoid arthritis who had failed treatment with Remicade or Enbrel. Another paper reported that abatacept was effective in decreasing signs and symptoms of rheumatoid arthritis in patients failing methotrexate.
Dr. Shiel's Perspective: Abatacept may be a viable option in the near future for those patients who do not respond to Humira, Remicade, or Enbrel. Importantly, abatacept halted erosion of joints in the patients studied.
There was a fine lecture concerning folic acid given by American Cancer Society Clinical Research Professor, Dr. Barton A. Kamen. The lecture highlighted the importance of taking folic acid supplement, especially in persons taking methotrexate.
Dr. Shiel's Perspective: Rheumatologists have long been adding folic acid with methotrexate or sulfasalazine (Azulfadine) in order to minimize risks of side effects, including anemia and mouth sores. It turns out that the biochemistry of folic acid is such that it can decrease the risk of blood vessel disease (atherosclerosis) by lowering homocysteine levels! Moreover, it may have additional benefits in decreasing the risk of cancer and Alzheimer's disease!!
There were numerous reports that found a direct association between rheumatoid arthritis and blood vessel disease, including atherosclerosis as well as carotid and coronary artery disease.
Dr. Shiel's Perspective: This was big at this meeting. Patients with rheumatoid arthritis are at an increased risk for developing heart disease and heart attacks. It is very important for patients with rheumatoid arthritis to optimize their heart disease risk factors. This includes stopping cigarette smoking, controlling blood pressure, exercising regularly, weight reduction when necessary, and having evaluation of cholesterol profile, homocysteine levels, and blood sugar testing.
Researchers from Harvard and Spain reported data that clearly suggests that EARLY treatment is better, more effective, and that the effect is sustained over the long-term.
Dr. Shiel's Perspective: This report complements many like it that document the need for early diagnosis and aggressive treatment. The long-term benefit of early initiation of disease-modifying agents is clear as they can permanently alter the course of the disease.
Researchers from Spain found that the incidence of cancer in patients with rheumatoid arthritis who took biologic treatments, such as Remicade, Enbrel, and Humira, had no more cancer than rheumatoid arthritis patients who did not take these treatments.
Dr. Shiel's Perspective: While there is a theoretical increased risk of cancer, because of the method of action of these medications, this does not in fact seem to be the case.
Flu vaccine worked in rheumatoid arthritis patients inspite of immune suppressive medications such as prednisone, methotrexate, Plaquenil, Remicade, or Enbrel. The rheumatoid disease was not affected by the vaccination.
Citrulline antibody testing (anti-CCP antibody) was reported in several papers to be helpful in diagnosing early and more aggressive rheumatoid arthritis. It was also shown to be helpful in distinguishing rheumatoid arthritis from hepatitis C associated joint disease, which can be difficult. Another report noted that children with rheumatoid arthritis who had citrulline antibodies also were found to have more aggressive arthritis
Dr. Shiel's Perspective: Again, the earlier we hit this disease, the better. Furthermore, the presence of citrulline antibodies indicated rheumatoid arthritis with a greater than 95% accuracy! This confirms similar data presented at last year's meeting. Patients who had citrulline antibodies in their blood also had more aggressive rheumatoid arthritis. Researchers also found that some people had these antibodies present before the onset of rheumatoid arthritis and implied that citrulline antibody testing could predict who might develop the disease. I currently use the blood test not only to define more aggressive disease, but also to diagnose rheumatoid arthritis in patients that do not have the typical rheumatoid factor blood test (this occurs in approximately 20% of patients with rheumatoid arthritis) and in distinguishing rheumatoid from other forms of arthritis, such as that associated with hepatitis C virus infection.
Vioxx, a drug that has been used to quiet inflammation of arthritis and relieve pain, was withdrawn from the market by its maker, Merck, on September 30, 2004. The reason for the withdrawal was the occurrence of side effects noted in a study that Merck was conducting to see if Vioxx could prevent polyps of the colon and rectum. During this trial, it was noted that there was an increased risk for heart attack and stroke in patients continuing to take Vioxx longer than 18 months.
Dr. Shiel's Perspective: Vioxx is no longer available for use and those taking it should contact their physicians to consider alternative treatment. The risk of heart attack or stroke was small, but real. It is of note that there was no increased risk of stroke in patients taking Vioxx less than 18 months in the study. There has been no indication that any long term damage occurs once the drug is discontinued. The question of interest is a natural concern for inflammation medications of the same class as Vioxx. This class is referred to as Cox-2 inhibitors and includes Celebrex and Bextra NOTE: April 7, 2005, Pfizer agreed to suspend sales and marketing of Bextra in the U.S., pending further discussions with the with the FDA. For more information, please read the FDA press release. . At the national meeting, an FDA spokesperson commented that there is currently an ongoing trial of Celebrex in the prevention of colon polyps. The FDA asked that the 5 year study (now at 2 years) be opened to see if there were signs that Celebrex was increasing the risk of heart attacks or stroke in the study patients. The FDA has allowed the study to continue after reviewing the preliminary data. It therefore seems that not all Cox-2 antiinflammatory drugs are the same. The FDA spokesperson stated that there is no definitive evidence that Celebrex carries an increased risk for heart disease or stroke. It may be, in fact, that different Cox-2 drugs, having different powers of selective action on the Cox-2 enzyme, may have different potential for these blood vessel risks. More data will be forthcoming that will help to clarify risks of drugs used to treat inflammation. Interestingly, Merck has a drug now on the market outside of the U.S. that is used for pain and inflammation relief. The drug, etoricoxib (Arcoxia) was presented in 4 studies at the national meeting and shown to be safe and effective in treating gout, osteoarthritis, and ankylosing spondylitis. Etoricoxib (Arcoxia) is awaiting approval for use in the U.S. and while its maker notes that it has been shown to be safe, I believe it will undergo serious scrutiny of longer term studies prior to approval for the U.S. market.
Researchers from Germany presented data that demonstrates that different persons with rheumatoid arthritis may respond to medications differently, according to their genes. Additional research from Cambridge, Massachusetts found that gene profiles could be used to determine which patients with rheumatoid arthritis are at risk for more aggressive disease.
Dr. Shiel's Perspective: Welcome to the future of medicine. Gene profiling, also known as gene array analysis, is being identified as a helpful method of defining which people will respond to which medications. Studies are underway that are using gene array analysis to determine which patients with a given condition will be at more risk for more aggressive disease. This is all occurring because of technology improvements. We are at the threshold of tremendous improvements in the way diseases are managed.
Well, to finish off, sit back and enjoy this one. Researchers from Tokyo, Japan reported their research that looked at levels of chemical messengers in the blood of patients with rheumatoid arthritis. They compared before and after exposure to rakugo, "a traditional Japanese comic story that has been shown to induce mirthful laughter and improve mental stress." They found that the levels of the chemical messengers were affected by mirthful laughter and that there were significant differences in the levels that depended on the activity of the rheumatoid arthritis in each patient.
Dr. Shiel's Perspective: I'm still laughing at this one! Nevertheless, I get asked about stress and its relation to arthritis and related diseases nearly every day I practice rheumatology. This study highlights potential mechanisms that might explain why stress and relief of stress could actually cause chemical changes in the body that affect the onset and severity of disease. Perhaps laughter is the best medicine!
For more information, please visit the Rheumatoid Arthritis Index.
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