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- Drug Withdrawn - Vioxx
- Fibromyalgia Treatment
Scientists throughout the world are studying many promising areas of new treatment approaches for arthritis and rheumatic diseases. These areas include monoclonal antibody therapy that is directed against a special inflammation factor called the tumor necrosis factor (TNFalpha) (as described below regarding Remicade and Enbrel), and new TNF human antibodies (see Humira below). Also, new non-steroidal antiinflammatory drugs (NSAIDs), with mechanisms of action that are different from current drugs, are on the horizon. There was interesting discussion about the arthritis drug Vioxx that was removed from the market on September 30, 2004 because of risks of heart attack and stroke (see below).Genetic research and engineering are also likely to bring forth many new avenues of earlier diagnosis and treatment in the near future.
Below are perspectives on key research reports presented at the recent national meeting of the American College of Rheumatology:
Vioxx, a drug that has been used to quiet inflammation of arthritis and relieve pain, was withdrawn from the market by its maker, Merck, on September 30, 2004.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.
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: Other reports of Remicade treatment of sarcoidosis and Behcet's disease are supported by this report. Remicade seems to have beneficial effects in many diseases that feature microscopic areas of tissue inflammation called granulomas. These diseases include Crohn's disease, Wegener's granulomatosis, and sarcoidosis.
Remicade was also reported to increase work productivity and decrease time lost from work in patients with psoriatic arthritis.
Dr. Shiel's Perspective: Part of overall health is function. This and other studies are reassuring in that the ultimate goals are being met for patients with serious forms of arthritis with aggressive treatments.
Dr. Shiel's Perspective: Enbrel has been approved for ankylosing spondylitis treatment within the past year. Remicade will be soon.
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. 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 rheumatoid arthritis was reported to have sustained benefit and safety after 7 years of treatment.
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!
Enbrel for ankylosing spondylitis was reported to have sustained benefit and safety for at least 24 months.
Dr. Shiel's Perspective: Enbrel appears to be a safe and effective treatment for ankylosing spondylitis. The only reason it is only 2 years is because that is how long the study has been running at this point.
Enbrel and Remicade were reported effective in treating ankylosing spondylitis as manifest by improvements in spinal MRI testing.
Dr. Shiel's Perspective: Enbrel has been approved for ankylosing spondylitis treatment within the past year. Remicade will be soon.
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.
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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.
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.
Etoricoxib (Arcoxia) is a Cox-2 inhibitor that is used in Europe and elsewhere to reduce pain and inflammation of arthritis.
Dr. Shiel's Perspective: This drug is somewhat related to Vioxx, another Cox-2 inhibitor that was withdrawn from the market by Merck because of heart attack and stroke side effects. 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. The drug is clearly effective for the inflammation of arthritis.
Several research centers reported on a new drug for treating the elevated levels of uric acid that lead to gout. This drug, febuxostat (Uloric), produced by TAP pharmaceuticals, can be used in persons who are allergic to allopurinol.
Dr. Shiel's Perspective: This is exciting news for the gout field. Rash allergic reactions to allopurinol do occur and this drug will provide a viable option in this setting. This is also important news for patients with kidney disease who have elevated blood levels of uric acid or gout because the drug is metabolized by the liver and not the kidneys like the traditional gout drug allopurinol. (Febuxostat) is not yet on the market in the U.S., but will likely be approved for use soon.
Etoricoxib (Arcoxia) is a new Cox-2 antiinflammation medication that can be effective in treating the acute attacks of gout.
Dr. Shiel's Perspective: We need more options in the treatment of arthritis attacks in gout patients. This drug is somewhat related to Vioxx, another Cox-2 inhibitor that was withdrawn from the market by Merck because of heart attack and stroke side effects. As a result, Arcoxia will likely be required to undergo significant further study before being released in the U.S. (It is already being used outside of the U.S.)
Dr. Shiel's Perspective: This one could be big. Cymbalta has been demonstrated by previous studies to be effective in relieving pain from nerve diseases. Early studies had suggested its potential as a treatment for fibromyalgia. It is classified as an antidepression medication. It is a potent inhibitor of the brain chemicals serotonin and norepinephrine. Interestingly, in this study, it worked whether or not the patients with fibromyalgia had depression.