Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease that affects 2 million Americans. It is not a benign disease. Up to half of those with the disease are disabled after 15 years due to crippling deformity.
The first example is methotrexate. This drug is an immunosuppressant that inhibits dihydrofolate reductase. By doing this it inhibits the growth and proliferation of lymphocytes which are important cells involved in the autoimmune process.
Another example is azathioprine (Imuran). This drug inhibits T-lymphocytes, a population of lymphiocytes that are important in the initiation of autoimmunity.
Cyclophosphamide (Cytoxan) alkylates and crosslinks DNA essentially poisoning cells. Neither azathioprine nor cyclophosphamide are used much anymore for rheumatoid arthritis because of toxicity issues. All three drugs… methotrexate, azathioprine, and cyclophosphamide are still used to treat various cancers.
More recently, biologic treatments have been used to treat RA. One biologic treatment that has performed well in RA is rituximab (Rituxan). This drug is considered one of the drugs of choice for the treatment of non-Hodgkins lymphoma. Rituximab depletes a population of B cells called CD20. CD20 cells are instrumental in the perpetuation of RA.
A recent intriguing study suggests another anti-cancer agent, Gleevec, may have promise in RA. Gleevec is currently used to treat leukemia and some gastrointestinal cancers.
Researchers at the Stanford University School of Medicine, led a team that set out to find drugs that might provide additional benefit to rheumatoid arthritis patients. They screened a range of drugs in mice that have a condition similar to human rheumatoid arthritis.
In their study, Gleevec almost completely prevented the development of a rheumatoid arthritis-like disease in mice. The drug also halted the progression of established disease, significantly reducing the amount of inflammation and bone destruction around the joints. The researchers also tested Gleevec on the cells of human rheumatoid arthritis patients and found that it reduced the processes associated with inflammation and abnormal growth in the joints.
Gleevec is the brand name of imatinib, a drug produced by the pharmaceutical company Novartis AG. It is part of a class of drugs called kinase inhibitors, which act by blocking communication signals between cells. These signals, when they go awry, are often at the root of diseases such as cancer and autoimmune conditions.
Gleevec targets kinase gene mutations seen in chronic myelogenous leukemia or CML (a bone marrow cancer) as well as certain types of stomach cancers. The same kinases turn out to play a critical role in rheumatoid arthritis.
William Robinson, senior researcher, said that the field of autoimmune disease research has been trying to develop kinase inhibitors for more than a decade. "We were very surprised that Gleevec worked as well as it did," said Robinson. "It just seemed too simple." The results are especially encouraging since the drug is already FDA-approved, and has relatively few side effects."
We have taken a very potent kinase inhibitor and discovered that it works very well for an autoimmune disease," said Robinson. "The significance is twofold. First, it might provide insights into the mechanisms underlying rheumatoid arthritis by figuring out what Gleevec inhibits. “Second,” he added, “it might represent a new therapeutic approach to rheumatoid arthritis and other autoimmune diseases. The kinases the drug inhibits likely play a role in other autoimmune diseases, such as scleroderma, psoriasis and inflammatory bowel disease.”
Robinson said he hopes that in the near future, clinical trials will be conducted that look at the drug's effectiveness for a range of autoimmune diseases.
(Paniagua RT, Ho PP, Chan SM, Changf A, Higgins JP, Tomooka BH, Thomas FM, Song JJ, Goodman SB, Lee DM, Genovese MC, Utz, PJ, Steinman L, Robinson WH. Selective tyrosine inhibition by imatinib mesylate for the treatment of autoimmune arthritis. J Clin Invest. 2006; 116: 2633-2642).
Note: Part of this story was adapted from a news release issued by Stanford University Medical Center.
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