RESEARCH - Gleevec (imatinib) may be effective therapy for RA, researchers find

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Stanford School of Medicine

Patient Care Spotlight

October 2006

Gleevec may be effective therapy for rheumatoid arthritis, researchers find

By Mitzi Baker

The potent cancer drug Gleevec, used to combat leukemia and some

gastrointestinal cancers, may be useful in treating rheumatoid arthritis,

according to a team of researchers at the School of Medicine. Their findings

will be published in the October issue of the Journal of Clinical

Investigation.

Although the study shows that Gleevec worked well in mice, the researchers

cautioned against doctors using Gleevec for treating rheumatoid arthitis

until clinical trials are completed demonstrating its effectiveness and

safety for people with the disease.

Rheumatoid arthritis is a painful chronic autoimmune disorder, characterized

by inflammation of the lining of the joints. It affects more than 2 million

Americans; up to half of those with the disease are disabled after 15 years

due to disfigured joints. Standard therapy for rheumatoid arthritis now

includes agents that suppress the immune system, but many patients do not

benefit from such treatments. They do not get adequate reduction in the

symptoms and signs of disease; they continue to have damage to their joints

or develop side effects that makes continued use of such existing therapies

impossible. Thus, newer approaches are still needed.

Bill , MD, PhD, assistant professor of medicine and the study's

senior author, 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.

Paniagua, an MD/PhD student and the study's first author, explained

that they looked at every drug approved by the U.S. Food and Drug

Administration, considering which ones might modulate the immune system and

thus be effective in combating an autoimmune condition, regardless of the

drug's FDA-approved use. Paniagua chose several drugs to test, including an

antihistamine, a platelet modulator and other approved drugs with known

effects on cells of the immune system.

" It was the combination of rational selection and serendipity that we found

that Gleevec worked better than anything else, " said Paniagua, who works in

's laboratory at the Geriatric Research, Education and Clinical

Center of the Palo Alto Veterans Affairs Health Care System.

In their study, Gleevec almost completely prevented the development of the

rheumatoid arthritis-like disease in the 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) and certain types of stomach cancers. The same

kinases turn out to play a critical role in rheumatoid arthritis.

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 . " It just seemed too

simple. " The results are especially encouraging since the drug is already

FDA-approved, and has relatively few side effects. None of the authors in

the study has any affiliation with Novartis.

" We have taken a very potent kinase inhibitor and discovered that it works

very well for an autoimmune disease, " said . " The significance is

two-fold. 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.

Gleevec's potential in humans is buoyed by two published case studies of

rheumatoid arthritis patients with CML; both experienced significant

improvements in their arthritis symptoms after taking Gleevec to treat their

cancer. In addition, there has been a published case study of Gleevec

alleviating psoriasis in a cancer patient.

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.

Others who contributed to the study are associate professors of medicine

Mark Genovese, MD, and Utz, MD; professor of orthopedic surgery Stuart

Goodman, MD; assistant professor of pathology Higgins, MD; professor of

neurology and neurological sciences and of pediatrics Lawrence Steinman, MD;

research associate Peggy Ho, PhD; research assistants Share Orr, MS, and

Beren Tomooka, MS; MD/PhD student Chan; medical fellow Song,

MD; Stanford undergraduate Chang, and visting undergraduate Fiona

.

To download a copy of the paper, which has been posted in advance of

publication, visit http://www.jci.org and do a search of the site using the

term " imatinib mesylate. "

Posted: 10/06/06

http://med.stanford.edu/patient_care/spotlight/archive/gleevec.html

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