For people with rheumatoid arthritis (search), methotrexate is the treatment of choice in reducing pain and inflammation. But there’s evidence the drug can activate a virus that can increase risk of lymphoma and similar cancers in some patients.

The study appears in this month’s issue of the Journal of the National Cancer Institute.

A number of reports have linked methotrexate (search) with lymphoma and similar cancers of the lymph glands, says senior researcher Shannon C. Kenney, MD, a microbiologist and infectious disease specialist with the Lineberger Comprehensive Cancer Center at the University of North Carolina at Chapel Hill.

Also, studies have shown that when rheumatoid arthritis patients quit taking methotrexate, their lymphoma went into regression, another sign that the drug directly contributes to the cancer, she tells WebMD. Some studies have indicated that the drug's immune-weakening effect places people at risk for viral-associated lymphomas.

Another factor in this story: Epstein-Barr virus (EBV) (search), a herpes virus that is common among adults. Some 90 percent of adults are said to have EBV, which is associated with mononucleosis (search) and other infections — but in the vast majority of people, the virus remains latent, never causing an infection, says Kenney. EBV has also been linked with lymphoma.

In this newest study, methotrexate has been shown to activate latent EBV in cells infected with the virus, Kenney reports. High levels of circulating infectious particles of the EBV were also found in patients taking methotrexate for rheumatoid arthritis compared with patients taking other immune-weakening drugs.

Methotrexate and Lymphoma

In a series of laboratory tests involving cells with latent EBV virus, Kenney found that using methotrexate on cells that contained the latent Epstein-Barr virus activated the virus, causing an increase in the release of infectious EBV.

“An infectious form of the virus was released from the cells,” she tells WebMD. “We were surprised by that. We had already shown that certain kinds of chemotherapy could induce release of a form of EBV, but none would allow the infectious virus to be released.

Kenney’s colleagues also measured Epstein-Barr virus blood levels in 29 patients with rheumatoid arthritis, 12 with polymyositis, and 47 with Wegener granulomatosis (both are relatively rare inflammatory diseases). Some were taking methotrexate; some were taking other immune-suppressing medications.

They found that methotrexate activated the Epstein-Barr virus; the other rheumatoid arthritis medications — including cyclosporine, cyclophosphamide, and prednisone — did not markedly affect EBV activity, even when doses of these drugs were higher than normal, she reports.

Patients taking methotrexate had significantly higher EBV viral loads in their blood than patients taking other immune weakening drugs.

With methotrexate, it’s different. “Methotrexate activates cells with the Epstein-Barr virus, but it doesn’t prevent replication of the [virus]. So it spews out the virus in an infectious form,” she explains.

Similar results were found with polymyositis patients. However, the pattern was not found with Wegener granulomatosis — just as few lymphomas have been reported in these patients, she notes.

The data shows that methotrexate has a “unique ability” to trigger Epstein-Barr virus while also suppressing the immune system — thereby triggering lymphoma in these patients, she adds.

What’s Going On?

Scientists once thought that — because methotrexate suppresses the immune system — the body has difficulty eliminating the Epstein-Barr virus, Kenney explains. “There’s no question that the immune-suppressing ability of methotrexate is important for allowing EBV lymphomas to grow,” she tells WebMD.

But why are EBV lymphomas so closely tied with methotrexate? The lymphomas likely arise because “a combination of bad things is happening,” she explains. “The immune system is suppressed and unable to handle the increasing amount of EBV in the blood.”

Why do some patients get lymphoma? “I’m not sure,” says Kenney. Research shows that rheumatoid arthritis patients have been shown to have higher levels of Epstein-Barr virus in their blood, and their T cells don’t control EBV very well. T cells help rid the body of cells that have been infected by viruses as well as cells that have been transformed into cancer.

Another recent study showed that antibodies, which can help diagnose rheumatoid arthritis called rheumatoid factor, can also reactivate EBV.

A cautionary note: “These lymphoma cases are rare among methotrexate takers,” Kenney tells WebMD. “We want to emphasize that fewer than 1 in 1,000 patients per year who get methotrexate who have rheumatoid arthritis get EBV lymphoma. It’s a very low-risk situation. We do not recommend that people stop taking methotrexate.”

Mary Jo Lechowicz, MD, professor of hematology/oncology at Emory University’s Winship Cancer Center in Atlanta, has conducted her own research of Epstein-Barr virus and HIV. “It’s not clear how long these patients had been treated with methotrexate. We don’t always see these lymphomas immediately after they start the treatment. Actually, with people living longer, this study also makes us wonder about the long-term risks of any drug treatment.”

Lechowicz says, “There are other factors, other lymphomas that are not EBV-related but may have EBV present. The question, as in this paper, is is EBV the cause? Is it the immune system’s inability to control EBV infection, so it goes out of control? Or is it something we don’t yet know at all? We need further studies to be able to delineate that further.”

She, too, does not advise quitting methotrexate in the short term, says Lechowicz.

By Jeanie Lerche Davis, reviewed by Brunilda Nazario, MD

SOURCES: Feng, W. Journal of the National Cancer Institute, Nov. 17, 2004; vol 96: pp 1691-1702. Shannon C. Kenney, MD, microbiologist and infectious disease specialist, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill. Mary Jo Lechowicz, MD, professor of hematology/oncology, Emory University Winship Cancer Center, Atlanta.