News Release

CHAPEL HILL -- In a recent study, researchers found that patients treated with methotrexate for rheumatoid arthritis or the muscle disease polymyositis may be more likely to develop certain types of cancer because of a reactivated virus.

The cancer incidence is rare, however – fewer than one in 1,000 per year in methotrexate-treated patients.

Methotrexate, a treatment for the autoimmune diseases rheumatoid arthritis and polymyositis, may promote the development of Epstein-Barr virus (EBV)-positive lymphomas in patients with these diseases, the researchers said.

Methotrexate may promote cancers by reactivating latent EBV and by suppressing the immune response, they added.

The findings are reported in the Nov. 16 issue of the Journal of the National Cancer Institute. The research team includes scientists at the University of North Carolina at Chapel Hill’s Lineberger Comprehensive Cancer Center and the National Institutes of Health

EBV is a human herpesvirus that causes mononucleosis and infects more than 90 percent of the adult population. The virus establishes a lifelong persistent infection of B cells, which is usually asymptomatic. In rare cases, EBV is associated with a variety of B-cell lymphomas, including Hodgkin’s and non-Hodgkin’s lymphoma.

EBV-positive lymphomas occur more frequently in rheumatoid arthritis and polymyositis patients taking the drug methotrexate than in patients treated with other equally immunosuppressive drugs.

Rheumatoid arthritis is a chronic autoimmune disease, mainly characterized by inflammation of the lining, or synovium, of the joints. It affects approximately 1 percent of the U.S. population, or 2.1 million people.

Polymyositis is a rare inflammatory muscle disease that causes varying degrees of decreased muscle power. The disease has a gradual onset and generally begins in the second decade of life.

By studying the effect of methotrexate on EBV-infected cell lines, Dr. Shannon Kenney and colleagues found that methotrexate induces reactivation of EBV from latent infection, leading to the release of infectious forms of virus called virions.

Kenney is Sarah Graham Kenan professor of medicine and microbiology and immunology in the School of Medicine and a member of UNC Lineberger. She is principal investigator of the study.

"We were really surprised to find out how potently methotrexate activates replication of the EB virus in cells," said Kenney. "These results may help explain why methotrexate treatment in patients sometimes, although rarely, is associated with the development of EBV-positive tumors."

Her laboratory research correlated with clinical findings of Dr. Jeffrey Cohen and other physicians at the National Institute of Allergy and Infectious Diseases who treat autoimmune disease patients at the NIH.

"While we did find an association between increased levels of EB virus in the blood of patients with rheumatoid arthritis receiving methotrexate which supports the in vitro data, the benefits of methotrexate for treatment of this disease outweigh the very low risk of EB virus-positive B-cell lymphoma in patients treated with this drug," said Cohen.

"Furthermore, patients with rheumatoid arthritis have developed B-cell lymphomas in the absence of methotrexate therapy."

The researchers also found that rheumatoid arthritis and polymyositis patients treated with methotrexate had a higher level of EBV in the blood than patients treated with other immunosuppressive regimens such as corticosteroids, leflunomide or etanercept (Enbrel).

The combination of methotrexate’s ability to induce EBV replication in such patients while promoting immunosuppression might explain the association of the drug with EBV-positive lymphomas, the researchers said.

Previous research has shown that in rheumatoid arthritis patients being treated with methotrexate, tumors regress once methotrexate therapy is reduced or discontinued.

One other group of patients with the autoimmune disease Wegener’s Granulomatosis (WG), a form of vasculitis, a disease that inflames small blood vessel, was included in the study. In WG, however, no correlation was found between being treated with methotrexate and an increase in EBV load or tumor development.

Other UNC Lineberger authors on this study are Dr. Nancy Raab-Traub, professor of microbiology and immunology in UNC’s School of Medicine and virology program leader for UNC Lineberger; and Wen-hai Feng, research associate in Kenney’s laboratory.

Funding was provided by several NIH grants.

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UNC Lineberger contact: Dianne Shaw, (919) 966-5905

National Institute of Allergy and Infectious Diseases contact: Office of Communications and Public Liaison, (301) 402-1663