Having rheumatoid arthritis (RA) could put you at greater risk of developing a type of cancer called lymphoma. But is it due to the RA itself, or are the medications used to treat the disease responsible? Despite years of study, many questions are still unanswered, says Margaret Miller, MD, a rheumatologist and infusion physician at the University of Arizona Cancer Center in Tucson.

Lymphoma is a cancer of the lymphatic system, an important part of your immune system that helps fight off infection and disease. Non-Hodgkin lymphoma is the most common type. It’s estimated that people with rheumatoid arthritis have twice the risk of lymphoma as people who don’t have RA, says Dr. Miller, adding that people with other autoimmune diseases, like lupus, also are at higher risk of lymphoma.

Rheumatoid Arthritis and Lymphoma: A Trigger?

Miller offers an explanation for the increased risk. Because of the chronic inflammation in RA, the immune system is constantly “turned on,” triggering cells called B lymphocytes to divide rapidly and multiply. As these cells duplicate, mistakes can be made, causing a normal lymphocyte to produce one with faulty DNA. The new cell malfunctions, reproduces itself, and results in cancer.

Should you fear getting lymphoma if you have rheumatoid arthritis? “The incidence of RA and lymphoma is small,” says Scott Zashin, MD, clinical associate professor of medicine at the University of Texas Southwestern Medical School and attending physician at Presbyterian Hospital in Dallas. However, he notes that the risk is higher than in the general population and thought to be linked to the severity of the RA. Zashin and Miller agree: It’s believed the more severe the disease, the higher the risk.

Both doctors pointed to Swedish research that looked at data from 75,000 RA patients in a cancer registry. The study published in Arthritis and Rheumatism compared 378 people diagnosed with lymphoma between 1964 and 1995 to 378 similar patients who did not have the cancer. Researchers found that those with moderate RA disease were eight times more likely to develop lymphoma than those with mild disease, but people with the most severe rheumatoid arthritis were about 70 times more likely to get the cancer. The authors found that standard non-biologic medication did not increase risk and concluded that marked inflammation was to blame.

Rheumatoid Arthritis and Lymphoma: A Look at Medications

Aspirin, non-steroidal anti-inflammatory drugs (NSAIDs), steroids, disease-modifying anti-rheumatic drugs (DMARDs), and targeted biologic agents are among the drugs used to treat RA.

DMARDs, and specifically methotrexate (Rheumatrex), are standard care for most RA patients and can put the brakes on inflammation and destruction of the joints. They work by suppressing the overactive immune system.

Miller says there have been cases, though rare, of people developing lymphoma while taking methotrexate, including some cases where the lymphoma disappeared after stopping the medication.

Biologic drugs suppress different parts of the immune system that play a role in RA. One type of biologic drug targets a specific protein called tumor necrosis factor (TNF), a leading culprit responsible for inflammation in the joints. The medications are called anti-TNF drugs and include etanercept (Enbrel), adalimumab (Humira), and infliximab (Remicade). Anti-TNF drugs and other biologics are seen as a major development in RA treatment, giving patients a new lease on life, but they also carry risks, including infection and possibly cancer.

Anti-TNF drugs came on the scene in the late 1990s. The Food and Drug Administration (FDA) has received reports of lymphoma and other cancers in people taking the drugs. In 2009, the FDA required manufacturers to issue stronger cancer warnings on drug labels, especially when the medications are used in children and adolescents.

Zashin says early studies did show a possible increased risk of lymphoma in RA patients taking the anti-TNF drugs, but longer term studies have not confirmed the risk. He says the results of the earlier studies “may have been skewed by the fact that those patients with more severe disease were initially put on these drugs.”

Treating RA While Watching for Lymphoma

Both Zashin and Miller say that right now there’s no way to prevent lymphoma in RA patients. Although not proven, it’s believed that early and aggressive treatment with DMARDs and anti-TNF drugs could keep the disease from becoming severe, thus lowering the risk of lymphoma. 

Your doctor will take a thorough look at your medical history and the severity of your RA before deciding on a treatment plan. Miller says rheumatologists keep an eye out for any possible signs of lymphoma, no matter what medications you take. She notes that abdominal problems, night sweats, fever, and persistent lymph node swelling are red flags. If lymphoma develops, DMARDs and biologic drugs, which suppress immune function, are discontinued. The drug rituximab (Rituxan) may be used as part of lymphoma treatment and is also used as a medication for RA.

Miller is encouraged that rheumatologists have had more options to offer patients in the last 10 years, adding that research continues to provide a better understanding of the immune system and, once the cause of rheumatoid arthritis can be determined, even more options will be on the horizon.