Rheumatoid Arthritis and Lymphoma

Having rheumatoid arthritis can increase the risk of a cancer called lymphoma. If you have RA, here's what you need to know about the arthritis-cancer connection

By Nancy Ross Flanigan

Maureen Lengel, 52, has been through a lot since being diagnosed with arthritis in her teens: several surgeries, including hip replacements, and an assortment of other treatments for rheumatoid arthritis. Lymphoma is the last thing she needs is to worry about. Along with the many difficulties of rheumatoid arthritis, cancer worries lurk in her mind.

"I know that people with RA have a higher risk of developing cancer," says Lengel, who keeps up on the latest news related to her disease by reading, sharing and discussing information with her doctor. The worry first set in for Lengel in the mid-1980s, when she realized the methotrexate she was taking for RA was the very same drug her friend’s mother was receiving for breast cancer. She did a little research and learned that higher doses of the drug kill abnormal cells in cancer treatment, whereas the lower doses used for RA merely quench the abnormal behavior of cells.

"Whether it is the disease itself or the drugs people take for it that increase the risk, I've seen articles on both sides of the story," she says. "Some say RA drugs may not raise cancer risk, but there are also articles that link cancer, specifically lymphoma, to one of the drugs I’m taking now. Naturally I am concerned."

So are many of the patients that Lengel’s rheumatologist, Mary Chester Wasko, MD, sees at the University of Pittsburgh Medical Center. Trying to help them sort out the facts isn’t always easy.

"The RA and cancer connection is such a worry of so many patients," says Dr. Wasko. "They read about studies that are highlighted in the press and then wonder why their doctors can't give them a straight answer. It is not that we’re trying to be elusive, it is just that many of the studies have limitations that make interpreting the results difficult."

We asked top experts to clarify the connection between cancer and rheumatoid arthritis – lymphoma in particular. Like Lengel, share this information with your doctor and have an open discussion about your own risks.

Cancer and RA: same system opposite effects

"RA is not cancer – let's be clear about that – but RA has some features that resemble cancer, so treatment we would normally think of as oncolytics have application to RA," says Gary S. Firestein, MD, chief of the Division of Rheumatology, Allergy and Immunology at the University of California, San Diego. Kinship at the cellular level makes such treatment crossovers possible, he says.

The two diseases have a faulty immune system in common, says rheumatologist Daniel E. Furst, MD, of the University of California, Los Angeles.  "Cancer occurs when the body's normal immune response to cancer cells, which appear in us all the time, fails. The immune system doesn’t catch something that’s abnormal. In autoimmune diseases such as RA, lupus, Sjogrens syndrome, psoriatic arthritis, myositis, sarcoidosis and scleroderma, the immune system overreacts to the normal, turning against itself," says Dr. Furst.

Those autoimmune diseases have been linked to an increased risk of cancer – lupus with lung or blood cancer; Sjogrens syndrome with lymphoma; psoriatic arthritis with skin cancer; myositis with all types of cancer; sarcoidosis with skin, liver, lung and lymphoma; and scleroderma with lung cancer. So why has RA's link to lymphoma been studied the most intensively? One reason is that many of the medications suspected of increasing the lymphoma risk are approved to treat RA but not the other autoimmune diseases. Another is that RA involves a cellular process akin to tumor growth.

In RA, the delicate lining that surrounds and protects a joint, known as the synovium, becomes inflamed, making the joint swollen and painful. As the disease progresses, the cells that make up the synovium go through a process much like what happens in cancerous tumors: Normal cells multiply unchecked and invade and destroy healthy tissue.

To complicate matters, says Dr. Furst, many drugs used to treat RA suppress the immune system, meaning the immune cells that search the body for cells gone bad aren’t able to do their job.  "If a drug suppresses not only the abnormality that’s causing the disease but also suppresses immune surveillance, one could get cancer from the therapy," he says.

That is the theory. What about the evidence? It has been accumulating for some time. The first hints that RA patients were more vulnerable to cancer surfaced in 1978, when researchers in Finland matched hospital records of patients treated for RA with patients treated for cancer and saw the overlap. That study, as well as subsequent studies of RA patients from around the world, showed a higher incidence of lymphoma, non-Hodgkins lymphoma in particular, in people with RA compared with people without RA.

By current estimates, the lymphoma risk is two to four times greater for people with rheumatoid arthritis. Cancer risk of any kind is certainly a weighty matter, but when you consider the rarity of non-Hodgkin's lymphoma – about 18 cases per 100,000 people compared with 119 per 100,000 for breast cancer and 150 per 100,000 for prostate cancer – even the elevated risk is still relatively low (less than 0.1 percent per year).

The risk is relatively low, but elevated nonetheless. Patients who have RA want answers, and researchers who study RA want to provide them. Whether it’s the RA, its treatment or some combination of the two that raises patients’ cancer risk is what medical scientists have been trying to determine ever since the 1978 Finland study.

Just as detectives first home in on suspects with criminal records, researchers turned their attention to a drug with a known cancer connection. The immunosuppressive drug azathioprine (Imuran) had first been linked to lymphoma in transplant patients who took it to prevent organ rejection. When investigators looked at RA patients who took Imuran to keep the immune system from overreacting against itself, they found the same association. And the longer a person had taken the drug, the higher their risk.

Methotrexate (Rheumatrex) was the next drug to come under scrutiny following a 1991 report of a patient developing lymphoma while taking it. A phenomenon called reversible lymphoma, which arises when people begin taking methotrexate and disappears when they stop, has been reported in some 50 RA patients. But large-scale studies have failed to finger methotrexate as the culprit behind the overall rise in cancer risk for people with RA.

Now attention has turned to the newer biologic drugs that inhibit tumor necrosis factor (TNF), and for good – or at least logical – reason. TNF is a versatile protein that promotes the inflammation associated with painful, swollen joints and bone tissue destruction in RA, but originally it was pegged for eliminating cancerous tumors. 

Might drugs that block TNF's pro-inflammatory properties also hamper its tumor-fighting tendencies? That's been the concern since TNF inhibitors such as adalimumab (Humira), etanercept (Enbrel) and infliximab (Remicade) came on the scene during the past decade. But because they've been on the scene for a relatively short period of time, many long-term studies looking at lymphoma risk haven't been done. 

So far, "the evidence is mixed," says Dr. Wasko. "Some studies point to a slight increase in risk of lymphoma in RA patients who receive TNF inhibitors, but it’s not a consistent finding across all studies."

It is possible that TNF-inhibiting drugs have contradictory effects, raising cancer risk in some situations and lowering it in others. That's a plausible scenario given the mercurial nature of the protein they target. 

TNF is important in containing or eliminating tumor cells, but there’s also some evidence that it may actually promote tumors, says Dr. Wasko. "The net effect could depend on your ethnic background, your exposure to toxins in the environment, or on multiple factors. And it may depend on what type of cancer you’re talking about. The effect on lymphoma risk could be different from the effect on colon or lung cancer risk."

Frederick Wolfe, MD, director of the National Data Bank for Rheumatic Diseases in Wichita, Kansas, points out another factor that makes it difficult to neatly tie together lymphoma and TNF inhibitors. "If you have severe RA, you are more likely to be prescribed a biologic, but you are also more likely to get lymphoma because of the severity of your disease whether or not you get the biologic," he notes. "It's difficult to disentangle the effect."

To tangle matters even more, lymphomas are relatively rare, so researchers must study large numbers of RA patients in order to find enough lymphoma cases to draw meaningful conclusions. But RA itself, although the second most common arthritis diagnosis, is fairly rare, occurring in only one percent of the general population.

With those caveats in mind, consider the results of recent studies, which shift the blame away from treatments and suggest that keeping RA in check should be your biggest concern.

In research published in Arthritis and Rheumatism, investigators at Harvard Medical School and the University of British Columbia pooled medical databases from Pennsylvania, New Jersey and British Columbia to compare cancer rates between patients using the older disease-modifying anti-rheumatic drug (DMARD) methotrexate and those using a newer, biologic drug such as a TNF-inhibitor. The conclusion? Users of biologic agents are no more likely than users of methotrexate to develop cancer. Similarly, a study of 19,562 patients led by Dr. Wolfe and his colleague, Kaleb Michaud, PhD, showed no evidence for an increase in lymphoma incidence in those on TNF inhibitors.

In another investigation, also published in Arthritis & Rheumatism, Swedish researchers mined a national registry of nearly 75,000 RA patients and analyzed medical records and case histories of a subset of 378 RA patients who had developed lymphoma between 1964 and 1995 and 378 lymphoma-free patients. They found a dramatic association between lymphoma and disease activity, which is determined by currently swollen or tender joints, increased levels of inflammatory markers and X-ray evidence of erosion in at least one joint.

Compared with patients with low RA activity, those with medium disease activity showed an eight-fold increase in the likelihood of developing lymphoma. For those with high activity, the probability took a staggering 70-fold jump, leading the authors to conclude that with aggressive treatment to suppress the disease activity of rheumatoid arthritis, lymphoma risk might actually be reduced.

As for other cancers, Dr. Wolfe and Michaud studied 13,000 patients participating in a research project between 1998 and 2005, looking specifically at links between treatment with a biologic agent and cancer risk. They found that biologic therapy doubled the odds of developing skin cancers, including melanoma, but did not put patients at greater risk for lymphoma, breast, lung, colon or any other cancer.

"These increased risks that we identify and report are extremely small," Dr. Wolfe stresses. "Melanoma is serious but not common; most other skin cancers are not serious. I don't think anyone should be concerned."

Weighing all the evidence about the rheumatoid arthritis–cancer connection, Dr. Furst offers this advice to patients: "Rheumatoid arthritis is a very serious disease, and overall, the therapeutic benefits of the drugs used to treat it far outweighs their downsides. The risk from not doing anything to contain the disease is much greater."