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."