Anti-TNF Blockers & Lymphoma

Ever since the first so-called TNF blocker was approved by the Food and Drug Administration in 1998, there have been concerns about an association between these drugs and the risk of developing certain subtypes of lymphoma.

A case is being heard in court in Chicago at the moment regarding a woman who developed a B-cell lymphoma after taking Humira, one of these TNF blockers. In this entry, I'll review what TNF blockers are, and take a look at contradictory studies about that risk that have been published over the years.

Inflammatory Conditions and TNF Blockers

Anti- tumor necrosis factor (TNF) blockers are in a class of drugs first approved for the US market in 1998. They help to reduce the inflammation and disease progression in inflammatory conditions such as rheumatoid arthritis (RA), psoriatic arthritis, juvenile arthritis, Crohn's colitis, ankylosing spondylitis and psoriasis by blocking the activity of TNF, a chemical in the body that causes inflammation.

The body's immune system produces TNF. When excess amounts appear in the blood, it gets blocked naturally in people who are otherwise healthy. In those who have an inflammatory condition, those rising blood levels of TNF don't get blocked. The result is unnecessary inflammation and subsequent damage to the joints, as well as possible damage to organs and other parts of the body.

According to the American College of Rheumatology, RA affects about 1.3 million people in the US, with women outnumbering men two to one.

FDA Approved TNF Blockers

There are currently five such drugs (listed below, followed by the year they were approved by the US Food and Drug Administration)

• Infliximab, marketed as Remicade (1998)
• Etanercept, marketed as Enbrel (1998)
• Adalimumab, marketed as Humira (2002)
• Certolizumab, marketed as Cimzia (2008)
• Golimumab, marketed as Simponi (2009)

Three of these are approved for specific use in children: Etanercept and Adalimumab for juvenile idiopathic arthritis (JIA), and Infliximab to treat Crohn’s disease.

In clinical trials of all these drugs for the treatment of RA, the majority of positive trials occurred when the anti-TNF blocker was combined with the chemotherapeutic drug methotrexate.

Reviewing the Flip-Flop

Prior to the arrival of TNF blockers, there was an understood association between inflammatory conditions and autoimmune disorders and increased cancer risk. Not well understood, the association was nonetheless identified. However, within a few years of FDA approval, studies began appearing that linked these disorders and TNF blockers with various cancers, especially lymphomas.

As these studies began to surface, other studies would surface contradicting them:

-- In 2002, researchers from the FDA's Center for Biologics Evaluation and Research published a report of 26 cases of lymphoma among patients taking TNF blockers in the journal Arthritis & Rheumatism.

-- In 2003 the FDA concluded that although non-Hodgkin's lymphoma incidence was slightly higher in people with RA compared to the rest of the population, they found no association with the use of TNF blockers and this elevated incidence.

-- In 2008 the FDA issued an alert that cancers were unusually high in children taking TNF blockers. Notably, they found 48 cases of cancer. More to the point, half of them were lymphomas: six cases of Hodgkin's, seven of non-Hodgkin's, and a startling ten were cases of a very rare subtype known as hepatosplenic T-cell lymphoma. Out of the 48 cancer cases, eleven had died—a jaw-dropping nine of them from hepatosplenic T-cell lymphoma.

-- In 2009, based on its work published the year before, the FDA called for stronger warnings in the prescribing information regarding TNF blockers and the risk of cancer in children.

-- In 2009 Swedish researchers published a study that demonstrated no increased risk of cancer among people with RA taking anti-TNF agents.

-- In 2010 a team led by researchers from the University of Alabama brought an abstract to the ACR's annual meeting that found that while children with JIA had a two to threefold increased risk of developing cancer compared to the general population, the increased risk had little or nothing to do with being treated with TNF blockers. The lead author specifically stated that he believed these findings should "mitigate concern" raised by the FDA's report.

-- In 2011 Swedish researchers returned with a study showing an increased risk of malignant melanoma among RA patients taking TNF blockers.

-- In 2011 University of Manchester researchers presented an abstract at the American College of Rheumatology's annual scientific meeting in Chicago that unequivocally asserted that there was no link between TNF blockers and the development of solid tumor cancers. In the wake of the Manchester abstract, and citing the fact that they continued to receive reports of hepatosplenic T-cell lymphoma, the FDA responded by updating the side effect information provided with anti-TNF blockers. They urged manufacturers to do the same.

Conclusion

Complicating any conclusion that the use of TNF blockers causes lymphoma in some patients are the fact the conditions themselves are already associated with cancer, and the fact that nobody can point to the actual mechanism of action that causes that cancer.

At best, people with inflammatory disorders and a history of lymphoma should learn all they can, then discuss the use of TNF blockers with their doctor so that they are making an informed decision, one that acknowledges the risk. At least this way patients might establish a care program that includes being vigilant about watching for the signs and symptoms of cancer.