This month, a report suggested some arthritis medications are increasing cancer rates in children.

Andrew Pollack wrote in The New York Times that the Food and Drug Administration (FDA) is investigating four drugs after having received “reports of 30 cases of cancer over 10 years among children and young adults treated with those drugs.” The patients primarily battled Juvenile Idiopathic Arthritis (JIA, formerly Juvenile Rheumatoid Arthritis – JRA) and Crohn’s disease.

Should this cause alarm?

In an e-mail to CreakyJoints, Dr. Theodore Fields of the Hospital for Special Surgery (Weill Medical Center of Cornell University) said, “Any data possibly relating malignancy to any rheumatic disease or treatment is important and bears careful consideration.”

However, he says, “Note that inflammatory disease, such as rheumatoid arthritis, has been shown to have an increased malignancy risk independent of any treatment.”

In other words, those battling autoimmune disorders such as arthritis and Crohn’s disease already carry a higher risk of battling cancer as well.

Is the FDA shedding light on this prior realization?

Or are these drugs actually increasing those cancer rates further?

As The New York Times reports, the FDA did not specify how many children had taken the medications it is now investigating — the TNF inhibitors Enbrel, Remicade, Humira, and Cimzia. The agency did not specify the treatment regimens of the children — only mentioning that some were taking “other immuno-suppressive medicines such as methotrexate, azathioprine or 6-mercaptopurine.”

It also did not say if the cancer rates among them were higher than expected.

“Without comparison to how many children with inflammatory [diseases] had malignancy with and without specific treatments, we can’t draw conclusions,” Dr. Fields said.

Dr. Roy Fleischmann of the University of Texas Southwestern Medical Center agrees.

'The TNF blocking agents have revolutionized the care of children with arthritis ... The benefits clearly outweigh the risks and it would be a tragedy for any parent to allow their child to be disabled by their disease.' -- Dr. Thomas Lehman, Weill Medical Center of Cornell University

“It is too little information to know if it is a true concern,” he said in an e-mail to CreakyJoints. “The risk benefit still has to favor the drugs.”

The FDA did concede that point. The agency told The New York Times that it believed “the potential benefits of the medicines outweighed the potential risks ‘in certain children and young adults.'”

However, the agency did not further describe just who this “certain” juvenile population is. Dr. Thomas Lehman of the Hospital for Special Surgery (Weill Medical Center of Cornell University) does not believe it to be as selective a group as it sounds.

“In my own practice I have seen hundreds of children with severe disease improve dramatically with these agents with no incidence of cancer or other serious side effects,” he said in an e-mail to CreakyJoints. “The benefits clearly outweigh the risks and it would be a tragedy for any parent to allow their child to be disabled by their disease which we know they have because of fear of a remote chance of side effects.”

In fact, Dr. Fields is seeing positive side effects of the medications.

“The risk/benefit of anti-TNF agents has generally seemed quite good, with some early suggestions in the literature of decreased heart attacks in RA [rheumatoid arthritis] patients taking the agents,” he said, “possibly related to the inflammatory aspect of atherosclerosis.”

All of the drugs bring inflammation to manageable levels by blocking the tumor necrosis factor (TNF) protein — a process of which the FDA has long been wary.

In its statement, the FDA said it “has been aware of the possible association between the use of TNF blockers and the development of cancer. The prescribing information for all four TNF blockers warns about the possible risk of cancer.”

That has not stopped the drugs from having a profoundly positive impact on patients.

“The TNF blocking agents have revolutionized the care of children with arthritis,” Dr. Lehman said. “In the past many children with severe disease were disabled and suffered permanent deformity or disability. The TNF blocking agents have made significant deformity or disability a rarity in the care of children with arthritis.”

Obtained by CreakyJoints, an American College of Rheumatology (ACR) e-mail sent to its members describes the FDA findings, explaining, “About half the cases are lymphoma (Hodgkin’s and non-Hodgkin’s), and half were solid organ cancers, melanoma or leukemia. There was no significant difference in type of cancer (lymphoma or solid organ) in patients with JIA and Crohn’s disease, and the rate of cancer is thought to be similar in patients receiving the available TNF blockers (Remicade, Enbrel and Humira) but the small number of cases limits this analysis.”

Sources: remicade.comenbrel.comhumira.comcimzia.com

As such, the FDA is now requesting the makers of Remicade, Enbrel, and Humira “to provide information about cases of cancer in children from post-marketing data,” the ACR said. The agency is also “gathering data to estimate the number of children with JIA and Crohn’s disease who are treated with TNF blockers.”

And, as Ed Silverman reports on pharmalot.com, “the FDA is requiring Nektar Therapeutics, which makes Cimzia, to conduct a study to assess long-term risks, including lymphoma and other cancers, to begin in 2009.” The study requires 10 years for completion.

Enbrel is sold by Amgen and Wyeth, Remicade by Johnson & Johnson (and by Schering-Plough in Europe), and Humira by Abbott Laboratories.

Determining causal links requires further study — which is exactly what the FDA action was meant to initiate.

Looking at adults, it is easy to see why: despite much more research, we continue to gain both insight into — and confusion about — the roles played by these medications in the treatment of adults.

“The data regarding TNF agents and malignancy in adults has had variable conclusions,” Dr. Fields said. “One study, using the Swedish patient registry — which is well-regarded and comprehensive — did not show an increased risk of malignancy in TNF-treated patients with RA vs. RA patients not treated with anti-TNF agents, but rather that more severe RA itself was associated with more malignancy.”

As CreakyJoints’ own Seth Ginsberg said, “It’s a risk / reward decision — taking the medication needed to live a very normal life with an autoimmune disease.”

Getting a clearer picture of the risk is really what the FDA is doing.

“Like all drugs they are associated with a small but real incidence of side effects,” Dr. Lehman said. “At this point the FDA is taking a careful look at the exact incidence.”

To read The New York Times article, the FDA’s statement, the pharmalot.com report, Dr. Theodore Fields’ bio page, Dr. Thomas Lehman’s bio page, or Dr. Roy Fleischmann’s bio page, click on one of the links below:


Article References
NYTimes.com: “FDA Reviews Arthritis Drugs for Links to Cancer”, site accessed on 06/06/08

FDA Statement: “Early Communication About an Ongoing Safety Review of Tumor Necrosis Factor (TNF) Blockers (marketed as Remicade, Enbrel, Humira, and Cimzia), site accessed on 06/06/08

pharmalot.com: “FDA: TNF Blockers May Cause Lymphoma In Kids”, site accessed on 06/06/08

Theodore R. Fields, MD, FACP, site accessed on 06/06/08

Thomas J.A. Lehman, MD, site accessed on 06/06/08

Roy Fleischmann, MD, site accessed on 06/06/08