By Dr Ananya Mandal, MD
A new study shows that kids with juvenile idiopathic arthritis develop cancer four times more often than children without the disease, but the treatments they receive - including biologic treatments like Enbrel - may not explain their increased risk. If confirmed, researchers say the findings should ease fears that biologic treatments known as TNF inhibitors cause cancer in children and young adults.
However the concerns over cancer associated with JIA may be real. Soon after the first TNF inhibitors became available almost 15 years ago, anecdotal reports of cancers in users of the drugs began surfacing. Reports of malignancies in nearly 50 children prompted the FDA to require TNF-inhibitor manufacturers to include a “black box” warning on their labeling, alerting users about a possible cancer risk. Last November, the agency announced that it would also require those manufacturers to perform “enhanced safety surveillance” on the drugs when used in children and adults under 30.
This new study is among the largest ever to examine cancers in children with juvenile idiopathic arthritis (JIA), a disease that afflicts close to 300,000 children and teens in the U.S. The researchers from the University of Alabama, Birmingham (UAB), looked at Medicaid records from 2000 to 2005 and identified 7,812 children with JIA.
For an "internal" comparison, the researchers also assessed the background cancer rate among children in the database who had two other chronic conditions: asthma (652,234 subjects) and attention-deficit/hyperactivity disorder (321,821 subjects). For an "external" comparison, they obtained population-based estimates of cancer rates from the SEER (Surveillance Epidemiology and End Results) database.
The JIA patients’ medication exposures were divided into three categories by drug class: methotrexate or leflunomide; TNF inhibitors (etanercept, infliximab, or adalimumab); and other immunomodulatory agents (abatacept, alefacept, anakinra, azathioprine, cyclophosphamide, cyclosporine, efalizumab, 6-mercaptopurine, mycophenolate mofetil, rituximab, or tacrolimus).
A total of 3,423 JIA patients (44%) had taken methotrexate or leflunomide; 1,484 (19%) had taken TNF inhibitors; 398 (5%) had taken other immunomodulatory agents; and 2,507 (32%) had not taken any of these drugs.
Only 10 cancers were identified in the JIA patients. Six of them (three brain malignancies, one leukemia, one soft tissue cancer, and one gastrointestinal cancer) developed in the children who had not been exposed to any of the drugs. Three malignancies (two leukemias and one soft tissue cancer) developed in children who had taken methotrexate but not TNF inhibitors. And one malignancy (uterine cancer) developed in a child who had taken TNF inhibitors
Compared to children without JIA, children with the rheumatic disease had a 4.4-times greater cancer risk. Treatment with a TNF inhibitor did not appear to influence this risk. The main TNF inhibitor reported used by children in the JIA group was Enbrel. The study appears online in the journal Arthritis & Rheumatism.
“The SEER external comparator standardized malignancy rates were significantly lower than the ADHD and asthma internal comparator rates,” the researchers noted. This means that study subjects with JIA had even higher rates of cancer, regardless of the treatments they received, than would be expected in the general population based on SEER data.
Researcher and UAB associate professor of pediatrics Timothy Beukelman, says the findings do not support the conclusion that TNF inhibitors are strongly linked to cancer. He says a similar study from Sweden, which found a two- to three-fold greater cancer risk in JIA patients, came to a similar conclusion. “It is unlikely that the increase was caused by these medications alone,” he says. “At least part of this risk appears to be due to the disease itself.” Other TNF inhibitors include Humira, Kineret, Orencia, Remicade, and Rituxan.
“Chronic autoimmune inflammatory conditions such as JIA may be associated with an increased risk of malignancy irrespective of specific therapeutic agents. For example, an increased risk of lymphoma has been observed among adults with rheumatoid arthritis, particularly among those with a high burden of inflammatory activity,” De. Beukelman and his colleagues noted.
In an accompanying editorial, Drs. Karen and Kenan Onel of the University of Chicago urged caution in interpreting the study results.
Although the UAB study does not fully exonerate Enbrel and the other TNF inhibitors, pediatric cancer specialist Kenan Onel, of the University of Chicago, calls the findings reassuring. “These drugs are very effective for the treatment of arthritis, so it is very reassuring to know that if they do carry a cancer risk it is probably very small,” Onel says. “The not-so-reassuring news here is that just by having juvenile arthritis, a child may have an increased risk for cancer.”
The study included only a small number of children with JIA and also included children with arthritis associated with inflammatory bowel disease, a condition that may carry a higher risk of cancer. Despite the limitations, they wrote that the research highlights the importance of long-term monitoring of children with JIA. Since the symptoms often resolve, children who no longer suffer from the condition may fall off the radar in terms of cancer risk.
The study was funded by grants from the federal government's Agency for Healthcare Research and Quality (AHRQ), the U.S. Department of Health and Human Services, the FDA, and the National Institutes of Health.