A study creates a deeper understanding of the link between juvenile idiopathic arthritis, or JIA, its treatment and cancer risk: It found that treatment with tumor necrosis factor-alpha inhibitors – a type of biologic – does not appear to increase a child’s risk of cancer. But it also found that children with JIA have a more than four times higher cancer risk compared to children without JIA  – an elevated risk that doctors stress is still very small, overall.

JIA, the most common type of arthritis seen in children, affects an estimated 294,000 kids in the United States; there are several subtypes, based on the disease’s severity and number of joints affected. Because many of the most effective drugs – including biologics – can come with potentially serious side effects, such as a higher risk of infection, and patients are often put on more than one drug, treating JIA can lead some parents to wonder if the treatment is worse than the disease.

Anti-TNFs and Black Box Warnings

The first biologic drug to be FDA-approved, in 1998, was etanercept, or Enbrel, a tumor necrosis factor-alpha inhibitor – alternately called TNF inhibitor or anti-TNF. It was approved for use in children with JIA in 1999. Etanercept, like the other anti-TNFs that followed, works by suppressing parts of the immune system, which goes awry and attacks a person’s own body in autoimmune conditions like rheumatoid arthritis, or RA, as well as ankylosing spondylitis, psoriatric arthritis and JIA. Biologics, like the anti-TNF etanercept, are used to control disease, prevent joint destruction and induce remission.

In 2009, amid case reports of cancer among children and adolescents using anti-TNFs, the FDA issued a “black box” warning stating that “lymphomas and other malignancies” have been reported in those treated with anti-TNFs.

But whether anti-TNFs are linked to a higher risk of cancer, among both adults and children, is a controversial issue: large analyses, one published in 2009 and two in 2011, found no increased risk of cancer with TNF inhibitors yet, a meta-analysis published in September 2011 linked TNF inhibitors to a higher incidence of skin cancer, but not to an increase in the risk of other cancers, in adult RA patients.  

Good News and Bad News for Parents

The newest study, finding that anti-TNF use in children with JIA does not appear to be linked to a higher cancer rate, was published online in February in the journal Arthritis & Rheumatism. The data were originally presented at the 2010 American College of Rheumatology Annual Scientific Meeting.
 

Using information from Medicaid records from 2000 through 2005, researchers at the University of Alabama at Birmingham compared cancer rates among 7,812 children with JIA and two groups without JIA – 652,234 children with asthma and 321,821 with attention-deficit hyperactivity disorder, or ADHD.

They found a 4.4 times higher cancer risk among all children with JIA, regardless of treatment, compared to those without JIA. The cancer risk among patients treated with methotrexate without TNF inhibitors was 3.9 times higher than children without JIA, and among children who were not exposed to immunomodulatory drugs, it was 6.9 times higher. Among patients using TNF inhibitors (etanercept, in 90 percent of cases), there were no cancers during the study period.

While it is considered one of the largest investigations into cancer rates among JIA patients related to their treatment, the study is not “definitive proof,” says lead author Timothy Beukelman, MD, associate professor of pediatrics, Division of Rheumatology, University of Alabama at Birmingham, referring to the small number of cancer cases seen in children and the relatively short follow up time of the study.

However, Dr. Beukelman says, “it appears that the TNF inhibitors are likely safer than previously suspected.”

A four-times greater cancer risk is higher than any previous reports, yet “cancer in children is very uncommon,” Dr. Beukelman says. “The overall risk of cancer for children with JIA is still very low.” He says it is possible that biologic agents will decrease the cancer risk caused by the disease through effectively decreasing inflammation that is present in JIA.

Uncontrolled JIA Is a Risk Factor, Too

“It’s important for families to realize that JIA itself can carry important risks too,” says Dr. Beukelman.

Barbara Adams, MD, chief of pediatric rheumatology at the University of Michigan at Ann Arbor, says she is not surprised about the increased cancer risk for children with JIA. “We see the same pattern in adults with RA,” she notes.

“As for many of the medications we use to control juvenile arthritis, I think they may actually reduce cancer risk because they control inflammatory damage from the disease,” says Dr. Adams, echoing Dr. Beukelman. “These medications are much better at preventing disability and loss of function in children with arthritis, compared with the limited range of medications that we had before.”

As for the risks of medications to treat JIA, “Parents are caught between rock and hard place,” says Dr. Adams, who is also on the medical advisory board for Arthritis Today. “If you want your child to be well, there are certain medications we need to use, even though there are small but definite risks involved. I try to be very clear about the risks involved in the medications I prescribe, but I also put those risks into context by explaining the risks of crippling arthritis, too.”

In an editorial accompanying the study, Kenan Onel, MD, PhD, an associate professor of pediatrics and director of the Pediatric Familial Cancer Clinic at the University of Chicago, writes that Dr. Beukelman’s findings “are at once concerning and reassuring for physicians, parents and patients.”
 

“It’s very difficult to determine what is innate cancer risk, and what is cancer risk that results from whatever diseases or exposures you may have had, as well as the role of these medications,” Dr. Onel says. “The fundamental problem is these cancers are rare events so it is hard to make absolute statements.”

Dr. Beukelman’s study “indicates the disease is causing most of the increased risk, with the caveat that his numbers are really too small and the follow-up period too short to say conclusively that the drugs are not adding risk on top of the disease,” says Dr. Onel. He would like to see studies of children treated with the other, newer types of biologics in addition to TNF inhibitors.

Dr. Onel also points out that the data shows increased risk of cancer due to JIA alone, even for children whose disease severity does not mandate treatment with disease modifying agents or biologic therapies.

“But is this something that a parent should lose sleep over?” asks Dr. Onel. “I would argue no. While the likelihood of cancer is higher, it is still such an uncommon occurrence.”

Says Dr. Beukelman: “The more we study, the more evidence we find that uncontrolled inflammation increases risk of infections, risk of cardiovascular disease and cancer. That is likely true for children as well. Getting JIA under proper control might benefit not only the joints, but also decrease the risk of cancer.”

Shaping the Future of Treatment

Studies that analyze large databases of patient treatment and outcome, like Dr. Beukelman’s, are critical as researchers strive to untangle the risks of JIA from the risks of the drugs used to treat it, and determine the best course of treatment for young patients.

Dr. Beukelman’s team relied on Medicaid records. Pediatric rheumatologists have also been building a large, detailed database of childhood arthritis cases through an Arthritis Foundation-supported project in collaboration with the Childhood Arthritis and Rheumatology Research Alliance, or CARRA.

“The CARRA network is so important for obtaining good data,” says Dr. Onel, “because it … ensures that patients are followed long enough so that we can really know what happens to them.” Parents of children with JIA who are interested in participating in the database, should talk to their rheumatologist or pediatric rheumatologist. Physicians register their patients and input the data, after receiving each parent's consent to participate.