Patients with juvenile idiopathic arthritis have an increased rate of malignancy, compared with unaffected children, according to a report published online Feb. 13 in Arthritis & Rheumatism.
The increased cancer incidence, which ranged from 1.4 to 4.5 times higher than that in comparison groups of children with other chronic diseases, is not significantly associated with JIA treatments, including tumor necrosis factor–inhibiting agents, said Dr. Timothy Beukelman of the division of pediatric rheumatology, University of Alabama at Birmingham, and his associates.
The Food and Drug Administration issued a black box warning on TNF inhibitors in 2009, cautioning that there was an increased risk of malignancy (particularly lymphoma) in pediatric patients who used the drugs, based on reports to the Adverse Event Reporting System. But critics argued that the warning was premature because of the limited data on the background rate of malignancy in this patient population.
"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.
Moreover, most JIA patients who are treated with TNF inhibitors also receive other drugs, including methotrexate, which may themselves contribute to a higher cancer risk.
The investigators assessed the background rate of malignancy in JIA by using the Medicaid Analytic eXtract (MAX) administrative database, hoping that such a large source would contain sufficient numbers to allow study of two rare disorders: JIA and childhood cancer. The MAX database includes the medical and pharmacy records of all low-income children who receive government medical assistance.
The study assessed 7,812 JIA patients who were followed for approximately 2 years, for a total follow-up time of 12, 614 person-years.
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.
Thus, there was no association between TNF inhibitors and cancer, and there were no cases of lymphoma in any of the children who had JIA, the investigators said (Arthritis Rheum. 2012 Feb. 13 [doi:10.1002/art.34348]).
Compared with the study subjects who had asthma or ADHD, the JIA group had an overall cancer rate that was 1.4-4.5 times higher. The findings were similar when the analysis was restricted only to hematologic cancers.
"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.
There are several reasons why JIA might be associated with an increased risk of cancer. Rheumatoid arthritis is known to raise the risk of malignancy, particularly lymphoma. And arthritis medications suppress the immune system, although "we also found an increased rate of malignancies among children not treated with systemic immunosuppression."
It is also possible that JIA patients are more carefully screened for cancer because of the extensive contact they have with the health care system. And finally, some malignancies, especially acute leukemias, may initially be misdiagnosed as JIA, Dr. Beukelman and his colleagues said.
This study was supported by the Agency for Healthcare Research and Quality, the FDA, and the National Institutes of Health. No financial conflicts of interest were reported by the researchers.