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.
Was FDA’s Black Box Warning Premature?
The findings of Dr. Beukelman and colleagues, together with flaws in the data that lead to the FDA’s black box warning, "suggest that this drastic step may have been premature," said Dr. Karen B. Onel and Dr. Kenan Onel.
The study findings "are at once concerning and reassuring for physicians, parents, and patients." It is reassuring that there appears to be no additional increase in cancer risk associated with frequently used medications, but it is concerning that JIA itself raises the risk of malignancy, "even for children whose disease severity does not mandate treatment with disease-modifying agents or biologic therapies."
Dr. Karen B. Onel is in the department of pediatrics, and Dr. Kenan Onel is on the committee on cancer biology, both at the University of Chicago. They reported no financial conflicts of interest. These remarks were adapted from the editorial accompanying Dr. Beukelman’s report (Arthritis Rheum. 2012 Feb. 13 [doi:10.102/art.34349]).
Submitting your vote...
The Oncology Report
Comprehensive reports and expert commentary
on the latest advances in cancer treatment from
the world's major oncology meetings.