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TNF Inhibitors Not Behind Juvenile Arthritis Risk of Cancer

February 16, 2012 — The black box warning about cancer risk that was added to the labeling for tumor necrosis factor (TNF) inhibitors in 2009 might have been premature, at least with regard to cancer risk in children with juvenile idiopathic arthritis (JIA), according to data reported in an article published online February 10 in Arthritis & Rheumatism.
Timothy Beukelman, MD, MsCE, from the University of Alabama at Birmingham, and colleagues, on behalf of the Safety Assessment of Biological Therapeutics Collaboration, conducted one of the largest investigations into the rates of incident malignancy among pediatric patients with JIA, relative to their treatment. Using data from Medicaid records from 2000 through 2005, the researchers identified 7812 children with JIA and 2 comparator groups of children without JIA (1 group with asthma [n = 652,234] and 1 group with attention-deficit/hyperactivity disorder [n = 321,821]).
The researchers categorized treatment with methotrexate and TNF inhibitors as "ever" or "never" used, although many children with JIA did not receive either of these treatments during the study. The research team did not have access to detailed medical records, and therefore categorized the identified incident malignancies as "possible," "probable," or "highly probable."
One goal of the study was to determine the background incidence of malignancy in children with JIA compared with that for children without JIA. The authors that standardized rates of overall malignancy ranged from approximately 1.4 to 4.5 times higher for the JIA groups compared with the asthma and attention-deficit/hyperactivity disorder comparator groups.
A second goal was to determine whether JIA treatment increased cancer incidence in these patients.
"[W]e found a significantly increased rate of incident malignancy among children diagnosed with JIA compared to children without JIA. JIA treatment, including TNF inhibitors, did not appear to be significantly associated with the development of malignancy. Larger and longer-term studies of the association between malignancy and JIA and its treatment are needed to confirm our findings," the authors write.
Children diagnosed with JIA had a total follow-up time of 12,614 person-years, with 1484 children in this group contributing 2922 person-years of anti-TNF exposure. Among children with JIA compared with those without JIA, the incidence rate was 4.4 times higher for probable and highly probable malignancies. Pediatric patients with JIA who were treated with methotrexate without TNF inhibitors had a cancer incidence 3.9 times higher than children without JIA. No probable or highly probable malignancies were identified in patients after any use of anti-TNF during the study period.
In an accompanying editorial, Karen B. Onel, MD, and Kenan Onel, MD, PhD, from the Department of Pediatrics at the University of Chicago, Illinois, write, "The results of this current study suggest that for children with JIA there is no additional increase in cancer risk associated with the use of the medications most commonly used for moderate to severe disease, methotrexate and etanercept. However, there is an 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."
They continue, "[A]lthough we have been very concerned as to the risk of cancer due to the potent medications we use, we have perhaps markedly understated the more significant risk from the disease itself and have not prepared patients and families for a possible serious life-long health concern."
The editorialists point out that most patients in this study were treated with etanercept, a soluble TNF receptor blocker, and that anti-TNF monoclonal antibodies might yield different results.
"While our findings show children with JIA have a higher incidence of cancer compared to peers without JIA, the greater frequency of malignancy does not appear to be necessarily associated with treatment, including use of TNF inhibitors. This highlights the critical importance of appropriate comparator groups when evaluating the safety of new medications. Further confirmation of our findings with large-scale and long-term investigation of the association between cancer and JIA, and its treatment is needed," Dr. Beukelman concluded in a news release.
The study was supported by grant funding from the Agency for Healthcare Research and Quality (AHRQ) and the US Food and Drug Administration. Dr. Beukelman was supported by a grant from the National Institutes of Health (NIH) via the University of Alabama at Birmingham Center for Clinical and Tranlsational Science. Another author received support from NIH and AHRQ as well. The other authors have disclosed no relevant financial relationships.

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