CHICAGO — The risk for cancer in children taking a biologic agent for management of juvenile idiopathic arthritis appears to be small, Dr. Daniel J. Lovell said.
Parents ask: “Is this therapy going to increase my child's risk for cancer?” said Dr. Lovell, a pediatric rheumatologist at the Cincinnati Children's Hospital Medical Center. To answer that question, one must determine:
1. the risk for cancer in the healthy pediatric population;
2. whether the cancer risk is increased in those who develop JIA;
3. whether the risk is increased by nonbiologic therapies for JIA; and
4. whether exposure to biologic therapy raises the risk.
We have an accurate answer to No. 1, but the accurate answer to No. 4 requires that we also have answers to Nos. 2 and 3, which we do not at this time, Dr. Lovell said.
The arthritis in children with persistent oligoarticular JIA can often be successfully treated only with intra-articular corticosteroids. However, the risk for uveitis is highest in this subtype of JIA. The uveitis of JIA is a chronic, nongranulomatous inflammation of the anterior uveal tract of the eye, and is asymptomatic in up to 80% of children. In 70% of the cases, both eyes will be involved within 1 year.
Although the proper initial treatment of JIA-associated uveitis is topical corticosteroid eye drops, Dr. Lovell suggested that if the need for ongoing topical therapy persists beyond 3 months, then there may need to be systemic anti-inflammatory treatment for the uveitis, even though this might alarm an ophthalmologist. Complications of topical or local corticosteroid therapy in the eyes include cataract, glaucoma, and band keratopathy.
With systemic JIA, which is thought by many to be an autoinflammatory disease rather than an autoimmune disease, the logical therapeutic choices are biologics that specifically block either interleukin (IL)-1 or IL-6, because they are the cytokines most directly involved in the disease's pathophysiology.
Some children with systemic JIA demonstrate a rapid and dramatic response to treatment with the IL-1 receptor antagonist anakinra, but some do not respond, and in some the benefit wanes with ongoing treatment (Ann. Rheum. Dis. 2008;67:302–8).
Results of treatment of systemic JIA with the IL-6 inhibitor tocilizumab have been very promising. Patients treated with this biologic often start to show improvement in systemic features within hours, and their arthritis was also greatly improved (Lancet 2008;371:998–1006).
On the subject of medications, including biologics, used to treat children with JIA, it is critical to calculate the dose on the basis of milligrams per kilogram or body surface area. “That really causes you to think about your medical math,” said Dr. Lovell. He gave the example of a 6-year-old child, height 4 feet 11 inches, weight 55 lb, whose dosages for common JIA treatments according to the published pediatric recommendations, which are based on weight or surface area, were very similar to adult doses. It is a common problem for adult rheumatologists who treat JIA patients to use the right drugs but in amounts below the efficacious dose because of concern about giving a child adult-sized dosages.
“My advice to you is look at the dosage based on milligrams per kilogram or milligrams per meter squared, do your math, gird your loins, and write the prescription. If you're going to use the agent, you have to do it in the proper dose in the kids to get the proper effect.”
In the polyarticular forms of JIA, where more than five joints are involved, the most common treatment approach is methotrexate.
“Methotrexate is our most studied agent ever in terms of kids with arthritis,” said Dr. Lovell. However, many children with polyarticular forms of JIA do not respond to or tolerate methotrexate. It is in these children that the anti–tumor necrosis factor (anti-TNF) biologics have shown dramatic benefit.
The question of whether biologics increase a child's risk for cancer is actually several linked questions, said Dr. Lovell. These include the child's background risk, independent of arthritis; the risk from just having JIA (which is unknown); the risk from prior treatments for JIA such as methotrexate and steroids; and the potential risk from taking biologics.
Dr. Lovell has developed his own unofficial estimate of risk, limited to etanercept, because that's where the best JIA-related data are found. The observed frequency of cancer in children with JIA treated with etanercept based on FDA data is six cases in 9,200 patients or one case per 1,533 children. Epidemiologic data for the overall incidence of cancer in American children under the age of 15 years are one case per 7,252 children. Accordingly, the relative risk compared with the healthy pediatric population is 4.7 – with many caveats, he says.