Tumor Necrosis Factor Alfa Antagonists for Pediatric Immune-Mediated Diseases

Marcia L. Buck, Pharm.D., FCCP

Pediatr Pharm. 2007;13(8):1-4. 

In This Article

Clinical Experience

A number of studies and case reports have documented the efficacy of the TNFα antagonists in reducing the symptoms of immune-mediated diseases in children.[9,10,11,12,13,14] In addition, these agents may reduce the need for long-term corticosteroid therapy in these patients and minimize the adverse effects associated with corticosteroid use in children, such as impaired growth.[15]

Infliximab is currently approved by the FDA for use in the treatment of Crohn's disease in both children and adults, as well as ankylosing spondylitis, psoriatic arthritis, rheumatoid arthritis, and ulcerative colitis.[6] The approval for pediatric patients was based on the results of the REACH study, a randomized, open-label trial of 112 children (6-17 years of age) with moderately to severely active Crohn's disease.[9] All patients received an infliximab infusion of 5 mg/kg on weeks 0, 2, and 6. At week 10, 103 children were randomized to a regimen of 5 mg/kg given every 8 or every 12 weeks. Patients were monitored for clinical response and adverse effects for another 44 weeks. Clinical response was defined as a decrease ≥15 points from the patient's baseline Pediatric Crohn's Disease Activity Index (PCDAI) score or a score ≤30.

At week 10, 99 children (88%) had a clinical response and 66 (59%) were in remission. The average PCDAI score decreased by 31.3 points from baseline. At week 30, there were significantly more responders in the every 8 week treatment group than in the every 12 week group (73% versus 47%). Similar results were observed at week 54 (64% versus 33%). The proportion of children in remission was also significantly higher in the every 8 week group at both time points. Sixty percent of the every 8 week group was in remission at week 30 versus 35% in the every 12 week group. At week 54, 56% of the every 8 week group remained in remission versus 24% of the every 12 week group. Corticosteroid use also decreased, with 46% of the every 8 week and 33% of the every 12 week subjects able to stop steroids at week 30. The authors concluded that children were more likely to have a significant response to infliximab if treated every 8 weeks.[9]

Etanercept is currently approved for the treatment of rheumatoid arthritis, psoriatic arthritis, plaque psoriasis, and ankylosing spondylitis in adults. It is also approved for the treatment of refractory juvenile rheumatoid arthritis (JRA) in patients 2 years of age and older.[7] The FDA approval was based on a two-part clinical trial conducted by the Pediatric Rheumatology Collaborative Study Group in 69 children with polyarticular JRA.[10] In the first part of the trial, patients 4-17 years of age were treated with etanercept 0.4 mg/kg (up to 25 mg) subcutaneously twice weekly for 3 months. In the second part of the trial, patients with a clinical response during the first phase were randomized to remain on treatment or receive placebo for 4 months. Response was determined as a ≥30% improvement in three of six JRA core criteria (global assessment by a physician, assessment by patient or parent, active joint count, limitation of motion, functional assessment, and erythrocyte sedimentation rate). In the first part of the study, 51/69 (74%) had a clinical response. In the second part, six (24%) of the etanercept patients had a disease flare versus 20 (77%) of the controls (p=0.007). The average time to disease flare was 116 days for the etanercept patients and 28 days for the controls.

The patients randomized to placebo were allowed to resume treatment after the study, and a total of 58 of the original 69 patients continued on therapy as part of an open-label extension study. A long-term follow-up of these patients was published in 2006.[11] Analysis of the 32 children with complete efficacy data for 4 years or more revealed a 94% response rate, using the American College of Rheumatology Pediatric 30 criteria. Etanercept was well tolerated, with serious adverse effects occurring at a rate of 0.13 per patient-year. The authors concluded that etanercept produced a significant, sustained improvement in disease symptoms with an acceptable safety profile.

Adalimumab is approved for the treatment of rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, and Crohn's disease in adults. Although it does not yet have FDA approval for use in children, adalimumab has been used to treat children with rheumatoid arthritis, Crohn's disease, psoriasis, and childhood uveitis (immune-mediated intraocular inflammation).[12,13,14] In a retrospective study of 18 children with uveitis treated with adalimumab doses of 2 to 40 mg every 1-2 weeks, 16 (88%) achieved a reduction in the number of relapses.[14] Ten of the 16 children (81%) who also had arthritis showed improvement. Three patients had a mild response and one did not improve. Infliximab and etanercept have also been used in treatment of uveitis, with mixed results.

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