Review of Biologics in Children With Rheumatic Diseases

Shabina Habibi; Athimalaipet V Ramanan


Int J Clin Rheumatol. 2012;7(1):81-93. 

In This Article


The design of the study that evaluated etanercept's effectiveness in JIA has become the model for subsequent studies of biologic agents in children.[8] Children with JIA refractory or intolerant to methotrexate, enrolled in the trial, enter an open-label lead-in phase, where all are treated with etanercept. Responders then enter a double-blind placebo-controlled phase, in which half continue to receive etanercept and the other half are given placebo. Children who flare on placebo are restarted on etanercept in an open-label extension phase. This strategy enables all children to receive the drug, making the study more ethical and acceptable to patients/parents.

In this study, 69 children with active arthritis despite 10 mg/m2/week of methotrexate were given etanercept 0.4 mg/kg twice weekly in an open-label fashion for 3 months. A total of 74% of children had an ACR-Pedi 30 response, and were entered into a randomized, double-blind, placebo-controlled withdrawal phase, in which half continued etanercept and the other half received placebo. Flare rates 4 months after randomization were 21/26 (81%) in those receiving placebo and only 7/25 (28%) in those children receiving etanercept. Those who flared were again restarted on etanercept in an open-label fashion, resulting in response rates equivalent to the initial open-label phase. Of these children, 82% were able to either completely discontinue or taper corticosteroids below 5 mg/day.[9] It was also noted that in those children with systemic-onset JIA (SOJIA), etanercept was less effective. Long-term sustained effectiveness over 8 years of the continued open-label phase has been demonstrated for a total of 318 patient-years of exposure.[10] This study also showed safety of long-term etanercept use, where the overall rates of serious adverse events (0.12 per patient-year) did not increase with continuous long-term use of the drug.

In the German Etanercept Register, which has data of approximately 1300 children, high rates of adherence to etanercept therapy were noted, with approximately 66% of children on the drug for 4 years, which again suggests a favorable efficacy and tolerability.[11,12]

The Dutch Etanercept Registry evaluated the effectiveness of etanercept in 146 children with JIA with a median follow-up of 2.5 years.[13] They found significant improvement within 3 months and in the years thereafter. Initial effectiveness was found to vary with the subtype of JIA. Children with SOJIA responded less favorably in the initial 3 months and had significantly more withdrawal of etanercept due to inefficacy. However, after 15 months of therapy, response rates were similar to other subgroups. In addition, 38% of these children had complete remission of their disease. Rates of serious adverse events were low. The inferior response rates of SOJIA were also observed in another multicenter French study, where 61 children with JIA, 22 with systemic-onset disease, responded less favorably as compared with other subtypes throughout the entire course of the study.[14]

The Dutch Etanercept Registry recently analyzed the costs and treatment success of etanercept.[15] The cost analysis revealed that although the costs of etanercept are substantial, other direct medical costs, such as costs related to hospitalization and concomitant medication had decreased after the start of etanercept therapy. A significant reduction in outpatient consultations at the outpatient clinic was observed. All the JIA core set variables had also improved significantly. Thus the authors concluded that, as these children were refractory to conventional treatment and at risk of long-term disability, the costs are potentially justifiable.[15]

The Biologics and New Drugs Registry (BNDR) of the British Society for Paediatric and Adolescent Rheumatology (BSPAR) recently published the reasons for discontinuation of etanercept therapy.[16] Four hundred and eighty three etanercept-treated JIA patients from 30 centers were enrolled in the registry, with 941 patient-years of follow-up. After a median follow-up of 2 years, 69% remained on the drug. One hundred (20.7%) discontinued etanercept, nine due to disease control and 88 because of treatment failure (53 due to inefficacy, 14 due to noncompliance and 21 due to adverse events). In two patients, the reasons for discontinuation were unknown and in one the diagnosis was changed. Cessation of therapy for inefficacy was associated with systemic arthritis subtype (odds ratio [OR]: 2.55), chronic anterior uveitis (OR: 2.39) and inefficacy of methotrexate before starting etanercept (OR: 8.3).

Etanercept is administered by subcutaneous injection, at a dose of 0.4 mg/kg (maximum 25 mg) twice weekly. It has recently received FDA approval for treatment of moderate-to-severe polyarticular JIA in children as young as 2 years of age.


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