Review of Biologics in Children With Rheumatic Diseases

Shabina Habibi; Athimalaipet V Ramanan

Disclosures

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

In This Article

Anti-IL-6 Therapy

Tocilizumab

Tocilizumab is a humanized recombinant antibody that binds to IL-6 receptor, and inhibits the downstream signaling of IL-6 and thus its proinflammatory effects. Serum and synovial fluid levels of IL-6 have been found to be elevated in children with SOJIA and correlate with disease activity.[42–45]

In a dose-escalating study of 11 children with active refractory SOJIA, in which all children were initially given 2 mg/kg of tocilizumab, repeated for two more doses 2 weeks apart in those who responded, or 4 mg/kg in those who flared, again repeated for two doses 2 weeks apart or 8 mg/kg, repeated as above for two more doses, abrupt reduction of disease activity was observed in ten out of 11 children, as assessed by fever, arthritis, childhood health assessment questionnaire or acute phase reactants.[46] A total of 90.9% of children achieved 30% response 2 weeks after a third fixed dose.

In another open-label single dose trial, 18 Caucasian children with active SOJIA despite receiving >0.2 mg/kg/day of prednisolone were recruited.[47] Fifteen out of 18 children enrolled were treated with 2, 4 or 8 mg/kg of body weight of tocilizumab intravenously. A marked clinical response was observed within 48 h in all children, which lasted up to 4–8 weeks. Eleven, eight and three children achieved ACR-Pedi 30, 50 and 70 responses (as defined by Giannini et al.).[48] The most dramatic responses were observed in the 4-mg/kg dose, and responses were most prolonged in the 4- and 8-mg/kg doses. Clinical improvement was accompanied by a parallel improvement of laboratory variables, such as C-reactive protein (CRP), anemia, white blood cell count and albumin.

There is only one double-blind placebo-controlled trial of tocilizumab in SOJIA.[49] This trial like the etanercept trial had an open-label lead-in phase of 6 weeks, a randomized double-blind placebo-controlled phase of 12 weeks and an open-label extension phase of at least 48 weeks. Fifty-six children were enrolled, and received 8 mg/kg of tocilizumab by intravenous infusion, every 2 weeks. At the end of the open-label lead-in phase ACR-Pedi 30, 50 and 70 responses were achieved in 91, 86 and 68% children, respectively. CRP concentration declined to <50 mg/dl in 86% children within 2 weeks. In the double-blind placebo-controlled phase, ACR-Pedi 30, 50 and 70 responses and CRP levels <15 mg/dl were maintained in 80, 80 and 75% children who received tocilizumab, versus 20, 17 and 13% who received placebo, respectively. Efficacy was sustained for a significantly longer duration in those receiving tocilizumab. At the end of the 48-week open-label extension phase, 96% children were still receiving tocilizumab, indicating good efficacy and tolerability. ACR-Pedi 30, 50 and 70 responses were 98, 94 and 90, respectively. Tolerability profile was good, much like other biologicals.

Interim results at 52 weeks of the ongoing multicenter, three part, 5-year TENDER trial of tocilizumab in SOJIA were recently presented at the The European League Against Rheumatism meeting.[50] Efficacy data at 52 weeks was available in 88 children and safety data in all 112 children. ACR 30 plus absence of fever and ACR 70/90 responses progressively improved in 88, 89 and 65% of children, respectively. There was also a marked reduction in the corticosteroid dose, with 48% children discontinuing corticosteroids. The drug was generally well tolerated. Thirty three serious adverse events were observed in 25 children, of which 12 were considered related to tocilizumab. Fifteen serious infections occurred; six considered related to the drug. All of these resolved and none led to drug discontinuation. One child died of a suspected tension pneumothorax, which was considered unrelated to tocilizumab.

Various side effects that can occur with the use of tocilizumab include serious infusion reactions, infections, transient increases in liver enzymes, which usually occur early in the course and tend to improve over time, neutropenia, formation of antitocilizumab antibodies, anaphylactoid reactions and hypercholesterolemia.

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