Randomized trial of tocilizumab in systemic juvenile idiopathic arthritis.

Abstract

BACKGROUND:

Systemic juvenile idiopathic arthritis (JIA) is the most severe subtype of JIA; treatment options are limited. Interleukin-6 plays a pathogenic role in systemic JIA.

METHODS:

We randomly assigned 112 children, 2 to 17 years of age, with active systemic JIA (duration of ≥6 months and inadequate responses to nonsteroidal antiinflammatory drugs and glucocorticoids) to the anti-interleukin-6 receptor antibody tocilizumab (at a dose of 8 mg per kilogram of body weight if the weight was ≥30 kg or 12 mg per kilogram if the weight was <30 kg) or placebo given intravenously every 2 weeks during the 12-week, double-blind phase. Patients meeting the predefined criteria for nonresponse were offered open-label tocilizumab. All patients could enter an open-label extension.

RESULTS:

At week 12, the primary end point (an absence of fever and an improvement of 30% or more on at least three of the six variables in the American College of Rheumatology [ACR] core set for JIA, with no more than one variable worsening by more than 30%) was met in significantly more patients in the tocilizumab group than in the placebo group (64 of 75 [85%] vs. 9 of 37 [24%], P<0.001). At week 52, 80% of the patients who received tocilizumab had at least 70% improvement with no fever, including 59% who had 90% improvement; in addition, 48% of the patients had no joints with active arthritis, and 52% had discontinued oral glucocorticoids. In the double-blind phase, 159 adverse events, including 60 infections (2 serious), occurred in the tocilizumab group, as compared with 38, including 15 infections, in the placebo group. In the double-blind and extension periods combined, 39 serious adverse events (0.25 per patient-year), including 18 serious infections (0.11 per patient-year), occurred in patients who received tocilizumab. Neutropenia developed in 19 patients (17 patients with grade 3 and 2 patients with grade 4), and 21 had aminotransferase levels that were more than 2.5 times the upper limit of the normal range.

CONCLUSIONS:

Tocilizumab was efficacious in severe, persistent systemic JIA. Adverse events were common and included infection, neutropenia, and increased aminotransferase levels. (Funded by Hoffmann-La Roche; ClinicalTrials.gov number, NCT00642460.).

• Authors: Fabrizio De Benedetti, Hermine I Brunner, Nicolino Ruperto, Andrew Kenwright, Stephen Wright, Inmaculada Calvo, Ruben Cuttica, Angelo Ravelli, Rayfel Schneider, Patricia Woo, Carine Wouters, Ricardo Xavier, Lawrence Zemel, Eileen Baildam, Ruben Burgos-Vargas, Pavla Dolezalova, Stella M Garay, Rosa Merino, Rik Joos, Alexei Grom, Nico Wulffraat, Zbigniew Zuber, Francesco Zulian, Daniel Lovell, Alberto Martini, PRINTO, PRCSG
• Journal: The New England journal of medicine (N Engl J Med) Vol. 367 Issue 25 Pg. 2385-95 (Dec 20 2012) ISSN: 1533-4406 [Electronic] United States
• PMID: 23252525 (Publication Type: Clinical Trial, Phase III, Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-Inflammatory Agents, Non-Steroidal
• Antibodies, Monoclonal, Humanized
• Glucocorticoids
• Receptors, Interleukin-6
• Transaminases
• tocilizumab
• Methotrexate

Topics

• Adolescent
• Anti-Inflammatory Agents, Non-Steroidal (therapeutic use)
• Antibodies, Monoclonal, Humanized (adverse effects, therapeutic use)
• Arthritis, Juvenile (blood, drug therapy)
• Child
• Child, Preschool
• Double-Blind Method
• Drug Therapy, Combination
• Female
• Glucocorticoids (therapeutic use)
• Humans
• Infections (chemically induced)
• Male
• Methotrexate (therapeutic use)
• Neutropenia (chemically induced)
• Receptors, Interleukin-6 (antagonists & inhibitors)
• Transaminases (blood)