Randomized trial of tocilizumab in systemic juvenile idiopathic arthritis
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, Roger Allen, Eileen Baildam, Diane Brown, Ruben Burgos-Vargas, Inmaculada Calvo, Jeffrey Chaitow, Elizabeth Chalom, Elisabetta Cortis, Ruben Cuttica, Fabrizio De Benedetti, Pavla Dolezalova, Graciela Espada, Berit Flato, Stella Maris Garay, Julia Garcia-Consuegra, Valeria Gerloni, Philip Hashkes, Michael Henrickson, Gerd Horneff, Hans-Iko Huppertz, Rita Jerath, Rik Joos, Yukiko Kimura, Daniel Lovell, Rocio Maldonado Velasquez, Evangelia Mantzourani, Alberto Martini, Kirsten Minden, Kevin Murray, Barry Myones, Kathleen M O'Neil, Karen Onel, Johannes Roth, Jozef Rovensky, Rayfel Schneide, Antigoni Siamopoulou-Mavridou, Clovis A Silva, Steven Spalding, Olga Vougiouka, Patricia Woo, Carine Wouters, Nico Wulffraat, Ricardo Xavier, Lawrence Zemel, Zbigniew Zuber, Francesco Zulian, Graciela Espada, Roger Allen, Jeffrey Chaitow, Kevin Murray, Clovis A Silva, Johannes Roth, Gerd Horneff, Hans-Iko Huppertz, Kirsten Minden, Evangelia Mantzourani, Antigoni Siamopoulou, Olga Vougiouka, Elisabetta Cortis, Valeria Gerloni, Maria del Rocio Maldonado-Velazquez, Berit Flato, Jozef Rovensky, Julia Garcia-Consuegra, Despina Eleftheriou, Diane Brown, Elizabeth Chalom, Philip Hashkes, Michael Henrickson, Rita Jerath, Yukiko Kimura, Barry Myones, Karen Onel, Kathleen M O'Neil, Steven J Spalding, 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, Roger Allen, Eileen Baildam, Diane Brown, Ruben Burgos-Vargas, Inmaculada Calvo, Jeffrey Chaitow, Elizabeth Chalom, Elisabetta Cortis, Ruben Cuttica, Fabrizio De Benedetti, Pavla Dolezalova, Graciela Espada, Berit Flato, Stella Maris Garay, Julia Garcia-Consuegra, Valeria Gerloni, Philip Hashkes, Michael Henrickson, Gerd Horneff, Hans-Iko Huppertz, Rita Jerath, Rik Joos, Yukiko Kimura, Daniel Lovell, Rocio Maldonado Velasquez, Evangelia Mantzourani, Alberto Martini, Kirsten Minden, Kevin Murray, Barry Myones, Kathleen M O'Neil, Karen Onel, Johannes Roth, Jozef Rovensky, Rayfel Schneide, Antigoni Siamopoulou-Mavridou, Clovis A Silva, Steven Spalding, Olga Vougiouka, Patricia Woo, Carine Wouters, Nico Wulffraat, Ricardo Xavier, Lawrence Zemel, Zbigniew Zuber, Francesco Zulian, Graciela Espada, Roger Allen, Jeffrey Chaitow, Kevin Murray, Clovis A Silva, Johannes Roth, Gerd Horneff, Hans-Iko Huppertz, Kirsten Minden, Evangelia Mantzourani, Antigoni Siamopoulou, Olga Vougiouka, Elisabetta Cortis, Valeria Gerloni, Maria del Rocio Maldonado-Velazquez, Berit Flato, Jozef Rovensky, Julia Garcia-Consuegra, Despina Eleftheriou, Diane Brown, Elizabeth Chalom, Philip Hashkes, Michael Henrickson, Rita Jerath, Yukiko Kimura, Barry Myones, Karen Onel, Kathleen M O'Neil, Steven J Spalding
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.).
Source: PubMed