A randomized, placebo-controlled trial of infliximab plus methotrexate for the treatment of polyarticular-course juvenile rheumatoid arthritis

Authors

  • Nicolino Ruperto,

    Corresponding author
    1. IRCCS, Istituto G. Gaslini, Genoa, Italy
    • IRCCS, Istituto G. Gaslini, Pediatria II–PRINTO, Largo Gaslini 5, 16147 Genoa, Italy
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    • Drs. Ruperto, Lovell, Woo, Prieur, Petty, Martini, and Giannini have received honoraria and/or consulting fees (less than $10,000) from Centocor for serving as members of the study steering committee. Dr. Lovell has received consulting fees, speaking fees, and/or honoraria (less than $10,000 each) from Hoffmann-LaRoche, Amgen, Novartis, Bristol-Myers Squibb, Abbott, and Xoma and (more than $10,000) from Regeneron. Dr. Saurenmann has received honoraria (less than $10,000) from Essex for serving as a member of the Remicade “Switzerland” advisory board. Drs. Travers, Beutler, Keenan, Clark, Visvanathan, Fasanmade, Raychaudhuri, and Mendelsohn own stock or stock options in Johnson & Johnson, of which Centocor, Inc., is a subsidiary.

  • Daniel J. Lovell,

    1. Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
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    • Drs. Ruperto, Lovell, Woo, Prieur, Petty, Martini, and Giannini have received honoraria and/or consulting fees (less than $10,000) from Centocor for serving as members of the study steering committee. Dr. Lovell has received consulting fees, speaking fees, and/or honoraria (less than $10,000 each) from Hoffmann-LaRoche, Amgen, Novartis, Bristol-Myers Squibb, Abbott, and Xoma and (more than $10,000) from Regeneron. Dr. Saurenmann has received honoraria (less than $10,000) from Essex for serving as a member of the Remicade “Switzerland” advisory board. Drs. Travers, Beutler, Keenan, Clark, Visvanathan, Fasanmade, Raychaudhuri, and Mendelsohn own stock or stock options in Johnson & Johnson, of which Centocor, Inc., is a subsidiary.

  • Ruben Cuttica,

    1. Hospital General de Niños Pedro de Elizalde, Buenos Aires, Argentina
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  • Nick Wilkinson,

    1. Nuffield Orthopaedic Centre, Oxford, UK
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  • Patricia Woo,

    1. Great Ormond Street Hospital, London, UK
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  • Graciela Espada,

    1. Hospital de Niños Ricardo Gutiérrez, Buenos Aires, Argentina
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  • Carine Wouters,

    1. University Hospital Gasthuisberg, Leuven, Belgium
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  • Earl D. Silverman,

    1. Hospital for Sick Children, Toronto, Ontario, Canada
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  • Zsolt Balogh,

    1. National Institute of Rheumatology and Physiotherapy, Budapest, Hungary
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  • Michael Henrickson,

    1. Children's Hospital, Oklahoma City, Oklahoma
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  • Maria-Teresa Apaz,

    1. Universidad Catolica, Cordoba, Argentina
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  • Eileen Baildam,

    1. Royal Liverpool Children's Hospital, Liverpool, UK
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  • Anders Fasth,

    1. Queen Silvia Children's Hospital, Goteborg, Sweden
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  • Valeria Gerloni,

    1. Istituto Gaetano Pini, Milan, Italy
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  • Pekka Lahdenne,

    1. Hospital for Children and Adolescents, Helsinki, Finland
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  • Anne-Marie Prieur,

    1. Hôpital Necker Enfants Malades, Paris, France
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  • Angelo Ravelli,

    1. IRCCS, Istituto G. Gaslini, and University of Genoa, Genoa, Italy
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  • Rotraud K. Saurenmann,

    1. Kinderspital Zurich, Zurich, Switzerland
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    • Drs. Ruperto, Lovell, Woo, Prieur, Petty, Martini, and Giannini have received honoraria and/or consulting fees (less than $10,000) from Centocor for serving as members of the study steering committee. Dr. Lovell has received consulting fees, speaking fees, and/or honoraria (less than $10,000 each) from Hoffmann-LaRoche, Amgen, Novartis, Bristol-Myers Squibb, Abbott, and Xoma and (more than $10,000) from Regeneron. Dr. Saurenmann has received honoraria (less than $10,000) from Essex for serving as a member of the Remicade “Switzerland” advisory board. Drs. Travers, Beutler, Keenan, Clark, Visvanathan, Fasanmade, Raychaudhuri, and Mendelsohn own stock or stock options in Johnson & Johnson, of which Centocor, Inc., is a subsidiary.

  • Maria Luz Gamir,

    1. Hospital Ramón y Cajal, Madrid, Spain
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  • Nico Wulffraat,

    1. Wilhelmina Kinderziekenhuis, Utrecht, The Netherlands
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  • Laszlo Marodi,

    1. University of Debrecen, Debrecen, Hungary
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  • Ross E. Petty,

    1. University of British Columbia, Vancouver, British Columbia, Canada
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  • Rik Joos,

    1. Universitair Ziekenhuis Ghent, Ghent, Belgium
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  • Francesco Zulian,

    1. Clinica Pediatrica, Padua, Italy
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  • Deborah McCurdy,

    1. Children's Hospital of Orange County, Orange, California
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  • Barry L. Myones,

    1. Texas Children's Hospital Pediatric Rheumatology Center, Houston
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  • Kalman Nagy,

    1. Borsod University Hospital, Miskolc, Hungary
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  • Peter Reuman,

    1. Children's Hospital Medical Center, Akron, Ohio
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  • Ilona Szer,

    1. Children's Hospital Medical Center, San Diego, California
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  • Suzanne Travers,

    1. Centocor, Inc., Malvern, Pennsylvania
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    • Drs. Ruperto, Lovell, Woo, Prieur, Petty, Martini, and Giannini have received honoraria and/or consulting fees (less than $10,000) from Centocor for serving as members of the study steering committee. Dr. Lovell has received consulting fees, speaking fees, and/or honoraria (less than $10,000 each) from Hoffmann-LaRoche, Amgen, Novartis, Bristol-Myers Squibb, Abbott, and Xoma and (more than $10,000) from Regeneron. Dr. Saurenmann has received honoraria (less than $10,000) from Essex for serving as a member of the Remicade “Switzerland” advisory board. Drs. Travers, Beutler, Keenan, Clark, Visvanathan, Fasanmade, Raychaudhuri, and Mendelsohn own stock or stock options in Johnson & Johnson, of which Centocor, Inc., is a subsidiary.

  • Anna Beutler,

    1. Centocor, Inc., Malvern, Pennsylvania
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    • Drs. Ruperto, Lovell, Woo, Prieur, Petty, Martini, and Giannini have received honoraria and/or consulting fees (less than $10,000) from Centocor for serving as members of the study steering committee. Dr. Lovell has received consulting fees, speaking fees, and/or honoraria (less than $10,000 each) from Hoffmann-LaRoche, Amgen, Novartis, Bristol-Myers Squibb, Abbott, and Xoma and (more than $10,000) from Regeneron. Dr. Saurenmann has received honoraria (less than $10,000) from Essex for serving as a member of the Remicade “Switzerland” advisory board. Drs. Travers, Beutler, Keenan, Clark, Visvanathan, Fasanmade, Raychaudhuri, and Mendelsohn own stock or stock options in Johnson & Johnson, of which Centocor, Inc., is a subsidiary.

  • Greg Keenan,

    1. Centocor, Inc., Malvern, Pennsylvania
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    • Drs. Ruperto, Lovell, Woo, Prieur, Petty, Martini, and Giannini have received honoraria and/or consulting fees (less than $10,000) from Centocor for serving as members of the study steering committee. Dr. Lovell has received consulting fees, speaking fees, and/or honoraria (less than $10,000 each) from Hoffmann-LaRoche, Amgen, Novartis, Bristol-Myers Squibb, Abbott, and Xoma and (more than $10,000) from Regeneron. Dr. Saurenmann has received honoraria (less than $10,000) from Essex for serving as a member of the Remicade “Switzerland” advisory board. Drs. Travers, Beutler, Keenan, Clark, Visvanathan, Fasanmade, Raychaudhuri, and Mendelsohn own stock or stock options in Johnson & Johnson, of which Centocor, Inc., is a subsidiary.

  • Jason Clark,

    1. Centocor, Inc., Malvern, Pennsylvania
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    • Drs. Ruperto, Lovell, Woo, Prieur, Petty, Martini, and Giannini have received honoraria and/or consulting fees (less than $10,000) from Centocor for serving as members of the study steering committee. Dr. Lovell has received consulting fees, speaking fees, and/or honoraria (less than $10,000 each) from Hoffmann-LaRoche, Amgen, Novartis, Bristol-Myers Squibb, Abbott, and Xoma and (more than $10,000) from Regeneron. Dr. Saurenmann has received honoraria (less than $10,000) from Essex for serving as a member of the Remicade “Switzerland” advisory board. Drs. Travers, Beutler, Keenan, Clark, Visvanathan, Fasanmade, Raychaudhuri, and Mendelsohn own stock or stock options in Johnson & Johnson, of which Centocor, Inc., is a subsidiary.

  • Sudha Visvanathan,

    1. Centocor, Inc., Malvern, Pennsylvania
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    • Drs. Ruperto, Lovell, Woo, Prieur, Petty, Martini, and Giannini have received honoraria and/or consulting fees (less than $10,000) from Centocor for serving as members of the study steering committee. Dr. Lovell has received consulting fees, speaking fees, and/or honoraria (less than $10,000 each) from Hoffmann-LaRoche, Amgen, Novartis, Bristol-Myers Squibb, Abbott, and Xoma and (more than $10,000) from Regeneron. Dr. Saurenmann has received honoraria (less than $10,000) from Essex for serving as a member of the Remicade “Switzerland” advisory board. Drs. Travers, Beutler, Keenan, Clark, Visvanathan, Fasanmade, Raychaudhuri, and Mendelsohn own stock or stock options in Johnson & Johnson, of which Centocor, Inc., is a subsidiary.

  • Adedigbo Fasanmade,

    1. Centocor, Inc., Malvern, Pennsylvania
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    • Drs. Ruperto, Lovell, Woo, Prieur, Petty, Martini, and Giannini have received honoraria and/or consulting fees (less than $10,000) from Centocor for serving as members of the study steering committee. Dr. Lovell has received consulting fees, speaking fees, and/or honoraria (less than $10,000 each) from Hoffmann-LaRoche, Amgen, Novartis, Bristol-Myers Squibb, Abbott, and Xoma and (more than $10,000) from Regeneron. Dr. Saurenmann has received honoraria (less than $10,000) from Essex for serving as a member of the Remicade “Switzerland” advisory board. Drs. Travers, Beutler, Keenan, Clark, Visvanathan, Fasanmade, Raychaudhuri, and Mendelsohn own stock or stock options in Johnson & Johnson, of which Centocor, Inc., is a subsidiary.

  • Aparna Raychaudhuri,

    1. Centocor, Inc., Malvern, Pennsylvania
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    • Drs. Ruperto, Lovell, Woo, Prieur, Petty, Martini, and Giannini have received honoraria and/or consulting fees (less than $10,000) from Centocor for serving as members of the study steering committee. Dr. Lovell has received consulting fees, speaking fees, and/or honoraria (less than $10,000 each) from Hoffmann-LaRoche, Amgen, Novartis, Bristol-Myers Squibb, Abbott, and Xoma and (more than $10,000) from Regeneron. Dr. Saurenmann has received honoraria (less than $10,000) from Essex for serving as a member of the Remicade “Switzerland” advisory board. Drs. Travers, Beutler, Keenan, Clark, Visvanathan, Fasanmade, Raychaudhuri, and Mendelsohn own stock or stock options in Johnson & Johnson, of which Centocor, Inc., is a subsidiary.

  • Alan Mendelsohn,

    1. Centocor, Inc., Malvern, Pennsylvania
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    • Drs. Ruperto, Lovell, Woo, Prieur, Petty, Martini, and Giannini have received honoraria and/or consulting fees (less than $10,000) from Centocor for serving as members of the study steering committee. Dr. Lovell has received consulting fees, speaking fees, and/or honoraria (less than $10,000 each) from Hoffmann-LaRoche, Amgen, Novartis, Bristol-Myers Squibb, Abbott, and Xoma and (more than $10,000) from Regeneron. Dr. Saurenmann has received honoraria (less than $10,000) from Essex for serving as a member of the Remicade “Switzerland” advisory board. Drs. Travers, Beutler, Keenan, Clark, Visvanathan, Fasanmade, Raychaudhuri, and Mendelsohn own stock or stock options in Johnson & Johnson, of which Centocor, Inc., is a subsidiary.

  • Alberto Martini,

    1. IRCCS, Istituto G. Gaslini, and University of Genoa, Genoa, Italy
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  • Edward H. Giannini

    1. Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
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  • ClinicalTrials.gov identifier: NCT00036374.

Abstract

Objective

To evaluate the safety and efficacy of infliximab in the treatment of juvenile rheumatoid arthritis (JRA).

Methods

This was an international, multicenter, randomized, placebo-controlled, double-blind study. One hundred twenty-two children with persistent polyarticular JRA despite prior methotrexate (MTX) therapy were randomized to receive infliximab or placebo for 14 weeks, after which all children received infliximab through week 44. Patients received MTX plus infliximab 3 mg/kg through week 44, or MTX plus placebo for 14 weeks followed by MTX plus infliximab 6 mg/kg through week 44.

Results

Although a higher proportion of patients in the 3 mg/kg infliximab group than in the placebo group had achieved responses according to the American College of Rheumatology (ACR) Pediatric 30 (Pedi 30) criteria for improvement at week 14 (63.8% and 49.2%, respectively), the between-group difference in this primary efficacy end point was not statistically significant (P = 0.12). By week 16, after the crossover from placebo to infliximab 6 mg/kg when all patients were receiving infliximab, an ACR Pedi 30 response was achieved in 73.2% of all patients. By week 52, ACR Pedi 50 and ACR Pedi 70 responses had been reached in 69.6% and 51.8%, respectively, of patients. Infliximab was generally well tolerated, but the safety profile of infliximab 3 mg/kg appeared less favorable than that of infliximab 6 mg/kg, with more frequent occurrences of serious adverse events, infusion reactions, antibodies to infliximab, and newly induced antinuclear antibodies and antibodies to double-stranded DNA observed with the 3 mg/kg dose.

Conclusion

While infliximab at 3 mg/kg and 6 mg/kg showed durable efficacy at 1 year, achievement of the primary efficacy end point at 3 months did not differ significantly between infliximab-treated and placebo-treated patients. Safety data indicated that the 6-mg/kg dose may provide a more favorable risk/benefit profile. These results warrant further investigation in children with JRA.

Ancillary