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The effect of infliximab plus methotrexate on the modulation of inflammatory disease markers in juvenile idiopathic arthritis: analyses from a randomized, placebo-controlled trial

Sudha Visvanathan12, Carrie Wagner2, Joseph C Marini2, Daniel J Lovell3, Alberto Martini4, Ross Petty5, Ruben Cuttica6, Patricia Woo7, Graciela Espada8, Marco Gattorno4, Maria T Apaz9, Eileen Baildam10, Anders Fasth11, Valeria Gerloni12, Pekka Lahdenne13, Pierre Quartier14, Rotraud Saurenmann15, Suzanne Travers2, Alan Mendelsohn2, Stephen Xu2, Edward H Giannini3, Nicolino Ruperto4*, the Paediatric Rheumatology INternational Trials Organization (PRINTO)16 and the Pediatric Rheumatology Collaborative Study Group (PRCSG)16

Author Affiliations

1 Current Address: Hoffmann-La Roche, Nutley, NJ, USA

2 Centocor Research & Development, Inc., Malvern, PA, USA

3 Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA

4 IRCCS G. Gaslini and University of Genoa, Genoa, Italy

5 British Columbia's Children's Hospital and the University of British Columbia, British Columbia, Canada

6 Hospital General de Niños Pedro de Elizalde, Buenos Aires, Argentina

7 Great Ormond St Hospital for Children, London, UK

8 Hospital de Ninos Ricardo Gutierrez, Buenos Aires, Argentina

9 Universidad Catolica, Cordoba, Argentina

10 Royal Liverpool Children's Hospital, Liverpool, UK

11 University of Gothenberg and The Queen Silvia Children's Hospital, Götenborg, Sweden

12 Istituto Gaetano Pini, Milano, Italy

13 Hospital for Children and Adolescents, Helsinki, Finland

14 Hopital Necker Enfants Malades, Assistance Publique Hopitaux de Paris and Universite Paris-Descartes, Paris, France

15 University Children's Hospital, Zürich, Switzerland

16 IRCCS G. Gaslini, Pediatria II, PRINTO, Genoa, Italy

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Pediatric Rheumatology 2010, 8:24  doi:10.1186/1546-0096-8-24

Published: 7 September 2010

Abstract

Background

We evaluated the effect of infliximab on markers of inflammation in patients with juvenile idiopathic arthritis (JIA).

Methods

In this randomized, placebo-controlled substudy, 122 patients with JIA received infliximab 3 mg/kg + methotrexate (MTX)(n = 60) or placebo + MTX (n = 62) at weeks 0, 2, and 6. At week 14, patients receiving placebo + MTX crossed over to infliximab 6 mg/kg + MTX; patients receiving infliximab 3 mg/kg + MTX continued treatment through week 44. Sera and plasma from eligible patients receiving infliximab 3 mg/kg + MTX (n = 34) and receiving placebo→infliximab 6 mg/kg +MTX (n = 38) were collected at weeks 0, 2, 14, 16, 28, and 52 and analyzed for inflammatory markers (IL-6, IL-12p40, ICAM-1, MMP-3, VEGF, TNF-α, and CRP).

Results

At week 2, decreases from baseline in IL-6, ICAM-1, MMP-3, TNF-α, and CRP were greater with infliximab versus placebo treatment, and with the exception of CRP, these differences were generally maintained through week 14. The decreases from baseline to week 52 in IL-6, ICAM-1, VEGF, MMP-3, and CRP and increases in IL-12p40 levels were larger in patients receiving placebo→infliximab 6 mg/kg +MTX versus infliximab 3 mg/kg + MTX treatment. Patients receiving infliximab 3 mg/kg+MTX who achieved an American College of Rheumatology Pediatric 30 (ACR-Pedi-30) response had significantly larger decreases from baseline in ICAM-1 (p = 0.0105) and MMP-3 (p = 0.0253) at week 2 and in ICAM-1 (p = 0.0304), MMP-3 (p = 0.0091), and CRP (p = 0.0011) at week 14 versus ACR-Pedi-30 nonresponders.

Conclusion

Infliximab + MTX attenuated several inflammatory markers in patients with JIA; larger decreases in ICAM-1, MMP-3, and CRP levels were observed in ACR-Pedi-30 responders versus nonresponders.

Trial Registration

NCT00036374