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 Visvanathan, Carrie Wagner, Joseph C Marini, Daniel J Lovell, Alberto Martini, Ross Petty, Ruben Cuttica, Patricia Woo, Graciela Espada, Marco Gattorno, Maria T Apaz, Eileen Baildam, Anders Fasth, Valeria Gerloni, Pekka Lahdenne, Pierre Quartier, Rotraud Saurenmann, Suzanne Travers, Alan Mendelsohn, Stephen Xu, Edward H Giannini, Nicolino Ruperto, Paediatric Rheumatology INternational Trials Organization (PRINTO), Pediatric Rheumatology Collaborative Study Group (PRCSG), Sudha Visvanathan, Carrie Wagner, Joseph C Marini, Daniel J Lovell, Alberto Martini, Ross Petty, Ruben Cuttica, Patricia Woo, Graciela Espada, Marco Gattorno, Maria T Apaz, Eileen Baildam, Anders Fasth, Valeria Gerloni, Pekka Lahdenne, Pierre Quartier, Rotraud Saurenmann, Suzanne Travers, Alan Mendelsohn, Stephen Xu, Edward H Giannini, Nicolino Ruperto, Paediatric Rheumatology INternational Trials Organization (PRINTO), Pediatric Rheumatology Collaborative Study Group (PRCSG)

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.

Figures

Figure 1
Figure 1
Change in median levels of serum inflammatory markers over time in patients who received infliximab 3 mg/kg + MTX or placebo + MTX through week 14 with a crossover to infliximab 6 mg/kg + MTX for ICAM-1 (A), IL-6 (B), VEGF (C), MMP-3 (D), CRP (E), and IL-12p40 (F). MTX, methotrexate; ICAM-1, intracellular cell adhesion molecule-1; IL-6, interleukin-6; VEGF, vascular endothelial growth factor; MMP-3, matrix metalloproteinase-3; CRP, C-reactive protein; IL-12p40, interleukin 12.

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