Baseline patient and disease characteristics were similar between the two randomized treatment groups. In addition, no significant differences were observed between the randomized treatment groups for the median baseline CRP, IL-6, MMP-3, ICAM-1, IL-12p40, VEGF, or TNF-α levels (Table ). Only 14 patients who received placebo + MTX and 9 patients who received infliximab 3 mg/kg + MTX had TNF-α levels above the lower limit of quantification of the assay, which restricted subsequent data analyses involving this inflammatory marker.
Disease characteristics and biomarker levels at baseline*
Correlations between inflammatory markers at baseline indicated that the strongest correlations were between CRP and IL-6 (r = 0.72, p < 0.0001), MMP-3 and CRP (r = 0.53, p < 0.0001), and MMP-3 and IL-6 (r = 0.52, p = 0.0001). Weaker correlations were also observed between MMP-3 and VEGF, TNF-α and ICAM-1, TNF-α and IL-12p40, and CRP and ICAM-1 (data not shown). Further, baseline IL-6 and ICAM-1 levels significantly correlated with the number of joints with active arthritis at baseline (r = 0.37, p = 0.0059; r = 0.32, p = 0.0096; respectively).
Changes in inflammatory marker levels during the placebo-controlled period assessed at weeks 2 and 14
At week 2, the median percent decreases from baseline in ICAM-1 (-13.6% vs. -1.7%; p = 0.0353), IL-6 (-61.6% vs. -15.4%; p = 0.0329), and CRP (-38.1% vs. 0.0%; p = 0.0020) were greater in patients receiving infliximab 3 mg/kg + MTX than in those receiving placebo + MTX. A 44.9% decrease from baseline to week 2 in MMP-3 was also observed in patients receiving infliximab 3 mg/kg + MTX, compared with an increase of 0.6% in patients receiving placebo + MTX (p = 0.0017) (Figures , and ). In contrast, a larger median percent decrease in IL-12p40 levels was observed in the placebo + MTX group (-16.6%) than in the infliximab 3 mg/kg + MTX group (-5.0%; p = NS).
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 (more ...)
Median reductions were numerically higher at week 14 in patients receiving infliximab 3 mg/kg + MTX compared with those receiving placebo + MTX for ICAM-1 (-14.4 vs. -0.4; p = NS), IL-6 (-51.6 vs. -16.2; p = NS), VEGF(-13.3 vs. -6.7; p = NS), and MMP-3(-42.4 vs. 0.7; p = 0.0120) levels (Figures . The decreases in CRP and IL-12p40 levels observed at week 14 were greater in patients receiving placebo + MTX (-31.8 and -19.4, respectively) than in those receiving infliximab 3 mg/kg + MTX (-24.7 and -2.0, respectively), but these changes were not significant (p = 0.9111 and 0.0622, respectively; Figures ).
Change in inflammatory marker levels during the crossover period assessed at weeks 16, 28, and 52
By week 20, at which point all patients were receiving either 3 or 6 mg/kg infliximab + MTX, reduced levels of inflammatory markers were observed in both treatment groups for ICAM-1, IL-6, VEGF, MMP-3 and CRP (Figures . Levels of IL-12p40 had also declined in the infliximab 3 mg/kg + MTX group, but showed an increase (3.5%) at week 16 in patients receiving placebo who crossed over to receive infliximab 6 mg/kg + MTX (Figure ).
Variable changes from baseline were observed across the inflammatory markers in patients receiving infliximab 3 mg/kg + MTX or infliximab 6 mg/kg + MTX at weeks 28 and 52. While inflammatory marker levels tended to rebound somewhat over time in the infliximab 3 mg/kg group, ICAM, IL-6, VEGF, MMP-3 and CRP levels at week 52 were generally below levels observed at baseline (Figures ). Conversely, IL-12p40 levels were slightly increased from baseline to week 52 (Figure ). The decreases from baseline to week 52 in IL-6, ICAM-1, MMP-3, and CRP and increases in IL-12p40 levels were larger in patients receiving placebo + MTX who crossed over to receive infliximab 6 mg/kg + MTX as compared with patients receiving infliximab 3 mg/kg + MTX. Only the differences in IL-6 (-77.8% vs. -37.7%; p = 0.0098, respectively) and MMP-3 (-70.2% vs. -23.8%; p = 0.0258, respectively) were statistically significant (data not shown).
Associations between inflammatory marker levels and clinical response as assessed by ACR-Pedi-30 response and the number of joints with active arthritis
At week 2, among patients receiving placebo + MTX, significantly larger median percent decreases in IL-6 (-49.6% vs. 6.8%; p = 0.0344) were observed in patients who were ACR-Pedi-30 responders as compared with ACR-Pedi-30 nonresponders. These results indicated a significant association between changes in IL-6 levels and ACR-Pedi-30 response in patients treated with placebo + MTX (Table ). Significantly larger median percent decreases in ICAM-1 (p = 0.0105) and MMP-3 (p = 0.0253) were also observed among ACR-Pedi-30 responders when compared with nonresponders in the infliximab 3 mg/kg + MTX group (Table ).
Median percent change in biomarker levels from baseline by ACR-Pedi-30 responder status
At week 14, in patients receiving infliximab 3 mg/kg + MTX, ACR-Pedi-30 responders had larger median percent reductions than ACR-Pedi-30 nonresponders in ICAM-1 (-21.7% vs. 4.8%; p = 0.0304), MMP-3 (-55.5% vs. 8.2%; p = 0.0091), and CRP (-55.0% vs. 0.0%; p = 0.0011; Table ).
Also, at week 14, decreases in IL-6, VEGF, and CRP levels correlated with the number of joints with active arthritis in patients treated with infliximab 3 mg/kg + MTX (r = 0.52, p = 0.005; r = 0.44, p = 0.011; r = 0.29, p = 0.027; respectively). In the placebo + MTX group, changes in ICAM-1 and CRP levels were significantly correlated with the number of joints with active arthritis at week 14 (r = 0.64, p < 0.0001; r = 0.38, p = 0.004; respectively) (data not shown).