jornal club pediatric rheumatology

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Slide 1 : Article title: The effect of infliximab plus methotrexate on the modulation of inflammatory disease markers in juvenile idiopathic arthritis: analyses from a randomized, placebo controlled trial
Slide 2 : Authors: 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 Fast, Valeria Gerloni, Pekka Lahdenne, Pierre Quartier, Rotraud Saurenmann, Suzanne Travers, Alan Mendelsohn, Stephen Xu, Edward H Giannini, Nicolino Ruperto
Slide 3 : Journal title: Pediatric Rheumatology 2010, 8:24
Slide 4 : What is already known? Tumor necrosis factor-alpha (TNF-a) plays an important role in the disease process underlying the chronic inflammation in Juvenile idiopathic arthritis (JIA, formerly polyarticular juvenile rheumatoid arthritis [JRA]). Elevated serum levels of inflammatory markers TNF-a, interleukin (IL)-6, IL-12 and vascular endothelial growth factor (VEGF) have been detected in patients with systemic onset of JIA. Increased levels of matrix metalloproteinase (MMP)-1 and MMP-3 and IL-17 have been observed in the synovial fluid of patients with JIA. Further, elevated levels of intercellular cell adhesion molecule (ICAM)-1 and E-selectin in serum have been correlated with active joint count in JIA patients
Slide 5 : Thus, different inflammatory processes are perpetuated in the JIA disease process and these may be associated with clinical manifestations. In the ASPIRE study of adults with early RA, treatment with infliximab plus methotrexate (MTX) resulted in rapid reduction in levels of MMP-3, ICAM-1, IL-8 & TNF-a. Wkly MTX treatment, at parenteral doses up to 15mg/m2, is an effective and safe therapy in JIA , Pediatric patients not responding to MTX may have other treatment options with the anti-TNF-a therapies etanercept and adalimumab. Recently, Levalampi et al showed that treatment with infliximab resulted in reductions in levels of CRP, ICAM-1, E -selectin and myeloperoxidase.
Slide 6 : Results from an RCT of the anti-TNF agent infliximab in the treatment of 122 children with persistent polyarticular JRA despite prior MTX, showed that infliximab treatment at doses of 3 mg/kg and 6 mg/kg yielded durable efficacy at 1 year but achievement of the primary clinical endpoint at 3 months did not differ significantly between infliximab 3 mg/kg- and placebo-treated patients.
Slide 7 : What does this study add? The results of a sub-analysis of the study that was performed to determine the effect of infliximab treatment on select markers of inflammation were reported and assessment of correlations between changes in the inflammatory markers and American college of Rheumatology pediatric -30 definitions of improvement (ACR Pedi-30 response) status were made.
Slide 8 : type of study Phase 3, double-blind, placebo-controlled study
Slide 9 : subjects pediatric patients age 4-17 years weight =35 kg JIA
Slide 10 : ACR-Pedi-30 responders ACR-Pedi-30 responders were defined as patients achieving an improvement of at least 30% in any 3 of the 6 core variables: physician global assessment parent/patient global assessment of overall well-being functional ability determined by the Childhood Health Assessment Questionnaire number of joints with active arthritis number of joints with limited range of motion,and erythrocyte sedimentation rate with no more than one variable worsening by more than 30%
Slide 11 : Randomization Patients were randomized in a 1:1 ratio to one of two treatment groups. Patients initially receiving placebo + MTX (n = 62) received placebo at weeks 0, 2, and 6, and then crossed over to receive infliximab 6 mg/kg + MTX at weeks 14, 16, 20, and then every 8 weeks through week 44. Patients in the infliximab 3 mg/kg + MTX group (n = 60) received infliximab 3 mg/kg + MTX at weeks 0, 2, 6, 14, 20, and then every 8 weeks through week 44; these patients also received a placebo infusion at week 16 to maintain the study blind. Patients in both groups received concomitant MTX (10 - 15 mg/m2 weekly) throughout the study. Sera and plasma samples were collected at weeks 0, 2, 14, 16, 28, and 52 in patients with an adequate body weight (=35 kg; 34 patients receiving infliximab 3 mg/kg + MTX and 38 patients receiving placebo/infliximab 6 mg/kg + MTX).
Slide 12 : Biomarker assessments Plasma levels of IL-6 and serum levels of MMP-3, ICAM-1, IL-12p40, and VEGF were measured using enzyme-linked immunosorbent assay (ELISA) kits (R&D Systems, Minneapolis, MN). TNF-a levels were measured using a Bio-plex™ bead-based sandwich enzyme immunoassay technique (Bio-Rad Laboratories, Hercules, CA). These validated analyses were conducted in a blinded manner at Centocor Ortho Biotech, Inc. Quintiles Laboratories (GA) measured serum CRP concentrations using the Roche Tinaquant assay (Roche-Diagnostics, IN).
Slide 13 : Statistical analysis The median percent changes from baseline in inflammatory marker levels at weeks 2, 14, 16, 28, and 52 were determined. Statistical comparisons were made between patients receiving placebo + MTX who crossed over to receive infliximab 6 mg/kg + MTX and those receiving infliximab 3 mg/kg + MTX using ANOVA on the van der Waerden scores. Univariate Spearman rank correlations were performed between individual marker levels at baseline. Correlation analyses were performed between changes from baseline to week 14 for each biomarker and the number of joints with active arthritis.
Slide 14 : Baseline levels and changes from baseline to week 2 and week 14 in levels of inflammatory markers were also compared between ACR-Pedi-30 responders and nonresponders at week 14 using analysis of variance on the van der Waerden scores.
Slide 15 : Results: Baseline characteristics Baseline patient and disease characteristics were similar between the two randomized treatment groups. 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-a levels (Table 1). Only 14 patients who received placebo + MTX and 9 patients who received infliximab 3 mg/kg + MTX had TNF-a levels above the lower limit of quantification of the assay, which restricted subsequent data analyses involving this inflammatory marker.
Slide 16 : 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 observed between MMP-3 and VEGF, TNF-a and ICAM-1, TNF-a and IL-12p40, and CRP and ICAM-1. 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).
Slide 17 : Changes in inflammatory marker levels during the placebo-controlled period assessed at wk 2nd and 14th At wk 2,the median percent decrease from baseline in ICAM-1 (-13.6% vs. -1.7%; p = 0.0353), IL-6 (-61.6% vs. - 5.4%; p = 0.0329), and CRP (-38.1% vs. 0.0%; p = 0.0020) were greater in patients receiving infliximab 3mg/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 In contrast, a larger median percent decrease in IL-12p40 levels was observed in the placebo + MTX group (-16.6%) than in the infliximab 3mg/kg + MTX group (-5.0%; p = NS).
Slide 18 : 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. 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.
Slide 19 : Change in inflammatory marker levels during the crossover period assessed at weeks 16, 28, and 52 By week 20, at this 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. 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. 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.
Slide 20 : 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. Conversely, IL-12p40 levels were slightly increased from baseline to week 52. 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.
Slide 21 : 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 2). 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 2)
Slide 22 : 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 2). 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)
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Slide 26 : Discussion JIA involves an inflammatory process that if unchecked will eventually lead to bone and cartilage damage. Markers associated with inflammation (IL-6, ICAM-1, MMP-3, VEGF, IL-12p40, TNF-a, and CRP) that may be modulated by infliximab + MTX therapy were examined. Although the primary clinical endpoint for this study was not achieved, results of the current analysis indicated that significant reductions from baseline in IL-6, ICAM-1, MMP-3, and CRP levels were observed as early as week 2 and sustained through week 14 of treatment with infliximab 3 mg/kg + MTX, relative to treatment with placebo + MTX.
Slide 27 : Similar findings were reported by Levalampi et al., who reported reductions in CRP, IL-6 and ICAM-1 levels by week 6 in JIA patients treated with infliximab. Further, in the current study, larger decreases in IL-6, ICAM-1, MMP-3 and CRP and increases in IL-12p40 levels were observed in patients receiving placebo + MTX who crossed over to receive infliximab 6 mg/kg + MTX relative to treatment with infliximab 3 mg/kg + MTX. Increased IL-12 and interferon gamma (IFN?) mRNA expression has previously been detected in synovial tissue from JIA patients, which suggests that IL-12 may have an important role in this disease. The increase in IL-12 levels in infliximab-treated patients may reflect a shift in the disease processes resulting from substantial reduction of peripheral TNF-a levels.
Slide 28 : In patients treated with infliximab 3 mg/kg + MTX, those who achieved an ACR-Pedi-30 response showed significant reductions in ICAM-1, MMP-3, and CRP levels compared with those who did not achieve an ACR-Pedi-30 response. Further, decreases in IL-6, VEGF, and CRP levels were correlated with the number of joints with active arthritis. These results suggest that ICAM-1, MMP-3, IL-6, VEGF, and CRP might be useful surrogate markers to monitor improvement in the signs and symptoms of JIA and joints with active arthritis after initiation of treatment with infliximab + MTX therapy. This biomarker substudy has several limitations. the substudy was designed as an exploratory assessment of changes in inflammatory biomarker levels after infliximab 3 mg/kg + MTX therapy versus treatment with placebo + MTX therapy in patients with JIA. the patients evaluated in both treatment groups were limited to those who were of adequate body weight (=35 kg) and analyses were based only on patients with levels of inflammatory markers above the lower limit of quantification for each assay.
Slide 29 : median TNF-a levels were not substantially elevated, which indicates that systemic levels of this biomarker are low in this evaluated patient population. inability to measure free TNF-a after infliximab treatment since the available commercial TNF-a assays were not designed to distinguish "free" from "infliximab-bound" TNF-a.
Slide 30 : Conclusions Findings of this biomarker substudy suggest that changes in ICAM-1, MMP-3, IL-6, VEGF and CRP levels may be useful markers to evaluate response to infliximab therapy in patients with JIA and thus may enable early identification of patients who could benefit from this treatment. \ Larger studies will be required to confirm the current preliminary findings and establish the relevance of these markers in predicting changes in signs and symptoms, as well as structural damage, of JIA.
Slide 31 : Similar studies: Changes in Biomarkers of Inflammation and Bone Turnover and Associations with Clinical Efficacy Following Infliximab plus Methotrexate Therapy in Patients with Early Rheumatoid Arthritis SUDHA VISVANATHAN, JOSEPH C. MARINI, JOSEF S. SMOLEN etal Objective. To determine if changes in biomarkers of inflammation and bone turnover in response to treatment with infliximab plus methotrexate (MTX) versus MTX alone are associated with improvement in clinical measures of signs, symptoms, and structural damage in early rheumatoid arthritis.
Slide 32 : Methods. Sera were collected from patients in the ASPIRE study who received 3 mg/kg (n = 48) or 6 mg/kg infliximab plus MTX (n = 55), or MTX alone (n = 41). Several baseline biomarker levels correlated with changes in median percentage of American College of Rheumatology improvement (ACR-N), 50% improvement in ACR response (ACR50), and van der Heijde-modified Sharp score (vdHSS) at Week 54. Results. Infliximab plus MTX treatment resulted in more rapid decreases in levels of matrix metalloproteinase-3 (MMP-3), intercellular cell adhesion molecule-1, interleukin 8 (IL-8), and tumor necrosis factor-a than treatment with MTX alone. Baseline levels and decreases from baseline to Weeks 6 and 54 in MMP-3 correlated with improvement in ACR-N response at Week 54. An increase in IL-8 levels from baseline to Week 54 correlated with worsening in vdHSS at Week 54 in the MTX-alone group.
Slide 33 : Regression analysis of markers at baseline showed that MMP-3 was the only variable associated with ACR50 response and less worsening in vdHSS at Week 54. Conclusion. Treatment with infliximab plus MTX resulted in a rapid decrease in inflammation markers. MMP-3 levels at different timepoints were consistently associated with clinical improvements at Week 54 in the infliximab plus MTX group, while increases in IL-8 levels correlated with a worsening in vdHSS at Week 54 in the MTX-alone group.

 


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