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Philippe Goupille - One of the best experts on this subject based on the ideXlab platform.
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Therapeutic Drug Monitoring of Infliximab in Spondyloarthritis: An Observational Open-Label Study
Ther. Drug Monit., 2011Co-Authors: Jean-camille Meric, Denis Mulleman, Francine Lauféron, Emilie Ducourau, Philippe Goupille, Hervé Watier, Delphine Chu Miow Lin, Gilles PaintaudAbstract:Background: Infliximab is a chimeric monoclonal antibody that binds to human tumor necrosis factor alpha and which is approved for refractory spondyloarthritis (SpA). Individual adjustment of Infliximab dosage may help to improve the therapeutic response in SpA. We investigated whether a knowledge of Infliximab serum concentration modifies physician decision and improves the control of disease activity in SpA. Methods: Thirty-two patients routinely treated with Infliximab were included in an observational open-label study. On visit 1 (V1), according to disease activity, a preliminary therapeutic decision was selected among 4 therapeutic options (ie, decrease, increase, maintain the dosage of Infliximab, or switch over for another treatment), and a blood sample was collected to measure Infliximab trough serum concentration. The final therapeutic decision, based on both disease activity and Infliximab serum concentration assessed at V1, was applied at the following infusion (V2). Clinical and biological evaluations were performed at V3 and V4 and compared with those at V1. Results: The measurement of Infliximab trough concentration modified the therapeutic decision for 10 patients (31%). For both patients with increased or decreased Infliximab dosage at V2, median Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) was similar at V3 or V4 as compared with that at V1. However, a trend for an inverse relationship between Infliximab serum concentrations and BASDAI was observed. Conclusions: Knowledge of Infliximab trough concentration modified the therapeutic decision for SpA patients with predominantly axial symptoms but did not improve the control of disease activity as estimated by the BASDAI.
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antibodies toward Infliximab are associated with low Infliximab concentration at treatment initiation and poor Infliximab maintenance in rheumatic diseases
Arthritis Research & Therapy, 2011Co-Authors: Emilie Ducourau, David Ternant, Gilles Paintaud, Denis Mulleman, Hervé Watier, Delphine Chu Miow Lin, F Lauferon, Philippe GoupilleAbstract:Introduction A proportion of patients receiving Infliximab have antibodies toward Infliximab (ATI), which are associated with increased risk of infusion reaction and reduced response to treatment. We studied the association of Infliximab concentration at treatment initiation and development of ATI as well as the association of the presence of ATI and maintenance of Infliximab.
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Infliximab in ankylosing spondylitis: alone or in combination with methotrexate? A pharmacokinetic comparative study.
Arthritis Research and Therapy, 2011Co-Authors: Denis Mulleman, David Ternant, Gilles Paintaud, Francine Lauféron, Daniel Wendling, Emilie Ducourau, Philippe GoupilleAbstract:INTRODUCTION: Methotrexate (MTX) has been shown to modify Infliximab pharmacokinetics in rheumatoid arthritis. However, its combination with Infliximab in the treatment of ankylosing spondylitis (AS) is not recommended. The objective of this study was to examine the influence of MTX on Infliximab exposure in patients with AS. METHODS: Patients with AS patients who had predominantly axial symptoms were randomised to receive Infliximab alone (infusions of 5 mg/kg at weeks 0, 2, 6, 12 and 18) or Infliximab combined with MTX (10 mg/week). Infliximab concentrations were measured before and 2 hours after each infusion and at 1, 3, 4, 5, 8, 10, 14 and 18 weeks. We estimated individual cumulative area under the concentration versus time curves (AUC) for Infliximab concentration between baseline and week 18 (AUC(0-18)). Clinical and laboratory evaluations were performed at each visit. The Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) score was the primary end point for clinical response. RESULTS: Twenty-six patients were included (Infliximab group: n = 12, Infliximab + MTX group: n = 14), and 507 serum samples were available for measurement of Infliximab concentration. The two groups did not differ with regard to AUC(0-18) or evolution of BASDAI scores and biomarkers of inflammation. CONCLUSIONS: The combination of MTX and Infliximab does not increase the exposure to Infliximab over Infliximab alone in patients with AS. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00507403.
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Antibodies toward Infliximab are associated with low Infliximab concentration at treatment initiation and poor Infliximab maintenance in rheumatic diseases.
Arthritis Research and Therapy, 2011Co-Authors: Emilie Ducourau, David Ternant, Gilles Paintaud, Denis Mulleman, Francine Lauféron, Delphine Chu Miow Lin, Hervé Watier, Philippe GoupilleAbstract:INTRODUCTION: A proportion of patients receiving Infliximab have antibodies toward Infliximab (ATI), which are associated with increased risk of infusion reaction and reduced response to treatment. We studied the association of Infliximab concentration at treatment initiation and development of ATI as well as the association of the presence of ATI and maintenance of Infliximab. METHODS: All patients with rheumatoid arthritis (RA) or spondyloarthritis (SpA) receiving Infliximab beginning in December 2005 were retrospectively followed until January 2009 or until Infliximab discontinuation. Trough serum Infliximab and ATI concentrations were measured at each visit. The patients were separated into two groups: ATI(pos) if ATI were detected at least once during the follow-up period and ATI(neg) otherwise. Repeated measures analysis of variance was used to study the association of Infliximab concentration at treatment initiation and the development of ATI. Maintenance of Infliximab in the two groups was studied by using Kaplan-Meier curves. RESULTS: We included 108 patients: 17 with RA and 91 with SpA. ATI were detected in 21 patients (19%). The median time to ATI detection after initiation of Infliximab was 3.7 months (1.7 to 26.0 months). For both RA and SpA patients, trough Infliximab concentration during the initiation period was significantly lower for ATI(pos) than ATI(neg) patients. RA patients showed maintenance of Infliximab at a median of 19.5 months (5.0 to 31.0 months) and 12.0 months (2.0 to 24.0 months) for ATI(neg) and ATI(pos) groups, respectively (P = 0.08). SpA patients showed Infliximab maintenance at a median of 16.0 months (3.0 to 34.0 months) and 9.5 months (3.0 to 39.0 months) for ATI(neg) and ATI(pos) groups, respectively (P = 0.20). Among SpA patients, those who were being treated concomitantly with methotrexate had a lower risk of developing ATI than patients not taking methotrexate (0 of 14 patients (0%) vs. 25 of 77 patients (32%); P = 0.03). CONCLUSIONS: High concentrations of Infliximab during treatment initiation reduce the development of ATI, and the absence of ATI may be associated with prolonged maintenance of Infliximab. Thus, trough serum Infliximab concentration should be monitored early in patients with rheumatic diseases.
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Trough Infliximab Concentrations Predict Efficacy and Sustained Control of Disease Activity in Rheumatoid Arthritis
Ther. Drug Monit., 2010Co-Authors: Denis Mulleman, David Ternant, Gilles Paintaud, Emilie Ducourau, Delphine Chu Miow Lin, Patrick Emond, Charlotte Magdelaine-beuzelin, Jean-pierre Valat, Philippe GoupilleAbstract:Infliximab is a chimeric monoclonal antibody that binds to human tumor necrosis factor alpha and is approved for refractory rheumatoid arthritis. We studied the association between Infliximab concentration and long-term control of disease activity in patients with rheumatoid arthritis treated on a routine basis both in cross-sectional analysis and over the long term. Trough serum Infliximab concentrations were measured in patients with rheumatoid arthritis receiving Infliximab infusions during the period August to October 2006. Disease activity was assessed by the Disease Activity Score for 28 Joints (DAS28) and usual biologic markers. During a 42-week follow-up period, patients were classified into two groups: those continuing with the same or lower doses of Infliximab (Group A = treatment success) and those who switched to another bio-pharmaceutical or required an increase in Infliximab dose (Group B = treatment failure). Treatment maintenance for Group A was analyzed by categories of Infliximab concentration at baseline and compared by the log rank test. In 28 patients, C-reactive protein and Infliximab concentrations were inversely related. Infliximab concentration in patients with low disease activity (DAS28 3.2 or less) was higher than in those with persistent active disease (DAS28 greater than 3.2); median values were 3.26 and 0.16 mg/L, respectively (P < 0.01). Analysis after 42 weeks showed that patients in Group A had higher Infliximab concentrations at baseline than those with treatment failure (P < 0.01). In rheumatoid arthritis, Infliximab concentration is predictive of sustained efficacy with the same Infliximab regimen and should be considered on a routine basis.
Gilles Paintaud - One of the best experts on this subject based on the ideXlab platform.
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Assessment of the Influence of Inflammation and FCGR3A Genotype on Infliximab Pharmacokinetics and Time to Relapse in Patients with Crohn’s Disease
Clinical Pharmacokinetics, 2015Co-Authors: David Ternant, Jean-frederic Colombel, Zahir Berkane, Laurence Picon, Valérie Gouilleux-gruart, Matthieu Allez, Edouard Louis, Gilles PaintaudAbstract:Infliximab is a monoclonal anti-tumor necrosis factor-α (anti-TNFα) antibody that profoundly modified the treatment of Crohn's disease (CD). The polymorphism of Fc fragment of IgG, low affinity IIIa, receptor (CD16a) [FCGR3A] influences the biological response to Infliximab in patients with CD. Our aim was to study its influence on Infliximab pharmacokinetics and risk of relapse after Infliximab discontinuation.
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Serum Infliximab concentrations in psoriatic patients treated with Infliximab: a systematic review
Acta Dermato-Venereologica, 2015Co-Authors: Carole Dannepond, Annabel Maruani, Laurent Machet, David Ternant, Gilles Paintaud, Mahtab Samimi-gharaeiAbstract:The efficacy of Infliximab is influenced by individual variability in its pharmacokinetics and pharmacodynamics. Serum Infliximab concentrations could therefore be related to the efficacy and tolerance of Infliximab, and assist adjustment of treatment. The aim of this systematic review was to assess the value of measuring serum Infliximab concentrations in psoriatic patients. A bibliographic search was performed on MEDLINE, CENTRAL, EMBASE, LILACS for original studies on serum Infliximab concentrations in psoriatic patients treated with Infliximab. Ten articles were included, representing evaluation of serum Infliximab concentrations in 733 patients. Predictive value of higher serum Infliximab concentrations on long-term response maintenance was suggested in 3 studies. There was no information regarding the value of such measurements for adjustment of Infliximab dosage. Trough serum Infliximab concentrations that are at least detectable (>0.1 mg/L) at steady state (week 22) seem to be associated with maintaining a clinical response in the long term.
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Therapeutic Drug Monitoring of Infliximab in Spondyloarthritis: An Observational Open-Label Study
Ther. Drug Monit., 2011Co-Authors: Jean-camille Meric, Denis Mulleman, Francine Lauféron, Emilie Ducourau, Philippe Goupille, Hervé Watier, Delphine Chu Miow Lin, Gilles PaintaudAbstract:Background: Infliximab is a chimeric monoclonal antibody that binds to human tumor necrosis factor alpha and which is approved for refractory spondyloarthritis (SpA). Individual adjustment of Infliximab dosage may help to improve the therapeutic response in SpA. We investigated whether a knowledge of Infliximab serum concentration modifies physician decision and improves the control of disease activity in SpA. Methods: Thirty-two patients routinely treated with Infliximab were included in an observational open-label study. On visit 1 (V1), according to disease activity, a preliminary therapeutic decision was selected among 4 therapeutic options (ie, decrease, increase, maintain the dosage of Infliximab, or switch over for another treatment), and a blood sample was collected to measure Infliximab trough serum concentration. The final therapeutic decision, based on both disease activity and Infliximab serum concentration assessed at V1, was applied at the following infusion (V2). Clinical and biological evaluations were performed at V3 and V4 and compared with those at V1. Results: The measurement of Infliximab trough concentration modified the therapeutic decision for 10 patients (31%). For both patients with increased or decreased Infliximab dosage at V2, median Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) was similar at V3 or V4 as compared with that at V1. However, a trend for an inverse relationship between Infliximab serum concentrations and BASDAI was observed. Conclusions: Knowledge of Infliximab trough concentration modified the therapeutic decision for SpA patients with predominantly axial symptoms but did not improve the control of disease activity as estimated by the BASDAI.
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antibodies toward Infliximab are associated with low Infliximab concentration at treatment initiation and poor Infliximab maintenance in rheumatic diseases
Arthritis Research & Therapy, 2011Co-Authors: Emilie Ducourau, David Ternant, Gilles Paintaud, Denis Mulleman, Hervé Watier, Delphine Chu Miow Lin, F Lauferon, Philippe GoupilleAbstract:Introduction A proportion of patients receiving Infliximab have antibodies toward Infliximab (ATI), which are associated with increased risk of infusion reaction and reduced response to treatment. We studied the association of Infliximab concentration at treatment initiation and development of ATI as well as the association of the presence of ATI and maintenance of Infliximab.
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Infliximab in ankylosing spondylitis: alone or in combination with methotrexate? A pharmacokinetic comparative study.
Arthritis Research and Therapy, 2011Co-Authors: Denis Mulleman, David Ternant, Gilles Paintaud, Francine Lauféron, Daniel Wendling, Emilie Ducourau, Philippe GoupilleAbstract:INTRODUCTION: Methotrexate (MTX) has been shown to modify Infliximab pharmacokinetics in rheumatoid arthritis. However, its combination with Infliximab in the treatment of ankylosing spondylitis (AS) is not recommended. The objective of this study was to examine the influence of MTX on Infliximab exposure in patients with AS. METHODS: Patients with AS patients who had predominantly axial symptoms were randomised to receive Infliximab alone (infusions of 5 mg/kg at weeks 0, 2, 6, 12 and 18) or Infliximab combined with MTX (10 mg/week). Infliximab concentrations were measured before and 2 hours after each infusion and at 1, 3, 4, 5, 8, 10, 14 and 18 weeks. We estimated individual cumulative area under the concentration versus time curves (AUC) for Infliximab concentration between baseline and week 18 (AUC(0-18)). Clinical and laboratory evaluations were performed at each visit. The Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) score was the primary end point for clinical response. RESULTS: Twenty-six patients were included (Infliximab group: n = 12, Infliximab + MTX group: n = 14), and 507 serum samples were available for measurement of Infliximab concentration. The two groups did not differ with regard to AUC(0-18) or evolution of BASDAI scores and biomarkers of inflammation. CONCLUSIONS: The combination of MTX and Infliximab does not increase the exposure to Infliximab over Infliximab alone in patients with AS. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00507403.
Gordon R Greenberg - One of the best experts on this subject based on the ideXlab platform.
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The relationship between Infliximab concentrations, antibodies to Infliximab and disease activity in Crohn's disease
Gut, 2014Co-Authors: Niels Vande Casteele, Scott Hauenstein, Reena Khanna, Barrett G. Levesque, Larry Stitt, Guangyong Zou, Sharat Singh, Steven Lockton, Linda Ohrmund, Gordon R GreenbergAbstract:Objective Although low Infliximab trough concentrations and antibodies to Infliximab (ATI) are associated with poor outcomes in patients with Crohn9s disease (CD), the clinical relevance of ATI in patients with adequate Infliximab concentrations is uncertain. We evaluated this question using an assay sensitive for identification of ATI in the presence of Infliximab. Design In an observational study, 1487 trough serum samples from 483 patients with CD who participated in four clinical studies of maintenance Infliximab therapy were analysed using a fluid phase mobility shift assay. Infliximab and ATI concentrations most discriminant for remission, defined as a C-reactive protein concentration of ≤5 mg/L, were determined by receiver operating characteristic curves. A multivariable regression model evaluated these factors as independent predictors of remission. Results Based upon analysis of 1487 samples, 77.1% of patients had detectable and 22.9% had undetectable Infliximab concentrations, of which 9.5% and 71.8%, respectively, were positive for ATI. An Infliximab concentration of >2.79 μg/mL (area under the curve (AUC)=0.681; 95% CI 0.632 to 0.731) and ATI concentration of Conclusions The development of ATI increases the probability of active disease even at low concentrations and in the presence of a therapeutic concentration of drug during Infliximab maintenance therapy. Evaluation of strategies to prevent ATI formation, including therapeutic drug monitoring with selective Infliximab dose intensification, is needed.
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trough serum Infliximab a predictive factor of clinical outcome for Infliximab treatment in acute ulcerative colitis
Gut, 2010Co-Authors: Cynthia H Seow, A Newman, Sandra Irwin, A H Steinhart, Mark S Silverberg, Gordon R GreenbergAbstract:Background and Aims: Antibodies to Infliximab reduce serum Infliximab with loss of clinical benefit, but undetectable trough serum concentrations of Infliximab may occur without antibody formation. The relationship between trough serum Infliximab and clinical outcomes was evaluated in acute ulcerative colitis. Methods: In a cohort of 115 patients with ulcerative colitis treated with three-dose induction followed by scheduled maintenance Infliximab, rates of clinical remission, colectomy, antibodies to Infliximab and trough serum Infliximab were determined. Results: Rates of remission were 32% at week 10 and 37% at week 54. Colectomy occurred in 40% of patients, at a median of 5.3 (IQR 1.9–12.1) months. Detectable trough serum Infliximab was present in 39% of patients and, among patients with undetectable Infliximab, 41% were antibody positive and 20% were antibody negative. For antibody-positive and antibody-negative patients, rates of remission (18% vs 14%), endoscopic improvement (25% vs 35%) and colectomy (52% vs 59%) were not different. A detectable serum Infliximab was associated with higher rates of remission (69% vs 15%; p Conclusions: For patients with ulcerative colitis treated with Infliximab, a detectable trough serum Infliximab predicts clinical remission, endoscopic improvement and a lower risk for colectomy. An undetectable trough serum Infliximab, irrespective of antibody status, is associated with less favourable outcomes.
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association of trough serum Infliximab to clinical outcome after scheduled maintenance treatment for crohn s disease
Clinical Gastroenterology and Hepatology, 2006Co-Authors: Elana Maser, Mark S Silverberg, Renata Villela, Gordon R GreenbergAbstract:Background & Aims: The effect of Infliximab infused at scheduled intervals on antibody formation, preinfusion trough serum concentrations of Infliximab, and their clinical significance was evaluated in patients with Crohn's disease. Methods: Antibodies to Infliximab and trough serum Infliximab were measured in 105 patients with Crohn's disease treated with 5 mg/kg Infliximab for induction followed by maintenance episodic re-treatment (n = 23) or scheduled therapy at 6- to 8-week intervals (n = 82). Results: After a median of 14 infusions (range, 2–45), 21% of patients had detectable antibodies, 25% were antibody negative, and 54% were antibody inconclusive. Antibody formation was higher after episodic compared with scheduled treatment (39% vs 16%; P = .036) and was associated with a higher rate of infusion reactions (50% vs 21%; P = .018). Ninety patients continued maintenance scheduled therapy beyond 12 months including 12 converted episodic patients, with a median follow-up of 23 months (range, 16–68 months). The rate of clinical remission was higher for patients with a detectable trough serum Infliximab compared with patients in whom serum Infliximab was undetectable, including those without antibodies (82% vs 6%; P P P Conclusions: For Crohn's disease patients treated with scheduled maintenance infusions of Infliximab, the trough serum concentration of Infliximab predicts clinical outcome. Factors in addition to antibody formation, likely pharmacokinetic, modulate serum Infliximab and thus the response to Infliximab therapy.
Denis Mulleman - One of the best experts on this subject based on the ideXlab platform.
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Therapeutic Drug Monitoring of Infliximab in Spondyloarthritis: An Observational Open-Label Study
Ther. Drug Monit., 2011Co-Authors: Jean-camille Meric, Denis Mulleman, Francine Lauféron, Emilie Ducourau, Philippe Goupille, Hervé Watier, Delphine Chu Miow Lin, Gilles PaintaudAbstract:Background: Infliximab is a chimeric monoclonal antibody that binds to human tumor necrosis factor alpha and which is approved for refractory spondyloarthritis (SpA). Individual adjustment of Infliximab dosage may help to improve the therapeutic response in SpA. We investigated whether a knowledge of Infliximab serum concentration modifies physician decision and improves the control of disease activity in SpA. Methods: Thirty-two patients routinely treated with Infliximab were included in an observational open-label study. On visit 1 (V1), according to disease activity, a preliminary therapeutic decision was selected among 4 therapeutic options (ie, decrease, increase, maintain the dosage of Infliximab, or switch over for another treatment), and a blood sample was collected to measure Infliximab trough serum concentration. The final therapeutic decision, based on both disease activity and Infliximab serum concentration assessed at V1, was applied at the following infusion (V2). Clinical and biological evaluations were performed at V3 and V4 and compared with those at V1. Results: The measurement of Infliximab trough concentration modified the therapeutic decision for 10 patients (31%). For both patients with increased or decreased Infliximab dosage at V2, median Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) was similar at V3 or V4 as compared with that at V1. However, a trend for an inverse relationship between Infliximab serum concentrations and BASDAI was observed. Conclusions: Knowledge of Infliximab trough concentration modified the therapeutic decision for SpA patients with predominantly axial symptoms but did not improve the control of disease activity as estimated by the BASDAI.
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antibodies toward Infliximab are associated with low Infliximab concentration at treatment initiation and poor Infliximab maintenance in rheumatic diseases
Arthritis Research & Therapy, 2011Co-Authors: Emilie Ducourau, David Ternant, Gilles Paintaud, Denis Mulleman, Hervé Watier, Delphine Chu Miow Lin, F Lauferon, Philippe GoupilleAbstract:Introduction A proportion of patients receiving Infliximab have antibodies toward Infliximab (ATI), which are associated with increased risk of infusion reaction and reduced response to treatment. We studied the association of Infliximab concentration at treatment initiation and development of ATI as well as the association of the presence of ATI and maintenance of Infliximab.
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Infliximab in ankylosing spondylitis: alone or in combination with methotrexate? A pharmacokinetic comparative study.
Arthritis Research and Therapy, 2011Co-Authors: Denis Mulleman, David Ternant, Gilles Paintaud, Francine Lauféron, Daniel Wendling, Emilie Ducourau, Philippe GoupilleAbstract:INTRODUCTION: Methotrexate (MTX) has been shown to modify Infliximab pharmacokinetics in rheumatoid arthritis. However, its combination with Infliximab in the treatment of ankylosing spondylitis (AS) is not recommended. The objective of this study was to examine the influence of MTX on Infliximab exposure in patients with AS. METHODS: Patients with AS patients who had predominantly axial symptoms were randomised to receive Infliximab alone (infusions of 5 mg/kg at weeks 0, 2, 6, 12 and 18) or Infliximab combined with MTX (10 mg/week). Infliximab concentrations were measured before and 2 hours after each infusion and at 1, 3, 4, 5, 8, 10, 14 and 18 weeks. We estimated individual cumulative area under the concentration versus time curves (AUC) for Infliximab concentration between baseline and week 18 (AUC(0-18)). Clinical and laboratory evaluations were performed at each visit. The Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) score was the primary end point for clinical response. RESULTS: Twenty-six patients were included (Infliximab group: n = 12, Infliximab + MTX group: n = 14), and 507 serum samples were available for measurement of Infliximab concentration. The two groups did not differ with regard to AUC(0-18) or evolution of BASDAI scores and biomarkers of inflammation. CONCLUSIONS: The combination of MTX and Infliximab does not increase the exposure to Infliximab over Infliximab alone in patients with AS. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00507403.
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Antibodies toward Infliximab are associated with low Infliximab concentration at treatment initiation and poor Infliximab maintenance in rheumatic diseases.
Arthritis Research and Therapy, 2011Co-Authors: Emilie Ducourau, David Ternant, Gilles Paintaud, Denis Mulleman, Francine Lauféron, Delphine Chu Miow Lin, Hervé Watier, Philippe GoupilleAbstract:INTRODUCTION: A proportion of patients receiving Infliximab have antibodies toward Infliximab (ATI), which are associated with increased risk of infusion reaction and reduced response to treatment. We studied the association of Infliximab concentration at treatment initiation and development of ATI as well as the association of the presence of ATI and maintenance of Infliximab. METHODS: All patients with rheumatoid arthritis (RA) or spondyloarthritis (SpA) receiving Infliximab beginning in December 2005 were retrospectively followed until January 2009 or until Infliximab discontinuation. Trough serum Infliximab and ATI concentrations were measured at each visit. The patients were separated into two groups: ATI(pos) if ATI were detected at least once during the follow-up period and ATI(neg) otherwise. Repeated measures analysis of variance was used to study the association of Infliximab concentration at treatment initiation and the development of ATI. Maintenance of Infliximab in the two groups was studied by using Kaplan-Meier curves. RESULTS: We included 108 patients: 17 with RA and 91 with SpA. ATI were detected in 21 patients (19%). The median time to ATI detection after initiation of Infliximab was 3.7 months (1.7 to 26.0 months). For both RA and SpA patients, trough Infliximab concentration during the initiation period was significantly lower for ATI(pos) than ATI(neg) patients. RA patients showed maintenance of Infliximab at a median of 19.5 months (5.0 to 31.0 months) and 12.0 months (2.0 to 24.0 months) for ATI(neg) and ATI(pos) groups, respectively (P = 0.08). SpA patients showed Infliximab maintenance at a median of 16.0 months (3.0 to 34.0 months) and 9.5 months (3.0 to 39.0 months) for ATI(neg) and ATI(pos) groups, respectively (P = 0.20). Among SpA patients, those who were being treated concomitantly with methotrexate had a lower risk of developing ATI than patients not taking methotrexate (0 of 14 patients (0%) vs. 25 of 77 patients (32%); P = 0.03). CONCLUSIONS: High concentrations of Infliximab during treatment initiation reduce the development of ATI, and the absence of ATI may be associated with prolonged maintenance of Infliximab. Thus, trough serum Infliximab concentration should be monitored early in patients with rheumatic diseases.
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Trough Infliximab Concentrations Predict Efficacy and Sustained Control of Disease Activity in Rheumatoid Arthritis
Ther. Drug Monit., 2010Co-Authors: Denis Mulleman, David Ternant, Gilles Paintaud, Emilie Ducourau, Delphine Chu Miow Lin, Patrick Emond, Charlotte Magdelaine-beuzelin, Jean-pierre Valat, Philippe GoupilleAbstract:Infliximab is a chimeric monoclonal antibody that binds to human tumor necrosis factor alpha and is approved for refractory rheumatoid arthritis. We studied the association between Infliximab concentration and long-term control of disease activity in patients with rheumatoid arthritis treated on a routine basis both in cross-sectional analysis and over the long term. Trough serum Infliximab concentrations were measured in patients with rheumatoid arthritis receiving Infliximab infusions during the period August to October 2006. Disease activity was assessed by the Disease Activity Score for 28 Joints (DAS28) and usual biologic markers. During a 42-week follow-up period, patients were classified into two groups: those continuing with the same or lower doses of Infliximab (Group A = treatment success) and those who switched to another bio-pharmaceutical or required an increase in Infliximab dose (Group B = treatment failure). Treatment maintenance for Group A was analyzed by categories of Infliximab concentration at baseline and compared by the log rank test. In 28 patients, C-reactive protein and Infliximab concentrations were inversely related. Infliximab concentration in patients with low disease activity (DAS28 3.2 or less) was higher than in those with persistent active disease (DAS28 greater than 3.2); median values were 3.26 and 0.16 mg/L, respectively (P < 0.01). Analysis after 42 weeks showed that patients in Group A had higher Infliximab concentrations at baseline than those with treatment failure (P < 0.01). In rheumatoid arthritis, Infliximab concentration is predictive of sustained efficacy with the same Infliximab regimen and should be considered on a routine basis.
Tore Saxne - One of the best experts on this subject based on the ideXlab platform.
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Monitoring patients treated with anti-TNF- biopharmaceuticals: assessing serum Infliximab and anti-Infliximab antibodies
Rheumatology (Oxford England), 2007Co-Authors: Morten Svenson, Pierre Geborek, Tore Saxne, K. BendtzenAbstract:Objectives. Infliximab is an anti-tumour necrosis factor-alpha (TNF-alpha) mousehuman IgG1/k antibody used to treat patients with rheumatoid arthritis (RA) and other inflammatory diseases. Unfortunately, response failure and side-effects due to immunogenicity of the drug are not rare. In this study, we have compared different methods of assessing drug levels and anti-Infliximab antibodies (Abs) and analysed the character of these Abs in sera of RA patients treated with Infliximab for 1.5-18 months. Methods. Functional serum Infliximab levels and anti-Infliximab Abs were measured by fluid-phase RIAs using I-125-labelled ligands in combination with molecular size and affinity chromatography, and immune complex precipitation. Results. Anti-Infliximab Abs were predominantly IgG, 36% being IgG4, and half the immune complexes were lambda-light-chain-positive. Ab titres were associated with inhibition of TNF binding to the drug, and low trough levels of Infliximab were most frequent in anti-Infliximab Ab-positive sera. Cross-binding to two other anti-TNF drugs was not observed. Detection of anti-Infliximab Abs by solid-phase RIA using cross-binding of plastic-fixed and soluble Infliximab exhibited low sensitivity and the data were inconsistent with results obtained from binding of the Abs to soluble Infliximab. Conclusions. Specific and neutralizing anti-Infliximab antibodies develop in RA patients treated with Infliximab, and that low trough levels of functional Infliximab are associated with the presence of such antibodies. The most sensitive antibody assay involved binding to soluble and intact Infliximab. Assessments of bioavailability and immunogenicity of anti-TNF biologicals may be used to optimize dose regimens and prevent prolonged use of inadequate therapy. (Less)
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individualized monitoring of drug bioavailability and immunogenicity in rheumatoid arthritis patients treated with the tumor necrosis factor alpha inhibitor Infliximab
Arthritis & Rheumatism, 2006Co-Authors: Klaus Bendtzen, Morten Svenson, Pierre Geborek, Lotta Larsson, Meliha C Kapetanovic, Tore SaxneAbstract:OBJECTIVE: Infliximab, an anti-tumor necrosis factor alpha (anti-TNFalpha) antibody, is effective in the treatment of several immunoinflammatory diseases. However, many patients experience primary or secondary response failure, suggesting that individualization of treatment regimens may be beneficial. This study was undertaken to investigate whether serologic monitoring of Infliximab bioavailability and immunogenicity in individual patients would be useful in optimizing treatment regimens to improve efficacy and tolerability. METHODS: To avoid the use of solid-phase assays, two radioimmunoassays were developed: one for measurement of levels of anti-Infliximab antibody, and a functional one for measurement of TNFalpha binding due to Infliximab. Sera from 106 randomly selected rheumatoid arthritis patients were tested within 6 months of therapy initiation, and associations between findings of serum assays and disease activity, infusion reactions, and treatment failure occurring within 18 months were assessed. RESULTS: Trough serum Infliximab levels after the first 2 intravenous infusions of Infliximab at 3 mg/kg varied considerably between patients (range 0-22 microg/ml). At this stage, only 13% of the patients were anti-Infliximab antibody positive. With subsequent infusions, the frequency of antibody positivity rose to 30% and 44% (at 3 months and 6 months, respectively), accompanied by diminished trough levels of Infliximab. Indeed, low Infliximab levels at 1.5 months predicted antibody development and later treatment failure. There were highly significant correlations between high levels of antibodies and later dose increases, side effects, and cessation of therapy. High baseline disease activity, judged by C-reactive protein level and Disease Activity Score, was associated with low levels of Infliximab at the early stage of treatment and later development of anti-Infliximab antibodies. Cotreatment with methotrexate resulted in slightly reduced antibody levels after 6 months; other disease-modifying antirheumatic drugs and prednisolone had no effect. CONCLUSION: Development of anti-Infliximab antibodies, heralded by low preinfusion serum Infliximab levels, is associated with increased risk of infusion reaction and treatment failure. Early monitoring may help optimize dosing regimens for individual patients, diminish side effects, and prevent prolonged use of inadequate Infliximab therapy.
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individualized monitoring of drug bioavailability and immunogenicity in rheumatoid arthritis patients treated with the tumor necrosis factor alpha inhibitor Infliximab
Arthritis & Rheumatism, 2006Co-Authors: Klaus Bendtzen, Morten Svenson, Pierre Geborek, Lotta Larsson, Meliha C Kapetanovic, Tore SaxneAbstract:Objective. Infliximab, an anti-tumor necrosis factor alpha (anti-TNF alpha) antibody, is effective in the treatment of several immunoinflammatory diseases. However, many patients experience primary or secondary response failure, suggesting that individualization of treatment regimens may be beneficial. This study was undertaken to investigate whether serologic monitoring of Infliximab bioavailability and immunogenicity in individual patients would be useful in optimizing treatment regimens to improve efficacy and tolerability. Methods. To avoid the use of solid-phase assays, two radioimmunoassays were developed: one for measurement of levels of anti-Infliximab antibody, and a functional one for measurement of TNF alpha binding due to Infliximab. Sera from 106 randomly selected rheumatoid arthritis patients were tested within 6 months of therapy initiation, and associations between findings of serum assays and disease activity, infusion reactions, and treatment failure occurring within 18 months were assessed. Results. Trough serum Infliximab levels after the first 2 intravenous infusions of Infliximab at 3 mg/kg varied considerably between patients (range 0-22 mu g/ml). At this stage, only 13% of the patients were anti-Infliximab antibody positive. With subsequent infusions, the frequency of antibody positivity rose to 30% and 44% (at 3 months and 6 months, respectively), accompanied by diminished trough levels of Infliximab. Indeed, low Infliximab levels at 1.5 months predicted antibody development and later treatment failure. There were highly significant correlations between high levels of antibodies and later dose increases, side effects, and cessation of therapy. High baseline disease activity, judged by C-reactive protein level and Disease Activity Score, was associated with low levels of Infliximab at the early stage of treatment and later development of anti-Infliximab antibodies. Cotreatment with methotrexate resulted in slightly reduced antibody levels after 6 months; other disease-modifying antirheumatic drugs and prednisolone had no effect. Conclusion. Development of anti-Infliximab antibodies, heralded by low preinfusion serum Infliximab levels, is associated with increased risk of infusion reaction and treatment failure. Early monitoring may help optimize dosing regimens for individual patients, diminish side effects, and prevent prolonged use of inadequate Infliximab therapy. (Less)