Gilles Paintaud

Withdrawal of immunosuppression in Crohn's disease treated with scheduled infliximab maintenance: a Randomized trial

BACKGROUND & AIMS The benefit to risk ratio of concomitant immunosuppressives with scheduled infliximab (IFX) maintenance therapy for Crohns disease is an issue of debate. We aimed to study the influence of immunosuppressives discontinuation in patients in remission with combination therapy in an open-label, randomized, controlled trial. METHODS Patients with controlled disease > or = 6 months after the start of IFX (5 mg/kg intravenously) combined with immunosuppressives were randomized to continue (Con) or to interrupt (Dis) immunosuppressives, while all patients received scheduled IFX maintenance therapy for 104 weeks. Primary end point was the proportion of patients who required a decrease in IFX dosing interval or stopped IFX therapy. Secondary end points included IFX trough levels, safety, and mucosal healing. RESULTS A similar proportion (24/40, 60% Con) and (22/40, 55% Dis) of patients needed a change in IFX dosing interval or stopped IFX therapy (11/40 Con, 9/40 Dis). C-reactive protein (CRP) was higher and IFX trough levels were lower in the Dis group (Dis: CRP, 2.8 mg/L; interquartile range [IQR], 1.0-8.0; Con: CRP, 1.6 mg/L; IQR, 1.0-5.6, P < .005; trough IFX: Dis: 1.65 microg/mL; IQR, 0.54-3.68; Con: 2.87 microg/mL; IQR, 1.35-4.72, P < .0001). Low IFX trough levels correlated with increased CRP and clinical score. Mucosal ulcers were absent at week 104 in 64% (Con) and 61% (Dis) of evaluated patients with ongoing response to IFX. CONCLUSIONS Continuation of immunosuppressives beyond 6 months offers no clear benefit over scheduled IFX monotherapy but is associated with higher median IFX trough and decreased CRP levels. The impact of these observations on long-term outcomes needs to be explored further.

Influence of Trough Serum Levels and Immunogenicity on Long-term Outcome of Adalimumab Therapy in Crohn's Disease

BACKGROUND & AIMS Adalimumab is an efficacious therapy for active Crohns disease, but long-term data are scarce. We conducted an observational study to assess the long-term clinical benefit of adalimumab in patients who failed to respond to infliximab, specifically focusing on the influence of trough serum concentration and antibodies against adalimumab on clinical outcome. METHODS A total of 168 patients with Crohns disease treated with adalimumab in a tertiary center were included in a prospective follow-up program. Trough serum concentration and antibodies against adalimumab were measured at predefined time points using enzyme-linked immunosorbent assays. RESULTS A total of 71% and 67% of patients responded by weeks 4 and 12, respectively; among them, 61.5% demonstrated sustained clinical benefit until the end of follow-up (median [interquartile range], 20.4 [11.7-30.0] months). Of the 156 patients receiving maintenance therapy, 102 (65.4%) had to step up to 40 mg weekly and 60 (38.5%) eventually stopped adalimumab therapy mainly due to loss of response. Significantly lower adalimumab trough serum concentrations were measured throughout the follow-up period in patients who discontinued therapy as compared with patients who stayed on adalimumab. Antibodies against adalimumab were present in 9.2% of the patients and affected trough serum concentration. Serious adverse events occurred in 12% of the patients. CONCLUSIONS Introduction of adalimumab after failure of infliximab therapy resulted in a sustained clinical benefit in two thirds of patients during a median follow-up period of almost 2 years. Discontinuation was directly related to low adalimumab trough serum concentration, which was observed more frequently in patients who developed antibodies against adalimumab.

Rituximab-Dependent Cytotoxicity by Natural Killer Cells Influence of FCGR3A Polymorphism on the Concentration-Effect Relationship

The FCGR3A gene dimorphism generates two allotypes: FcγRIIIa-158V and FcγRIIIa-158F. The genotype homozygous for FcγRIIIa-158V (VV) is associated with higher clinical response to rituximab, a chimeric anti-CD20 IgG1 used in the treatment of B lymphoproliferative malignancies. Our objective was to determine whether this genetic association relates to rituximab-dependent cytotoxicity mediated by FcγRIIIa/CD16a+ cells. The number of CD16+ circulating monocytes, T cells, and natural killer (NK) cells in 54 donors was first shown to be unrelated to FCGR3A polymorphism. We then demonstrated that FcγRIIIa-158V displays higher affinity for rituximab than FcγRIIIa-158F by comparing rituximab concentrations inhibiting the binding of 3G8 mAb (anti-CD16) with VV NK cells and NK cells homozygous for FcγRIIIa-158F (FF). VV and FF NK cells killed Daudi cells similarly after FcγRIIIa engagement by saturating concentrations of rituximab or 3G8. However, the rituximab concentration resulting in 50% lysis (EC50) observed with NK cells from VV donors was 4.2 times lower than that observed with NK cells from FF donors (on average 0.00096 and 0.00402 μg/ml, respectively, P = 0.0043). Finally, the functional difference between VV and FF NK cells was restricted to rituximab concentrations weakly sensitizing CD20. This study supports the conclusion that FCGR3A genotype is associated with response to rituximab because it affects the relationship between rituximab concentration and NK cell-mediated lysis of CD20+ cells. Rituximab administration could therefore be adjusted according to FCGR3A genotype.

Maintenance of remission among patients with Crohn's disease on antimetabolite therapy after infliximab therapy is stopped.

BACKGROUND & AIMS It is important to determine whether infliximab therapy can be safely interrupted in patients with Crohns disease who have undergone a period of prolonged remission. We assessed the risk of relapse after infliximab therapy was discontinued in patients on combined maintenance therapy with antimetabolites and identified factors associated with relapse. METHODS We performed a prospective study of 115 patients with Crohns disease who were treated for at least 1 year with scheduled infliximab and an antimetabolite and had been in corticosteroid-free remission for at least 6 months. Infliximab was stopped, and patients were followed up for at least 1 year. We associated demographic, clinical, and biologic factors with time to relapse using a Cox model. RESULTS After a median follow-up period of 28 months, 52 of the 115 patients experienced a relapse; the 1-year relapse rate was 43.9% ± 5.0%. Based on multivariable analysis, risk factors for relapse included male sex, the absence of surgical resection, leukocyte counts >6.0 × 10(9)/L, and levels of hemoglobin ≤145 g/L, C-reactive protein ≥5.0 mg/L, and fecal calprotectin ≥300 μg/g. Patients with no more than 2 of these risk factors (approximately 29% of the study population) had a 15% risk of relapse within 1 year. Re-treatment with infliximab was effective and well tolerated in 88% of patients who experienced a relapse. CONCLUSIONS Approximately 50% of patients with Crohns disease who were treated for at least 1 year with infliximab and an antimetabolite agent experienced a relapse within 1 year after discontinuation of infliximab. However, patients with a low risk of relapse can be identified using a combination of clinical and biologic markers.

Association between polymorphism in IgG Fc receptor IIIa coding gene and biological response to infliximab in Crohn's disease

Aim : To test the hypothesis of an association between polymorphism in FCGR3A (the gene coding for FcγRIIIa, which is expressed on macrophages and natural killer cells, is involved in antibody‐dependent cell‐mediated cytotoxicity and has recently been associated with a positive response to rituximab, a recombinant immunoglobulin G1 antibody used in non‐Hodgkins lymphomas) and response to infliximab in Crohns disease.

Bevacizumab in Patients With Hereditary Hemorrhagic Telangiectasia and Severe Hepatic Vascular Malformations and High Cardiac Output

CONTEXT The only treatment available to restore normal cardiac output in patients with hereditary hemorrhagic telangiectasia (HHT) and cardiac failure is liver transplant. Anti-vascular endothelial growth factor treatments such as bevacizumab may be an effective treatment. OBJECTIVES To test the efficacy of bevacizumab in reducing high cardiac output in severe hepatic forms of HHT and to assess improvement in epistaxis duration and quality of life. DESIGN, SETTING, AND PATIENTS Single-center, phase 2 trial with national recruitment from the French HHT Network. Patients were 18 to 70 years old and had confirmed HHT, severe liver involvement, and a high cardiac index related to HHT. INTERVENTION Bevacizumab, 5 mg per kg, every 14 days for a total of 6 injections. The total duration of the treatment was 2.5 months; patients were followed up for 6 months after the beginning of the treatment. MAIN OUTCOME MEASURE Decrease in cardiac output at 3 months after the first injection, evaluated by echocardiography. RESULTS A total of 25 patients were included between March 2009 and November 2010. Of the 24 patients who had echocardiograms available for reread, there was a response in 20 of 24 patients with normalization of cardiac index (complete response [CR]) in 3 of 24, partial response (PR) in 17 of 24, and no response in 4 cases. Median cardiac index at beginning of the treatment was 5.05 L/min/m(2) (range, 4.1-6.2) and significantly decreased at 3 months after the beginning of the treatment with a median cardiac index of 4.2 L/min/m(2) (range, 2.9-5.2; P < .001). Median cardiac index at 6 months was significantly lower than before treatment (4.1 L/min/m(2); range, 3.0-5.1). Among 23 patients with available data at 6 months, we observed CR in 5 cases, PR in 15 cases, and no response in 3 cases. Mean duration of epistaxis, which was 221 minutes per month (range, 0-947) at inclusion, had significantly decreased at 3 months (134 minutes; range, 0-656) and 6 months (43 minutes; range, 0-310) (P = .008). Quality of life had significantly improved. The most severe adverse events were 2 cases of grade 3 systemic hypertension, which were successfully treated. CONCLUSION In this preliminary study of patients with HHT associated with severe hepatic vascular malformations and high cardiac output, administration of bevacizumab was associated with a decrease in cardiac output and reduced duration and number of episodes of epistaxis. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00843440.

Mechanism-Based Pharmacokinetic–Pharmacodynamic Modeling—A New Classification of Biomarkers

In recent years, pharmacokinetic/pharmacodynamic (PK/PD) modeling has developed from an empirical descriptive discipline into a mechanistic science that can be applied at all stages of drug development. Mechanism-based PK/PD models differ from empirical descriptive models in that they contain specific expressions to characterize processes on the causal path between drug administration and effect. Mechanism-based PK/PD models have much improved properties for extrapolation and prediction. As such, they constitute a scientific basis for rational drug discovery and development. In this report, a novel classification of biomarkers is proposed. Within the context of mechanism-based PK/PD modeling, a biomarker is defined as a measure that characterizes, in a strictly quantitative manner, a process, which is on the causal path between drug administration and effect. The new classification system distinguishes seven types of biomarkers: type 0, genotype/phenotype determining drug response; type 1, concentration of drug or drug metabolite; type 2, molecular target occupancy; type 3, molecular target activation; type 4, physiological measures; type 5, pathophysiological measures; and type 6, clinical ratings. In this paper, the use of the new biomarker classification is discussed in the context of the application of mechanism-based PK/PD analysis in drug discovery and development.

Infliximab Pharmacokinetics in Inflammatory Bowel Disease Patients

Infliximab, a chimeric monoclonal antibody, has profoundly modified the treatment of several inflammatory diseases, but no satisfactory description of its pharmacokinetics is available. The objective of this study is to describe the pharmacokinetics of infliximab and to explore the sources of its interindividual variability. Thirty-three chronic inflammatory bowel disease patients were studied. Infliximab serum concentrations, obtained during therapeutic drug monitoring, were analyzed using a population approach. Influence of sex, weight, age, concomitant immunosuppressive treatment, and development of antibodies toward infliximab (ATI) on pharmacokinetic parameters was investigated. A two-compartment model with first-order distribution and elimination constants allowed a satisfactory description of infliximab serum concentrations. Mean population distribution and elimination half-lives were 4.3 and 18.5 days, respectively. Weight and sex were found to significantly influence volume of distribution of the central compartment, which increased with weight and was higher in men. Clearance was 2.7 times higher, and elimination half-life was 34% lower in the presence of ATI. In two patients, an increase in infliximab dose or a decrease in dosing interval lead to a decrease in infliximab clearance toward its value in patients without ATI. Infliximab pharmacokinetics are similar to those of other monoclonal antibodies, notably with an elimination half-life of approximately 3 weeks. Both body weight and sex were found to influence infliximab pharmacokinetics, and its clearance increased thrice in the presence of ATI.

Antibodies toward infliximab are associated with low infliximab concentration at treatment initiation and poor infliximab maintenance in rheumatic diseases

IntroductionA 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.MethodsAll 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: ATIpos if ATI were detected at least once during the follow-up period and ATIneg 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.ResultsWe 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 ATIpos than ATIneg 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 ATIneg and ATIpos 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 ATIneg and ATIpos 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).ConclusionsHigh 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.

An enzyme-linked immunosorbent assay for therapeutic drug monitoring of cetuximab.

An enzyme-linked immunosorbent assay (ELISA) measuring serum infliximab concentrations in treated patients was developed. Microtiter plates were sensitized with tumor necrosis factor α (TNF-α) and saturated with phosphate-buffered saline (PBS) containing 1% bovine serum albumin (BSA). Samples diluted 1:100 in PBS-1% BSA were added and bound infliximab was detected using peroxidase-conjugated goat anti-human immunoglobulin G specific for Fc fragment (HRP-anti hIgG). Reading was performed using an ELISA plate reader. The limit of detection, calculated by assaying 10 replicates of a drug-free serum sample or blank sample and defined as the lowest concentration distinguishable from zero at 2 standard deviations, was 0.014 μg/mL. Each quality control sample was tested on 7 occasions on 1 day and on 5 separate days. The intraday precision indices of the method were (percent coefficients of variation, CV%) 11.7%, 6.2%, and 6.9% for 0.04 μg/mL, 2 μg/mL, and 4.5 μg/mL, respectively. The corresponding bias measures (percent deviation) were −5.5%, −1.9%, and −7.9%, respectively. The between-days precision was 9.8%, 5.3%, and 5.3% for 0.04 μg/mL, 2 μg/mL, and 4.5 μg/mL, respectively. The corresponding bias were +0.3%, −0.3%, and −7.8%, respectively. Lower limit of quantitation and upper limit of quantitation were 0.04 μg/mL and 4.5 μg/mL, respectively. Trough serum concentrations of infliximab were measured in 6 adult patients with various diseases and in 5 pediatric patients with Crohns disease. For the latter group, samples drawn 1 hour after the end of the infusion and repeated measurements also were available. Data were described using a 1-compartment population pharmacokinetic model. Terminal elimination half-life was 10.9 days. This method is rapid, accurate, and reproducible, and may be useful in therapeutic drug monitoring of infliximab.