Casper Steenholdt

Individualised therapy is more cost-effective than dose intensification in patients with Crohn’s disease who lose response to anti-TNF treatment: a randomised, controlled trial

Objective Although the reasons for secondary loss of response to infliximab (IFX) maintenance therapy in Crohn’s disease vary, dose intensification is usually recommended. This study investigated the cost-effectiveness of interventions defined by an algorithm designed to identify specific reasons for therapeutic failure. Design Randomised, controlled, single-blind, multicentre study. 69 patients with secondary IFX failure were randomised to IFX dose intensification (5 mg/kg every 4 weeks) (n=36) or interventions based on serum IFX and IFX antibody levels using the proposed algorithm (n=33). Predefined co-primary end points at week 12 were proportion of patients responding (Crohns Disease Activity Index (CDAI) decrease ≥70, or ≥50% reduction in active fistulas) and accumulated costs related to treatment of Crohn’s disease, expressed as mean cost per patient, based on the Danish National Patient Registry for all hospitalisation and outpatient costs in the Danish healthcare sector. Results Costs for intention-to-treat patients were substantially lower (34%) for those treated in accordance with the algorithm than by IFX dose intensification: €6038 vs €9178, p<0.001. However, disease control, as judged by response rates, was similar: 58% and 53%, respectively, p=0.81; difference 5% (−19% to 28%). For per-protocol patients, treatment costs were even lower (56%) in the algorithm-treated group (€4062 vs €9178, p<0.001) and with similar response rates (47% vs 53%, p=0.78; difference −5% (−33% to 22%)). Conclusions Treatment of secondary IFX failure using an algorithm based on combined IFX and IFX antibody measurements significantly reduces average treatment costs per patient compared with routine IFX dose escalation and without any apparent negative effect on clinical efficacy. Trial Registration No NCT00851565.

Cut-off levels and diagnostic accuracy of infliximab trough levels and anti-infliximab antibodies in Crohn's disease

Abstract Introduction. Reasons for infliximab failure in Crohns disease and ulcerative colitis are debated. Serum levels of infliximab and anti-infliximab antibodies have been associated with loss of response. We aimed at determining cut-off levels for infliximab and anti-infliximab antibody concentrations associated with clinical response to infliximab maintenance therapy. Methods. Patients with inflammatory bowel disease (n = 106) were retrospectively classified as having maintained response or loss of response to infliximab maintenance therapy. Trough concentrations were measured by fluid-phase radioimmunoassays. Results. Infliximab levels were significantly lower, and anti-infliximab antibody levels significantly higher, in Crohns disease patients with loss of response (median infliximab 0 μg/ml, median anti-infliximab antibodies 35 U/ml) compared to patients with maintained response (median infliximab 2.8 μg/ml, median anti-infliximab antibodies 0 U/ml; p < 0.0001). Receiver operating characteristic (ROC) analysis identified optimal cut-off values: infliximab <0.5 μg/ml, which was associated with loss of response with sensitivity 86% [64–97] and specificity 85% [72–94]; and anti-infliximab antibodies ≥10 U/ml yielding a sensitivity of 81% [61–93] and specificity 90% [79–96]. Combined measurements of infliximab and anti-infliximab antibodies using these cut-off values had higher accuracy yielding a sensitivity of 81% [57–94] and specificity 94% [82–98]. Similar pattern was observed in a smaller cohort of patients with ulcerative colitis. Conclusions. Combined measurements of infliximab and anti-infliximab antibodies using cut-off levels provided high accuracy for discriminating between clinical response types to infliximab maintenance therapy. Cut-off levels are considered a prerequisite to further investigations of clinical usefulness of measurements of infliximab and anti-infliximab antibodies in patients failing infliximab therapy.

Individual medicine in inflammatory bowel disease: monitoring bioavailability, pharmacokinetics and immunogenicity of anti-tumour necrosis factor-alpha antibodies.

Antibody constructs targeting tumour necrosis factor-alpha (TNF) have become important in the management of several chronic immunoinflammatory diseases. Four recombinant anti-TNF drugs are currently approved for clinical use in patients with various chronic inflammatory diseases, three of which are effective in chronic inflammatory bowel disease. These proteins can dramatically lower disease activity and, in some patients, induce remission. Unfortunately, however, not all patients respond favourably to anti-TNF antibodies. For example, patients suffering from Crohns disease do not benefit from etanercept, and some patients treated with the other anti-TNF constructs either do not respond at all (primary response failure), or they respond initially but have later relapses (secondary response failure) despite increased dosage and/or more frequent administration of the drugs. The reason(s) for these response failures are not clear but inter-individual and even intra-individual differences in bioavailability and pharmacokinetics may contribute. Furthermore, immunogenicity of the drugs, causing patients to develop anti-drug antibodies (ADAs), contributes to treatment failure. Monitoring patients for circulating levels of functional anti-TNF drugs and ADAs is therefore warranted so that treatment can be tailored to the individual patient (individual medicine or personal medicine) in order that effective and economical long-term therapy can be given with minimal risks to the patients.

Severe infusion reactions to infliximab: aetiology, immunogenicity and risk factors in patients with inflammatory bowel disease

Aliment Pharmacol Ther 2011; 34: 51–58

Doubling the infliximab dose versus halving the infusion intervals in Crohn's disease patients with loss of response

Background: Intensifying infliximab therapy is often practiced in Crohns disease (CD) patients losing response to the drug but there are no data if halving the interval is superior to doubling the dose. We aimed to assess the efficacy of infliximab dose intensification by interval‐halving compared with dose‐doubling. Methods: A multicenter retrospective study of CD patients losing response to infliximab was undertaken. The clinical outcome of patients whose infusion intervals were halved (5 mg/kg/4 weeks) was compared with patients treated by dose‐doubling (10 mg/kg/8 weeks). Results: In all, 168 patients were included from 18 centers in Europe, USA, and Israel. Of these, 112 were intensified by dose‐doubling and 56 received interval‐halving strategy. Early response to dose‐escalation was experienced by 86/112 (77%) patients in the dose‐doubling group compared with 37/56 patients (66%) in the interval‐halving group (odds ratio [OR] 1.7, 95% confidence interval [CI] 0.8–3.4, P = 0.14). Sustained clinical response at 12 months postescalation was maintained in 50% of patients in the dose‐doubling group compared with 39% in the interval‐halving group (OR 1.5, 95% CI 0.8–2.9, P = 0.2). On multivariate analysis, predictors of long‐term response to escalation were a nonsmoking status, CD diagnosis between 16–40 years of age, and normal C‐reactive protein (CRP). Conclusions: Dose intensification leads to a sustained regained response in 47% of CD patients who lost response to standard infliximab dose, but halving the infusion intervals is probably not superior to dose‐doubling. Given the costs and patient inconvenience incurred by an additional infusion visit, the dose‐doubling strategy may be preferable to the interval‐halving strategy. (Inflamm Bowel Dis 2012;)

Clinical Implications of Measuring Drug and Anti-Drug Antibodies by Different Assays When Optimizing Infliximab Treatment Failure in Crohn's Disease: Post Hoc Analysis of a Randomized Controlled Trial

OBJECTIVES:Cost-effective guidance of therapeutic strategy in Crohns disease patients with secondary infliximab (IFX) treatment failure may be achieved by serum IFX and anti-IFX antibody (Ab) measurements by radioimmunoassay (RIA). This study investigated implications of using other techniques for this purpose.METHODS:This is a post hoc analysis of randomized clinical trial including 66 Crohns disease patients with IFX failure in whom IFX and anti-IFX Ab measurements by RIA had been used for therapeutic guidance. Samples were additionally assessed by enzyme-linked immunosorbent assay (ELISA), homogeneous mobility shift assay (HMSA), and functional cell-based reporter gene assay (RGA).RESULTS:IFX detection was comparable between assays (82% RIA, 76% ELISA, 88% HMSA, and 74% RGA), and it correlated significantly (Pearsons r=0.91–0.97, P<0.0001). However, IFX concentrations varied systematically between all pair of assays except RIA-RGA. Anti-IFX Ab detection was variable (27% RIA, 9% ELISA, 33% HMSA, and 11% RGA), but correlated significantly (Pearsons r=0.77–0.96; P<0.0001). Anti-IFX Abs detected by RIA and HMSA were often from sera without drug-neutralizing activity (RGA). Assays agreed on classification of underlying mechanism for treatment failure in most cases (79–94%). The majority (74–88%) failed IFX owing to pharmacodynamic problems, or had noninflammatory pathophysiology for symptoms resembling relapse. Applied threshold for therapeutic vs. subtherapeutic IFX level influenced classifications. The four different assays did not differ in terms of the ability to predict response to interventions defined by the algorithm.CONCLUSIONS:Despite variable analytical properties, common assays result in similar classifications and interventions in patients with IFX treatment failure, and with comparable clinical outcomes. Implications are, however, profound for the minority classified differently.

Clinical implications of variations in anti-infliximab antibody levels in patients with inflammatory bowel disease†‡

Background: The aim of the study was to investigate variations in anti‐infliximab (IFX) antibody (Ab) levels and clinical implications thereof in patients with inflammatory bowel disease (IBD). Methods: A retrospective, explorative, single‐center study of patients with IBD who developed anti‐IFX Ab and in whom anti‐IFX Ab were reassessed. Results: IFX was administered to 316 patients; anti‐IFX Ab was determined in 180 patients and detected in 83 (46%). During ongoing IFX maintenance therapy, anti‐IFX Ab disappeared at later reassessment in two‐thirds of patients with clinical response after median 4 (3–5) infusions. In contrast, anti‐IFX Ab persisted in all patients without clinical response. Anti‐IFX Ab appeared pharmacologically active, as IFX levels were high when anti‐IFX Ab disappeared (median 3.7 &mgr;g/mL, interquartile range [IQR] 2.8–5.5), while undetectable or low when anti‐IFX Ab persisted (median 0 &mgr;g/mL, IQR 0–0). In 56 patients, anti‐IFX Ab were assessed after IFX discontinuation. The proportion of patients with anti‐IFX Ab gradually declined over time, with a few patients having anti‐IFX Ab up to about 4 years after initial assessment. No variables were associated with anti‐IFX Ab disappearance in multivariate analysis. Conclusions: Discontinuation of IFX is advisable in patients with inadequate response and repeat positive anti‐IFX Ab measurements. Anti‐IFX Ab can persist for years after discontinuation, which could impact efficacy and safety at retreatment. Continued IFX treatment may, however, be considered in patients with clinical response and a single positive anti‐IFX Ab measurement, as anti‐IFX Ab disappears in two‐thirds of these during continued treatment. (Inflamm Bowel Dis 2012;)

Comparison of techniques for monitoring infliximab and antibodies against infliximab in Crohn's disease.

Background: Several techniques are used to measure infliximab (IFX) and anti-IFX antibodies (Abs) in Crohns disease. The aim of this study was to compare different assays for this purpose. Methods: Fluid-phase radioimmunoassay (RIA), solid-phase enzyme-linked immunosorbent assay (ELISA), reporter gene assay (RGA), and enzyme immunoassay (EIA; anti-IFX Ab only) were assessed. IFX was added to pooled serum from 13 patients with inactive Crohns disease to yield concentrations of 0, 1, 3, and 9 µg/mL. Anti-IFX Abs were assessed in 6 patients. Results: IFX assessments: RIA and RGA had lower limit of detection than ELISA (0.07 µg/mL and 0.13 versus 0.26). Maximal inaccuracies were 39%, 24%, and 23%. Imprecisions (coefficients of variation) were ⩽20% within IFX concentrations between 1 and 9 µg/mL. All assays showed linear correlations (R2 = 0.97–0.99), but sample concentrations differed by up to 1.55 µg/mL for RIA and RGA, 1.41 µg/mL for ELISA and RIA, and 0.48 µg/mL for ELISA and RGA (P < 0.05). Anti-IFX Ab assessments: RGA gave highly reproducible results (coefficients of variation ⩽ 7%) compared with all others (24%–26%). All assays had linear correlations (R2 = 0.71–0.93), except ELISA versus RGA and EIA. Assays disagreed on anti-IFX Ab titers with mean difference −420 (−1200 to 210) in RGA and EIA, and up to 4500 (−2700 to 11,800) in RIA and RGA. A contributing factor to these discrepancies was inability of ELISA to detect IgG4 anti-IFX Abs. Conclusions: Performances of assays for IFX and anti-IFX Abs are comparable. However, IFX concentrations and anti-IFX Ab titers show systematic differences, and in individual patients, only the same assay should be used. Problems may arise when different assays are used to manage therapies in the same patient.

Outcome after discontinuation of infliximab in patients with inflammatory bowel disease in clinical remission: an observational Danish single center study

Abstract Objective. To investigate duration of remission, including risk factors for relapse and response to retreatment with infliximab (IFX), in patients with Crohns disease (CD) and ulcerative colitis (UC) who had discontinued IFX while in clinical remission. Methods. Observational, single-center, retrospective study of all patients with a primary response to IFX who discontinued IFX therapy while in steroid-free remission. Relapse was defined as reintroduction of treatment with a biologic, systemic steroid or surgery. Results. Of 219, 53 (24%) CD patients, and 28 of 97 (30%) UC patients discontinued IFX while in clinical steroid-free remission. The proportion of patients in remission declined steadily with 61% of CD patients, and 75% of UC patients being in remission after 1 year. Half the patients maintained remission after median 2 years (680 days (412–948)) and 3.5 years (1334 days (995–1673)), respectively; p = 0.057. Twelve percent with CD and 40% with UC were in remission at the end of follow-up after 10 and 4.5 years, respectively. Longer disease duration was associated with relapse in univariate analysis in CD, OR 1.1 (1.0–1.1), p = 0.022. Of 25, 24 CD patients (96%), and 5 of 7 UC patients (71%) experienced complete clinical remission when retreated with IFX after relapse. Conclusion. While the short-term prognosis seems favorable, the majority of patients who discontinue IFX while in remission relapse over time. The response to retreatment with IFX at relapse seems favorable in this subpopulation.

Reporter gene assay for the quantification of the activity and neutralizing antibody response to TNFα antagonists.

A cell-based assay has been developed for the quantification of the activity of TNFα antagonists based on human erythroleukemic K562 cells transfected with a NFκB regulated firefly luciferase reporter-gene construct. Both drug activity and anti-drug neutralizing antibodies can be quantified with a high degree of precision within 2h, and without interference from cytokines and other factors known to activate NFκB. The assay cells also contain the Renilla luciferase reporter gene under the control of a constitutive promoter that allows TNFα-induced firefly luciferase activity to be normalized relative to Renilla luciferase expression. Thus, results are independent of cell number or differences in cell viability, resulting in intra and inter assay coefficients of variation of 10% or less. Normalization of results relative to the expression of an internal standard also provides a means for correcting for serum matrix effects and allows residual drug levels or anti-drug neutralizing antibodies to be quantified even in serum samples with a relatively high degree of cytotoxicity.