Casper Steenholdt

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 (Crohn's 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.

INTRODUCTION: Reasons for infliximab failure in Crohn's 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 Crohn's 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.

BACKGROUND: Infliximab (IFX) elicits acute severe infusion reactions in about 5% of patients with inflammatory bowel disease (IBD). AIM: To investigate the role of anti-IFX antibodies (Ab) and other risk factors. METHODS: The study included all IBD patients treated with IFX at a Danish university hospital until 2010 either continuously (IFX every 4-12 weeks) or episodically (reinitiation after >12 weeks). Anti-IFX Ab were measured using radioimmunoassay. RESULTS: Twenty-five (8%) of 315 patients experienced acute severe infusion reactions. Univariate analysis showed that patients who reacted were younger at the time of diagnosis (19 vs. 26 years, P=0.013) and at first IFX infusion (28 vs. 35 years, P=0.012). Furthermore, they more often received episodic therapy (72% vs. 31%, P<0.001) and logistic regression revealed this as the only significant predictor of reactions (OR 5 [2-13]; P<0.001). IFX reinitiation after 6 months intermission further increased the risk (OR 8 [3-20], P<0.001). Most reactions (n=14, 88%) occurred at 2nd infusion in the 2nd treatment series (P=0.006). Anti-IFX IgG Ab were highly positive in 19 of 20 patients (95%) shortly after the reactions (median 84 U/mL). Anti-IFX IgG Ab measured prior to the retreatment series were negative in 7 of 11 patients tested (64%). Anti-IFX IgE Ab were negative in all patients with reactions. CONCLUSIONS: Acute severe infusion reactions were strongly associated with development of anti-IFX IgG Ab, but not with anti-IFX IgE Ab. The risk was particularly high at the 2nd infusion in retreatment series. Negative anti-IFX Ab before reinitiation did not rule out reactions.

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 Crohn's 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.

OBJECTIVES: Cost-effective guidance of therapeutic strategy in Crohn's 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 Crohn's 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 (Pearson's 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 (Pearson's 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.