Mark A. Ainsworth

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.

Tumor Necrosis Factor Inhibitors for Inflammatory Bowel Disease

A 35-year-old man presents with an exacerbation of Crohn’s ileocolitis. He received a diagnosis of Crohn’s disease 8 years ago and has been treated on three previous occa sions with prednisone. Because of a recurrent need for glucocorticoids, treatment with azathioprine (150 mg per day) was started 1 year ago. He now reports abdominal pain in the right lower quadrant, which developed 1 week ago, with an increase in stool frequency to eight to nine stools per day. Laboratory tests show a hemoglobin concentration of 10.7 g per deciliter and a C-reactive protein level of 21 mg per liter. Magnetic resonance enterography shows inflammation localized to the distal ileum and colon. The patient is referred to a gastroenterologist. An ileocolonoscopy reveals patchy erythema and ulcerations near the hepatic flexure as well as similar lesions in the terminal ileum. Biopsy specimens obtained during colonoscopy show acute and chronic granulomatous inflammation, and the gastroenterologist recommends treatment with a tumor necrosis factor (TNF) inhibitor. T h e C l i nic a l Probl e m Inflammatory bowel disease, an umbrella term for a range of diseases of which ulcerative colitis and Crohn’s disease are the two prevailing entities, is a common chronic gastrointestinal disorder. Extrapolation from available data suggests that in the United States and Canada, more than 780,000 persons have ulcerative colitis and 630,000 have Crohn’s disease, and the global incidence of both disorders is increasing. 1 Inflammatory bowel disease has serious effects in terms of morbidity and qual ity of life. 2 In the era before biologic therapy was available, the rate of hospitaliza tion owing to medical complications, the need for surgery, or both was 194 admis sions per 1000 patient-years in a population-based cohort of patients with Crohn’s disease. 3 In the first 10 years after a diagnosis of Crohn’s disease, the cumulative rate of surgery is 40 to 55%. 3 In a recent large, population-based epidemiologic study of ulcerative colitis, the rate of colectomy 20 years after diagnosis was 14.8%. 4 Furthermore, extraintestinal manifestations (rheumatologic, dermatologic, oph thalmologic, hematologic [including thromboembolic], and hepatic complications) may at any time affect a third of all patients with inflammatory bowel disease. 5 According to meta-analyses of studies in unselected population-based cohorts, the risk of colorectal cancer is modestly increased among patients with both ulcerative colitis and Crohn’s disease, 6 and the latter disorder also carries a markedly in creased relative risk of small-bowel cancer among those with ileal inflammation, 7 although the absolute risk is low. However, these data are primarily from studies conducted at a time when there were fewer treatment options than there are today.

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.

Rectal dialysate and fecal concentrations of neutrophil gelatinase-associated lipocalin, interleukin-8, and tumor necrosis factor-α in ulcerative colitis

Objective:Neutrophil gelatinase-associated lipocalin (NGAL) is a newly described neutrophil lipocalin that may bind the proinflammatory bacterial tripeptide N-formylmethionyl-leucyl-phenylalanine. In situ hybridization and immunohistochemical studies have shown a strong NGAL expression in colonocytes and neutrophils in ulcerative colitis (UC). Because NGAL is highly protease resistant, it should be ideal for in vivo fecal and dialysate studies. Our aim was to investigate the potential of NGAL as a disease activity marker in UC and to compare it with IL-8 and TNF-α.Methods:Twenty-three patients with UC, 14 with Crohns disease (CD), 19 patients with acute infectious enterocolitis, and 20 healthy controls were included. The disease activity of UC and CD was scored semiquantitatively. Concentrations of NGAL, IL-8, and TNF-α were determined in rectal dialysis fluid, feces, and serum using sandwich enzyme-linked immunosorbent assays. The total protein concentration in feces and dialysate fluid was measured, and the amount of markers was expressed as ng/mg protein.Results:In healthy controls and non-IBD (irritable bowel disease) colitis, the median values for NGAL in feces were 183 ng/mg protein and 546 ng/mg protein (p < 0.01), respectively. When separating UC into clinical activity groups (remission, mild/moderate, and severe disease activity) the corresponding values of NGAL were 442 ng/mg (p > 0.05), 605 ng/mg (p < 0.02), and 3646 ng/mg (p < 0.001, compared with controls), respectively, and in quiescent colonic CD 368 ng/mg (p > 0.05) and in active stages 751 ng/mg (p < 0.01). NGAL levels in dialysis fluid listed in the same order were: 11 ng/mg for controls, 71 ng/mg (p > 0.05) for non-IBD colitis, 100 ng/mg (p < 0.02), 179 ng/mg (p < 0.01), and 2053 ng/mg (p < 0.001) for UC, and 14 ng/mg (p > 0.05) and 121 ng/mg (p < 0.02) for CD, respectively. Serum NGAL concentrations did not differ between UC and CD in quiescent versus active stages. A significant increase of NGAL in both feces and dialysate with increasing disease activity of UC was found (p= 0.02 and p= 0.003, respectively).Conclusion:The NGAL content in rectal dialysate and particularly in feces seems to be a reliable marker for severe disease activity in UC, whereas serum NGAL concentrations do not reflect disease activity.

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

Aliment Pharmacol Ther 2011; 34: 51–58

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.