Gitte Pedersen

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.

Tumour necrosis factor α converting enzyme (TACE) activity in the colonic mucosa of patients with inflammatory bowel disease

Background: Anti-tumour necrosis factor α (TNF-α) antibodies are effective in Crohns disease and perhaps ulcerative colitis but antigenicity and the high cost have raised interest in other strategies to block TNF-α. These include the TNF-α converting enzyme (TACE) which releases soluble TNF-α from transmembrane pro-TNF-α. Aim: To investigate whether TACE activity is present in human colonic mucosa. Materials and methods: Detergent extracts of cell membranes from colonic biopsies were obtained from 12 controls and 28 patients with inflammatory bowel disease. Enzyme activity was measured by hydrolysis assays using pro-TNF-α or oligopeptide substrates spanning the known pro-TNF-α cleavage site at Ala(76)-Val(77). Cleavage products were identified by western blotting, high pressure liquid chromatography, or mass spectrometry. TACE protein was localised by immunohistochemistry and identified by western blotting of detergent extracts from purified lamina propria mononuclear cells (LPMNC) or epithelial cells. Results: Detergent extracts released TNF-α from pro-TNF-α and cleaved a model oligopeptide as predicted. Substrate hydrolysis was sensitive to known TACE/matrix metalloproteinase (MMP) inhibitors, but not trocade which has low activity against TACE. The median TACE level was increased in active ulcerative colitis (147 arbitrary units (AU)/mg; p<0.01) but not in Crohns disease (81 AU/mg) compared with controls (79 AU/mg). Both the full length proform and the active form of TACE protein were expressed in LPMNC cells and epithelial cells. Conclusions: Functional TACE activity is ubiquitously expressed in the human colon and increased in ulcerative colitis, raising interest in MMP inhibitors targeting TACE.

Chronic pancreatitis in Copenhagen. A retrospective study of 64 consecutive patients.

A longitudinal study of 64 patients with chronic pancreatitis is presented. The patients were followed up for a median period of 4 years. Pain was the dominant symptom in 43 of the patients, but only 5 patients had pancreatic resection because of pain. Alcoholism was the etiology in 45 patients. Complications were common: 34 patients developed steatorrhea and 29 diabetes. Two major groups of associated diseases contributed to a high morbidity in chronic pancreatitis: 24 patients presented with duodenal ulcer, and 8 developed malignant tumors. This number is significantly higher than expected in a matched population (P less than 0.01). Twenty-six of the patients died within the observation period from complications of chronic pancreatitis (38%), from malignant neoplasms (15%), or from other causes (46%). The calculated mortality rate after 7 years of observation was close to 50%. Most patients were recruited from the lower social classes, and most were unemployed. We conclude that chronic pancreatitis in Copenhagen is associated with a high morbidity, a high mortality, and a poor social prognosis.

Peroxisome proliferator-activated receptor expression and activation in normal human colonic epithelial cells and tubular adenomas

Objective Peroxisome proliferator-activated receptor (PPAR) ligands, widely used in type 2 diabetes treatment, have variably been shown to promote or prevent colon tumor formation in animal models and cell lines, but their role in normal human colon is unknown. The aim of this study was to determine PPARδ expression and function in normal human colonic epithelial cells and tubular adenomas. Material and methods Short-term cultures of normal human colonic epithelial cells were established from biopsies obtained in 42 patients with normal colonoscopy. PPAR and adipophilin mRNA expression was assessed by real-time RT-PCR. PPARs were activated by ligands for PPARα (Wy-14643), PPARδ (GW-501516) and PPARγ (rosiglitazone or troglitazone). Cell viability was measured using the methyltetrazoleum assay, proliferation by thymidine incorporation, and DNA profiles by flow cytometry. PPAR mRNA levels in tubular adenomas or metaplastic polyps (n=12) were compared with those in controls. Results PPARα and γ were consistently expressed in normal colonocytes while no PPAR expression could be detected. PPARγ activation induced a 7.5-fold increase in adipophilin expression (a PPAR-activated gene). PPARγ activation had no effect on viability or DNA profiles, but led to a 25% significant decrease in cell proliferation. Finally, a selective and significant 2.5-fold decrease in PPARα expression was observed in tubular adenomas, but not in metaplastic polyps, compared to controls. Conclusions Our findings support the view that PPARγ ligands act as anti-proliferative agents rather than as promoters of tumorigenesis in normal human colon. Moreover, they raise interest in investigation of PPARα as a therapeutic target to prevent adenoma formation.

Phenol Toxicity and Conjugation in Human Colonic Epithelial Cells

Background: Colonic epithelial cells are exposed to a range of potentially harmful luminal factors, including phenols, but it is unresolved whether these compounds impair the integrity of the epithelium. The aim of this study was to describe the effect of phenol exposure on human colonic epithelial cells in vitro and the conjugation pathways involved in detoxification. Methods: Primary human colonic epithelial cell cultures or HT-29 cell cultures were exposed to paracetamol, dinitrophenol or phenol (0.1-5 mM) for 24 h. Cell viability was measured using the methyltetrazoleum test. Phenol conjugation products released from cell cultures were identified by high-pressure liquid chromatography. Phenol glucuronidase (PGD) and sulphotransferase (PST) enzyme activities were measured in isolated cell homogenates. Results: Paracetamol, dinitrophenol and phenol ( S 1.25 mM) significantly impaired the viability of primary colonic epithelial cell cultures. No differences between cell cultures from ulcerative colitis and control patients were observed. Paracetamol (5 mM) also induced significant cell damage in HT-29 cells. Glucuronidation was the preferred conjugation pathway in both cell models, despite the presence of PGD and PST activity. Conclusion: Phenols have a direct toxic effect on human colonic epithelial cells in vitro, which supports the view that dietary fermentation metabolites may be involved in the modulation of chronic bowel inflammation.

Changes in serum trough levels of infliximab during treatment intensification but not in anti-infliximab antibody detection are associated with clinical outcomes after therapeutic failure in Crohn’s disease

BACKGROUND AND AIMS Intensification of the infliximab (IFX) regimen is recommended if the treatment effect is inadequate. However, the rationale for this is not well defined as the underlying mechanisms vary. The aim of this study was to explore the association between changes in serum IFX and anti-IFX antibodies (Abs) after IFX intensification and clinical outcomes. METHODS We performed a post hoc analysis of a randomized clinical trial including 42 Crohns disease patients with IFX treatment failure, all treated with an intensified IFX regimen (5mg/kg every 4 week) for 12 weeks. Trough serum IFX and anti-IFX Ab concentrations were measured by a homogeneous mobility shift binding assay (HMSA) and a functional cell-based reporter gene assay (RGA) at treatment failure and the end of the trial. RESULTS Twenty-one patients (50%) regained clinical response on the intensified IFX regimen. The increase in serum trough levels of IFX during treatment intensification was higher among responders than non-responders (RGA, 8.8 versus 3.0 μg/mL, p = 0.035; HMSA, 9.9 versus 4.7 μg/mL, p = 0.040), and differentiated patients by clinical outcome (RGA, area under receiver operating characteristic curve [AUC] 0.75 [0.53-0.97], p = 0.035; HMSA, AUC 0.74 [0.53-0.95], p = 0.042). All responders exhibited an IFX increase ≥2.6 μg/mL (sensitivity 100%, specificity 50%). Anti-IFX Abs detected by HMSA in 13 patients (32%) were often non-functional and became undetectable during IFX intensification. However, even functional anti-IFX Abs detected by RGA in six patients (15%) became undetectable. CONCLUSION Increase in IFX levels following treatment intensification was associated with improved clinical outcomes, indicating insufficient drug levels in a subgroup of patients. Anti-IFX Abs may become undetectable during treatment intensification, suggesting lowered production or the formation of immune complexes.

Cultures of Human Colonic Epithelial Cells Isolated from Endoscopical Biopsies from Patients with Inflammatory Bowel Disease. Effect of IFNγ, TNFα and IL-1β on Viability, Butyrate Oxidation and IL-8 Secretion

Cytokjne-mediated impairment of viability and metabolic function of epithelial cells has been suggested as a possible early pathogenic event in the development of inflammatory bowel disease (IBD). It is currently unknown whether pro-inflammatory cytokines have a direct effect on human nontransformed colonic epithelial cells. We investigated the effects of TNFα, IFNγ and IL-1β on viability, short chain fatty acid (butyrate) oxidation and IL-8 secretion in human colonic epithelial cell cultures in vitro obtained from macroscopically normal mucosa from IBD patients and controls. Colonic crypts were isolated from endoscopical biopsies by ultra-short (10 min) EDTA/EGTA treatment, and exposed to TNFα, IFNγ and IL-1β for 24 hours. The combination of TNFoc+IFNγ induced a significant decrease in cell viability as judged by methyltetrazoleum (MTT) metabolism which decreased to median 68 % of unexposed cultures (P<0.01). This effect was more pronounced than that observed after addition of TNFα (median 88 %) (P<0.05), but not IFNγ alone (median 78 %), whereas IL-1(3 had no significant effect. Cells from IBD patients were significantly less sensitive to TNFα + IFNγ exposure (median 74 %) compared to cells from controls (median 58 %) (P < 0.05). Butyrate oxidation, as measured by entrapment of CO2, was not inhibited in cells exposed to TNFα + IFNγ, neither from controls (median 112%) nor from IBD patients (median 108%), suggesting a relative increase of this specific metabolic function in living cells in response to immunoinflammatory stress. IL-8 levels in cell supernatants were increased by TNFα + IFNγ, supporting the role of the epithelium in signalling between luminal factors and mucosal immune cells. In conclusion, we report that TNFα and IFNγ damage and influence human colonic epithelial cell function in vitro and that such mechanisms, if operative in vivo, also may be involved in the pathogenesis of IBD

Adhesion Molecules in Inflammatory and Neoplastic Intestinal Diseases

Adhesion molecules participate in a broad variety of biological processes, i.e. tumor progression and inflammation, through their involvement in cell-to-cell interactions and immunoinflammatory cell migration. This review describes the basic properties of adhesion molecules with reference to inflammatory bowel disease and colorectal carcinoma. Accumulating data suggest that adhesion molecules could be pathogenetically pertinent to other gastrointestinal disorders such as celiac disease (nontropical sprue) and gastroduodenal ulcer. Future therapeutic approaches in inflammatory and malignant disorders may possibly be development of principles targeting adhesion molecules.

Implications of Infliximab Treatment Failure and Influence of Personalized Treatment on Patient-reported Health-related Quality of Life and Productivity Outcomes in Crohn’s Disease

BACKGROUND This study assessed the effects of infliximab (IFX) treatment failure on patient-reported outcomes and explored the influence of using personalized treatment in this situation. METHODS Sixty-nine Crohns disease patients with IFX treatment failure were randomized to an intensified IFX regimen (n = 36) or personalized treatment defined by IFX and anti-IFX antibodies (n = 33). Health-related quality of life evaluated with the Short Inflammatory Bowel Disease Questionnaire (IBDQ) and productivity evaluated with the Work Productivity and Activity Impairment Questionnaire (WPAI:CD) were assessed at treatment failure and after 4, 8, 12 and 20 weeks. RESULTS Median IBDQ score at manifestation of IFX treatment failure was 40 and improved markedly in responders by 11 at weeks 4 and 8 (p < 0.001) and by 13 at weeks 12 and 20 (p < 0.001). Non-responders improved modestly at weeks 12 and 20 (increase of median 4, p < 0.05). Overall activity impairment was high at IFX failure (median 70%) and decreased substantially in responders (40-50%, p < 0.001) and to a lesser extent in non-responders (15-40%, p < 0.05). In employed patients (55%), absenteeism was negligible during the entire study period. However, median presenteeism was 40% at manifestation of IFX failure and decreased only among responders across time (decrease 10-30%, p < 0.05). Although anti-tumour necrosis factor (TNF) therapy was discontinued in most patients handled by personalized treatment, IBDQ and WPAI:CD scores were similar in these patients compared with patients routinely dose-intensified on IFX. CONCLUSION Regaining low disease activity after IFX failure is necessary for minimizing patient impairment and indirect disease-related costs. A personalized treatment strategy does not have a negative influence on patient-reported outcomes.

Sa1268 Individualized Therapy Is Long-Term Cost-Effective Compared to Dose Intensification in Crohn's Disease Patients Failing Infliximab

Background: Infliximab (IFX) treatment failure in patients with Crohns disease is generally handled by intensifying the IFX regimen. However, an alternative strategy defined by an algorithm based on serum IFX and anti-IFX antibody measurements to identify reasons for failure and corresponding interventions has been proposed. In a randomized controlled trial, we observed substantial cost reductions after 12 weeks when using this algorithm as compared to IFX intensification, and without negative influence on symptom control.(1) The current study primarily investigated long-term cost outcomes at time of the week 20 follow-up study visit and after 1 year. In addition, clinical outcomes were assessed at week 20. Methods: Predefined follow-up from a 12-week, single-blind, clinical trial where Crohns disease patients with IFX treatment failure (CDAI ≥220 or ≥1 draining perianal fistula) were randomized to IFX intensification (5 mg/kg every 4 weeks) (n=36), or algorithm-defined interventions in form of IFX intensification, change to adalimumab, or use of pharmaceuticals other than TNF-inhibitors (n=33). Patients were treated at the discretion of the physician from week 12 onwards. Blinding was maintained until week 20. Accumulated costs, expressed as mean costs per patient, were based on the Danish National Patient Registry. Data were analyzed in the following populations: intention-to-treat (ITT) (n=69), per protocol (PP) (n=55), per protocol completion at end of trial week 12 (PPCw12) (n=45) or end of followup week 20 (PPCw20) (n=29). NCT00851565. Results: At the scheduled follow-up study visit at week 20, response (CDAI reduction ≥70 point or ≥50% reduction of active fistulas) and remission rates (CDAI ≤150 or closure of all fistulas) were similar in all study populations between patients treated by the algorithm or by IFX intensification (p>0.05). However, the sum of health care costs related to Crohns disease was substantially lower (31%) for patients randomized to algorithm-based interventions than IFX intensification in the ITT population: