Exabis Library

Educational objectives:
Know the role of faecal calprotectin measurements in the management of IBD patients.
Know the pitfalls in the interpretation of the results of such tests.

Summary
1) Fecal calprotectin can be used to predict histological remission/activity in UC patients, even in quiescent disease
2) There are however different tests, a large variation in reported cut-off values, and different endoscopic sampling methods and histological scores have been applied.
3) Data are very limited in patients with Crohn’s disease.

Educational objectives
•What is fermentation? What are fermented food?
•History of fermented foods
•Do fermented foods necessarily contain live microorganisms?
•Are fermented foods the same as probiotic foods?
•Do microorganisms in fermented foods become established in the gut or influence gut microbiota?
•Do fermented foods provide health benefits?
• Main studies on fermented foods and gastrointestinal tract: yogurt, cheese, kefir , sourdough bread, sauerkraut, kimchi, fermented soy products

To review the state-of-the-art in the field of intestinal fibrosis, with a focus on the inflammation-independent causes
To provide an overview of the main differences and similarities between CD and UC-associated fibrotic complications

Crohn's disease (CD) and ulcerative colitis (UC), belonging to the class of Inflammatory Bowel Diseases (IBD), are chronic inflammatory disorders of the gastrointestinal tract, that may affect any location of the gastrointestinal tract, or the large intestine only, respectively. While CD is characterized by transmural inflammation, UC is mainly featured by colonic epithelial ulcerations, both sharing an overwhelming immune response of the gut mucosa, which leads to severe clinical symptoms. CD patients, and to a lesser extent the UC, may develop a penetrating or stricturing disease due to fibrostenosis, which most of the time requires surgical intervention since no therapies have been found as effective yet. Among the histological features, the thickening of the muscularis mucosae and muscularis propria is the main hallmark, primarily due to the excessive proliferation of mesenchymal cells and the increased accumulation of a collagen-rich extracellular matrix in the submucosa, caused by multiple mechanisms, including i) the proliferation of existing local fibroblasts, the induction of both ii) epithelial-to-, and iii) endothelial-to-mesenchymal transition. Even if the alteration of these mucosal functions is mainly caused by the continuous tissue injury occurring during intestinal chronic inflammation, recent reports suggested that fibrosis may be driven by inflammation-independent triggers, such as microbiota dysbiosis. Shedding the light on this aspect of CD fibrosis may lead to the development of innovative therapeutic strategies eventually blocking the gut thickening and facilitating the management of stricturing IBD.

new endpoints for multiple orphan indications are being defined in this lecture

 
Educational objectives:

1. Typical symptoms presented by a patient

2. Epidemiological IBD data from Austria

3. Ulcerative colitis: typical symptoms, endoscopy examples, complications, extraintestinal involvement, differential diagnoses

4. Crohn´s disease: typical symptoms, clinical investigation, typical endoscpy, differential diagnoses, environmental risk factors, extraintestinal complications

Educational objectives: 

1. To understand the different treatment algorithms for treatment of patients with IBD
2. To understand the role of patient stratification
3. To understand the basics of a treat-to-target strategy
4. Tounderstand the different exit strategies

First-line infliximab (FL-IFX) induction treatment combined with azathioprine (AZA) is more effective to achieve clinical remission without treatment escalation at week 52 compared to conventional induction treatment (CONV) (Exclusive Enteral Nutrition or prednisone) combined with AZA in children with moderate-to-severe Crohn’s disease (CD). FL-IFX may lead to higher treatment costs compared to conventional treatment. However, data on cost-effectiveness of FL-IFX in children with CD is still limited. Therefore, our aim is to investigate the cost-effectiveness of FL-IFX in comparison with CONV. We hypothesized that cost effectiveness of FL-IFX is comparable to CONV in children with newly diagnosed moderate-to-severe CD in the first two years after treatment.

We included patients from the TISKids international randomized controlled trial in which children with moderate-to-severe CD were treated with either FL-IFX (Inflectra, biosimilar of IFX) or CONV.(1) Patients included outside of the Netherlands (n=6) or patients with serious comorbidity besides CD were excluded from this analysis (n=2). Data on healthcare consumption and costs were obtained per hospital for all included patients until week 104. Direct health-related costs were collected, including hospital visits, drug costs, laboratory tests, endoscopies and surgeries. The effectiveness of treatment was assessed by mean weighted paediatric CD activity index (wPCDAI) and faecal calprotectin (fcal) levels (µg/g) measured over time until week 104. This analysis was performed by a mixed model. Moreover, time to additional anti-tumor necrosis factor-α (anti-TNF) treatment up to 104 weeks after inclusion was assessed.

In this analysis, 89 patients were included, 44 in the FL-IFX group and 45 in the conventional treatment group. There were no significant differences between the two groups at baseline. Interestingly, the mean costs were similar for FL-IFX (€34,783) and CONV (€34,923) after two years, p=0.97 (Figure 1). Mean fcal levels were lower for FL-IFX compared to CONV over two years (416 vs. 625, p=0.03). The mean wPCDAI scores over two years were numerically lower for FL-IFX compared to CONV (5.95 vs. 10.34, p=0.01), but this difference became smaller over time. Furthermore, the time to (re)start anti-TNF treatment was significantly longer in the FL-IFX group (median 68 weeks) compared to the conventional treatment group (median 32 weeks) (p=0.02) (Figure 2).

Treatment with FL-IFX is cost-effective compared to conventional treatment in the first two years after diagnosis in children with moderate-to-severe CD.

References:
1. Jongsma MME et al. Gut. 2020 Dec 31; DOI: 10.1136/gutjnl-2020-322339. / PMID: 33384335

Vedolizumab is a monoclonal antibody which blocks integrin α4β7 inhibiting trafficking of T-lymphocytes into the gut. Unfortunately, up to 60% of vedolizumab patients experience non-response. The mechanism of action of vedolizumab is not elucidated, predictors of response are unknown and data for local drug distribution in the gut are lacking. In this clinical trial, we investigated the feasibility of assessing local distribution of fluorescently labelled vedolizumab in the gut mucosa of inflammatory bowel diseases (IBD) patients to finally enable prediction of therapy response in individual patients.

Vedolizumab (Entyvio, Takeda Pharma) was labelled to IRDye 800CW under cGMP conditions to yield clinical grade vedolizumab-800CW. In this dose-escalation trial, vedolizumab naïve IBD patients and IBD patients treated with vedolizumab for at least 14 weeks were included. Patients received an intravenous dose of fluorescently labelled vedolizumab of either 0 mg, 4.5 mg, 15 mg or 15 mg + 75 mg unlabelled vedolizumab 3 days prior colonoscopy. In vivo fluorescence imaging was assessed by fibre-based wide-field fluorescence molecular endoscopy (FME) and quantified by spectroscopy in healthy, mildly inflamed and severely inflamed tissue. All assessed tissue was biopsied for ex vivo examination of the fluorescent signal, fluorescence microscopy and spectroscopy.

Up to submission 34 patients completed tracer injection and FME. An interim analysis was performed after 20 patients (5 in each dose group), which showed in severely inflamed tissue an 8 fold higher fluorescent signal in the 15 mg dose group (0.049 Q*μfa,x [mm-1]) compared to the control group (0.006 μfa,x [mm-1]) (p<0.05). Furthermore, the fluorescent signal within the 15 mg dose group was also 2.5 fold higher compared to healthy tissue (0.019 Q*μfa,x [mm-1]) (p<0.05).The addition of unlabelled vedolizumab gave similar results to the 15 mg group (p>0.99), suggesting that the drug target was still not saturated. The optimal dosage group of 15 mg was expanded up to 18 IBD patients, amongst them 6 IBD patients after 14 weeks of treatment regimen. Fluorescence microscopy showed clustering of fluorescent signals especially in inflamed mucosa. Additional experiments to detect vedolizumab target cells are ongoing.

In vivo visualization of fluorescent vedolizumab revealed a clear dose-dependent correlation between mucosal drug concentrations and the severity of mucosal inflammation. Fluorescence molecular endoscopy is a promising novel tool to get insight in drug distribution in IBD, detect target cells, assess target engagement and possibly predict therapy response in individual patients.

Inflammation in the Inflammatory bowel diseases may be driven by diet , as evidenced to date by the return of inflammation in patients transitioning from exclusive enteral nutrition to partial enteral nutrition. Exclusion diets such as the Crohn’s disease exclusion diets cause a decrease in inflammation and mucosal healing in Crohn’s disease. These findings suggest that certain dietary components may be one of the culprits in driving the surge of IBD around the globe. One of the key suspects are dietary additives.
In the current talk we will review the effects of dietary additives such as:
maltodextrins
carrageenans
 gums
emulsifiers
and the effects upon the microbiome and goblet cells.