Exabis Library

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.

Educational objectives:
1. To understand recent epidemiology of IBD, particularly early and very early onset IBD (VEO-IBD)
2. To review the diagnostic work-up of VEO-IBD with a focus on early identification of immunodeficiency syndromes
3. To emphasise early discussion/referral with clinical immunology to identify patients most likely to benefit from transplant and reduce pre-transplant morbidity/mortality
4. To review potential future applications of genome-informed therapeutics in IBD

Elucidate factors that help to make the successful transition from the bench to research group leader.

This study aimed at comparing functional outcomes and quality of life (QoL) after transanal and transabdominal approach for ileal-pouch surgery in ulcerative colitis (UC)Ileal-pouch surgery ensures satisfactory intestinal function and QoL. The transanal ileal pouch-anal anastomisis (Ta-IPAA) has recently been developed in the effort to address the technical shortfalls of the traditional transabdominal approach (Tabd-IPAA). According to previous studies, Ta-IPAA is safe. However, functional outcomes after ta-IPAA are scarcely described. 

This is a retrospective study of consecutive UC patients who underwent IPAA from 2011 to 2017.  Only patients operated according to a modified-2 or 3 stage approach were included in the analysis. Close rectal dissection was systematically performed in Ta-IPAA as opposed to total mesorectal excision in Tabd-IPAA. Groups were compared after propensity score weighting. Functional outcomes were assessed using two functional scoring systems: the Pouch Functional Score (PFS) and the Öresland score (OS). The global quality of life scale (GQOL) was used for patients’ overall perspective on QoL. Follow-up was scheduled at 1, 3, 6, and 12 months postoperatively.

One hundred and nine patients were included. Of them, 38 patients underwent Ta-IPAA. At 12 months follow-up, mean OS and PFS were 4.6 (CI 3.2-6.0) vs 6.2 (CI 5.0-7.3), p=0.02 and 6.1 (CI 3.5-8.8) vs 7.4 (CI 5.4-9.5), p=0.32, for Ta and Tabd-IPAA, respectively. Mean GQOL score for Ta-IPAA was 82.7 (CI 75.1-90.2) vs 75.5 (69.4-81.6) for Tabd-IPAA (p=0.038).

Transanal IPAA provides better functional results and QoL scores than Tabd-IPAA in UC patients. 

Recent data havehighlighted adverse clinical outcomes in IBD patients treated with infliximab/thiopurines (IFX/THIO) upon infection with SARS-CoV-2, as well as attenuated serological responses after infection and vaccination in patients treated with IFX. To provide mechanistic insight, we explored the serological and functional anti-viral response after infection in IBD patients treated with VDZ, IFX or IFX/THIO compared to healthy controls to guide clinical decision-making regarding treatment and vaccination strategies.

Serum from 640 IBD patients attending routine infusions in Oxford and London in May to December 2020 was screened for anti-SARS-CoV-2 antibody responses by the Abbott assay. Serum from seropositive patients was compared to seropositive health care workers (Table 1). Antibody reactivity to the SARS-CoV-2 wild type strain receptor-binding domain (RBD), full-length spike, and nucleocapsid was assayed by IgG/IgA ELISA over time as well as by IgG high-throughput MSD V-PLEX ELISA at the time of seropositivity. A pseudotyped SARS-CoV-2 virus microneutralization assay was used to detect neutralising antibodies to the wild type, and an ELISA-based inhibition assay to compare differential inhibition of the wild type vs. delta variant SARS-CoV-2 RBD-ACE2 interaction.

All IBD patients showed significantly reduced IgG antibody responses compared to healthy controls for all SARS-CoV-2 antigens, using MSD V-PLEX ELISA (Figure 1). The greatest reduction in IgG response by ELISA was observed in individuals treated with IFX/THIO (p=0.00019), whereas IgG response over time declined significantly faster in the IFX treated group (p=0.019). IgA responses were significantly reduced in the IFX/THIO group compared to healthy controls (p=0.009), but not in the IFX or VDZ monotherapy group. The rate of decline in these monotherapy groups was also not significantly different to healthy controls. Functional SARS-CoV-2 neutralisation was significantly lower in all IBD patients compared to healthy controls, with the greatest reduction in patients receiving IFX/THIO (Figure 2A; p=0.00000091). The delta variant inhibition capacity was significantly reduced in 68.1% of IBD patients (30/44, Figure 2B; p=0.0005).

IFX/THIO is associated with significantly lower IgA and IgG responses, and with impaired functional SARS-CoV-2 neutralising antibody capacity, compared to healthy individuals. Whilst IgG and neutralisation responses are reduced in each group of IBD patients, these findings were most pronounced in the combination treatment group. As neutralising antibody responses are associated with protection, this observation may impact on decision-making regarding treatment and vaccination/antiviral strategies.

Recent data havehighlighted adverse clinical outcomes in IBD patients treated with infliximab/thiopurines (IFX/THIO) upon infection with SARS-CoV-2, as well as attenuated serological responses after infection and vaccination in patients treated with IFX. To provide mechanistic insight, we explored the serological and functional anti-viral response after infection in IBD patients treated with VDZ, IFX or IFX/THIO compared to healthy controls to guide clinical decision-making regarding treatment and vaccination strategies.

Serum from 640 IBD patients attending routine infusions in Oxford and London in May to December 2020 was screened for anti-SARS-CoV-2 antibody responses by the Abbott assay. Serum from seropositive patients was compared to seropositive health care workers (Table 1). Antibody reactivity to the SARS-CoV-2 wild type strain receptor-binding domain (RBD), full-length spike, and nucleocapsid was assayed by IgG/IgA ELISA over time as well as by IgG high-throughput MSD V-PLEX ELISA at the time of seropositivity. A pseudotyped SARS-CoV-2 virus microneutralization assay was used to detect neutralising antibodies to the wild type, and an ELISA-based inhibition assay to compare differential inhibition of the wild type vs. delta variant SARS-CoV-2 RBD-ACE2 interaction.

All IBD patients showed significantly reduced IgG antibody responses compared to healthy controls for all SARS-CoV-2 antigens, using MSD V-PLEX ELISA (Figure 1). The greatest reduction in IgG response by ELISA was observed in individuals treated with IFX/THIO (p=0.00019), whereas IgG response over time declined significantly faster in the IFX treated group (p=0.019). IgA responses were significantly reduced in the IFX/THIO group compared to healthy controls (p=0.009), but not in the IFX or VDZ monotherapy group. The rate of decline in these monotherapy groups was also not significantly different to healthy controls. Functional SARS-CoV-2 neutralisation was significantly lower in all IBD patients compared to healthy controls, with the greatest reduction in patients receiving IFX/THIO (Figure 2A; p=0.00000091). The delta variant inhibition capacity was significantly reduced in 68.1% of IBD patients (30/44, Figure 2B; p=0.0005).

IFX/THIO is associated with significantly lower IgA and IgG responses, and with impaired functional SARS-CoV-2 neutralising antibody capacity, compared to healthy individuals. Whilst IgG and neutralisation responses are reduced in each group of IBD patients, these findings were most pronounced in the combination treatment group. As neutralising antibody responses are associated with protection, this observation may impact on decision-making regarding treatment and vaccination/antiviral strategies.

Educational objectives:

1. To understand the research in the missing links in the pathophysiology of IBD
2. To understand the need for increased quality of care in IBD and the impact on long term outcomes
3. To review the need for personalized medicine and the requirement from a research perspective

Understand the clinical features of IBD
Recognise the endoscopic findings in IBD
Review the potential treatments for IBD