Exabis Library

Educational objectives:
1/ To understand the limitation of human interpretation of endoscopic images
2/ To review the rational and goals for implementing artificial intellegence in image processing
3/ To understand the different types of artificial intelligence applications in image processing
4/ To have an overview of the future potential application of artificial intelligence in IBD endoscopy

There is a scarcity of data regarding the role of histopathology evaluation in Crohn’s disease (CD) and how it relates to endoscopy. Mirikizumab (miri) has shown efficacy in Ph2 studies in CD and ulcerative colitis (UC). Here we explore the agreement of histologic response and remission with endoscopic outcomes after 12 and 52 weeks of treatment with miri in a phase 2 randomized clinical trial (SERENTIY; NCT02891226) in patients with moderate-to-severe CD.

Patients were randomized 2:1:1:2 across 4 treatment arms (PBO, 200, 600, 1000mg miri) administered intravenously (IV) every four weeks (Q4W) at Weeks 0, 4, and 8. Those who received miri and achieved ≥1 point improvement from baseline (BL) at W12 in Simple Endoscopic Score for Crohn’s Disease (SES-CD) were re-randomized 1:1 into double-blind maintenance to continue their IV dose assignment Q4W (IV/IV) or to 300mg miri SC Q4W (IV/SC); due to small numbers, maintenance IV arms were pooled for analysis. W12 non-improvers and all induction PBO patients received 1000mg miri Q4W from W12 through W52. Biopsies were obtained during endoscopy at W0, 12 and 52 from the edge of the ulcers and the most inflamed mucosa in terminal ileum and 4 colonic segments (ascending, transverse, descending, rectum; N=10/patient, 2 per location with the more severe score used), and scored by central readers blind to study treatment, timepoint, and response status. Histologic endpoints were defined post-hoc but prior to performing the analyses (see Table footnotes for definitions). Cohen’s Kappa Coefficient was used to evaluate the degree of agreement of two measures.

At Week 12, there was an overall 69.6% agreement in histologic and endoscopic response, and 84.2% agreement between histologic remission and endoscopic remission (Table 1). After 52 weeks of miri treatment, the agreement between histologic and endoscopic response was 61.9%, while the agreement between histologic and endoscopic remission was 70.6% (Table 2). Interestingly, in every comparison, the percentage of patients achieving the histologic outcome but not the endoscopic outcome was greater than that of patients achieving the endoscopic outcome but not the histologic outcome.

Histologic and endoscopic outcomes demonstrated fair association after both 12 and 52 weeks of miri treatment. Histologic endpoints, despite the stringent criteria, appear to be more sensitive to change than endoscopic endpoints. However, variability of biopsy sampling may be an additional factor contributing to these differences.

The human gut is colonized by diverse microbes including fungi such as Candida albicans, which has been implicated in the pathogenesis of Crohn’s disease (CD). Intestinal C. albicans typically exists as commensal yeast, but can also form tissue-invasive filaments that secrete Candidalysin toxin to disrupt epithelial barriers. Commensal gut bacteria produce molecules that induce host immunity, including phosphoantigen HMB-PP which stimulates Vδ2+ T-cell homing to intestine and mucosal expression of IL-22 to promote barrier integrity. We aimed to identify mechanisms of gut barrier defence against fungal invasion in health and CD.

Colonic biopsies / resected tissue were stimulated or not with HMB-PP in the presence or absence of anti-IL-22 blocking antibody and analysed by flow-cytometry / microscopy to determine extent of fungal outgrowth. Fungal isolates were identified using standard morphological and biochemical criteria before assessment of filamentation, cell wall composition, and NETosis induction.

Mucosal Vδ2+ T-cell activation with bacterial phosphoantigen HMB-PP, in the presence of epithelial damage-associated cytokine IL-15, potently suppressed growth of endogenous fungi in human colonic organ cultures. Vδ2-mediated fungal suppression required IL-22 and was sufficient to restrict the growth of multiple fungal species, including a range of emerging pathogenic moulds as well as archetypal pathobiont C. albicans. In Vδ2-deficient CD patients, mucosal biopsy stimulation with HMB-PP failed to control fungal growth. CD-derived C. albicans strains also displayed rapid filamentation ex vivo and higher levels of NOD2 ligand chitin than were observed in isolates from healthy controls. Comparing hypoxic with oxygenated cultures that mimic inflamed intestine, pSILAC proteomic analysis of a representative CD-derived C. albicans strain confirmed features of invasive growth (e.g. DAO1, IHD1), whereas a healthy control isolate exhibited metabolic hallmarks of symbiosis (Jen1p, SCH9). These divergent characteristics directly impacted on host anti-fungal immune responses, since the CD-derived strain rapidly induced neutrophil extracellular traps in vitro, whereas the healthy control isolate did not.

These data suggest that commensal bacteria can activate host Vδ2 T-cells to suppress fungal invasion of the gut epithelium via an IL22-dependent mechanism that is deficient in CD patients.

Conflicting evidence exists regarding whether low baseline Triggering Receptor Expressed on Myeloid cells (TREM)1 whole-blood gene expression predicts response or non-response to anti-tumour necrosis factor agents in patients with Ulcerative Colitis (UC) or Crohn’s Disease (CD). This study investigated whether baseline TREM1 expression predicted outcomes following adalimumab treatment in patients with UC or CD in the SERENE Phase 3 studies.

The SERENE studies (SERENE-UC, NCT02065622; and SERENE-CD, NCT02065570) compared a higher adalimumab induction dosing regimen versus the standard regimen in patients with UC or CD. Whole-blood TREM1 expression was analysed by RNA sequencing in patients who received standard-dose adalimumab and had clinical and endoscopic outcomes at Week 8 or 52 in SERENE-UC (n=95 for Week 8 and n=70 for Week 52 outcomes), or Week 12 or 56 in SERENE-CD (n=106 for all Week 12 outcomes; n=48 for clinical and n=50 for endoscopic outcomes at Week 56). Outcome definitions are summarised in Table 1. A 2-sample t-test was used to compare baseline TREM1 gene expression (log2 counts per million) in clinical or endoscopic remitters or responders versus non-remitters or non-responders at Weeks 8 and 52 (SERENE-UC) or Weeks 12 and 56 (SERENE-CD). 

In SERENE-UC, baseline TREM1 expression did not predict clinical remission at Week 8 (Figure 1a; p=0.7942) and was only weakly predictive of clinical remission at Week 52 (Figure 1b; p=0.04997). Further, it was not predictive of clinical response at Week 8 or Week 52, nor of endoscopic remission or endoscopic response (Figure 1c) at Week 8 (p>0.05 in all cases), although a weak correlation was observed with both endoscopic remission (p=0.0484) and endoscopic response (p=0.01162; Figure 1d) at Week 52. In SERENE-CD, baseline TREM1 expression was not linked to endoscopic or clinical outcomes at either Week 12 or Week 56 (p>0.05 in all cases; Figure 2a–d). Stratification by adalimumab quartiles did not increase the ability of baseline TREM1 expression to predict clinical outcomes in either study. Of note, a highly positive correlation was observed between baseline TREM1 expression and neutrophils in endoscopic responders and non-responders in both studies. Regardless of clinical or endoscopic response or non-response, TREM1 expression decreased over time following adalimumab treatment. All results obtained with standard-dose adalimumab were replicated with the higher dose (data not shown). 

The findings of this study suggest that baseline whole-blood TREM1 gene expression is not a robust predictor of clinical or endoscopic outcomes following adalimumab treatment in patients with UC or CD. 

To understand the pros and cons of evidenced based diet therapy for IBD. 
To understand the potential nutritional and psychological dangers of restrictive diets.
To highlight the importance of MDT working to support patients with diet therapy.

To assess the risk of postoperative peristomal pyoderma gangrenosum in Crohn’s disease patients undergoing bowel resection with formation of an ostomy.

All patients with Crohn’s disease undergoing intestinal resection with formation of an ostomy were included in the present retrospective analysis. The data collection was performed prospectively. All cases of pyoderma gangrenosum were identified by clinical examination and documented on photographs. “Extended colectomies” were total colectomy and proctocolectomy.

Between 2009 and 2021, 99 patients underwent intestinal resections with formation of an ostomy – 95 ileostomies and 4 colostomies. Ileocolic resections were performed in 62 patients, small bowel resections in 2 and colorectal resections in 35 patients. Additional abdominoperineal rectal resections were performed in 19 out of latter 35 patients. At the time of surgery, 31 patients were on biological treatment, 19 on steroids. Postoperatively, 10 patients (10%) developed peristomal pyoderma gangrenosum – all during first 3 postoperative months and all in presence of an ileostomy. By univariate analysis, abdominoperineal resection (26% vs. 9%, p=0.03), presence of colonic disease (20% vs. 2%, p=0.005), preoperative biological treatment (24% vs. 4%, p=0.008), extended colectomy (27% vs. 5%, p=0.008), non-stricturing/non-penetrating disease (35% vs. 5%, p=0.002) were associated with an increased risk of peristomal pyoderma gangrenosum. By multivariate analysis, preoperative intake of biologic treatment (Hazard Ratio 5.5, p=0.03), and non-stricturing/non-penetrating disease (HR 8.3, p=0.006) were associated with the risk of postoperative pyoderma gangrenosum.

Crohn’s disease patients with colonic disease undergoing bowel resections for non-stricturing/non-penetrating disease are at high risk to develop peristomal pyoderma gangrenosum during the early postoperative period. Preoperative biological treatment does not decrease the risk of pyoderma formation; moreover, it might even increase it.

Circulating serum proteins have provided insights into disease pathogenesis and are being used to identify prognostic, diagnostic and therapeutic biomarkers for chronic inflammatory diseases. With this pilot project, the Collaborative IBD Biomarker Research Initiative (COLLIBRI) consortium aimed to unravel disease heterogeneity in inflammatory bowel disease (IBD).

Serum samples were cross-sectionally obtained from 3,390 individuals (Crohn's disease (CD), n=1815; ulcerative colitis (UC), n=1170; healthy, n=405) recruited at nine centres from Sweden and Belgium. Relative levels of 92 proteins were analysed using the Proseek Multiplex Inflammation I Probe kit 96x96 (Olink Proteomics, Uppsala, Sweden) and reported as arbitrary units, i.e., normalised protein expression on a log2 scale. Using a multivariate integrative approach, we identified protein signatures distinguishing CD and UC samples and attempted to identify clusters or subgroups within patients. Recruiting centre, cohort and batch information were considered for the integrative analysis. Optimisation was performed for identifying the number of components and features per component using 5-fold cross-validation and Leave-One-Group-Out-Cross-Validation, respectively. Information on transcriptional regulators was retrieved from the ReMap project using the orthogonal regulatory resource ChEA3.

A panel of 8 proteins was identified which could segregate CD and UC patients (Figure 1). FGF19 exhibited a consistent trend of expression (downregulated in CD) across all batches of datasets.  An integrated AUC of 72.5% was achieved across the different batches of samples used in the study with the highest AUC (79.2%, P-value 8.5e-07) being recorded for a single batch of samples (CD = 42, UC = 56). On a centre-specific dataset, the cross-centre integrated signature achieved an AUC of 75.1%.  We identified three transcription factors (MEF2A, BATF, NFKB2), of which the two latter ones are known to modulate intestinal inflammation and which could potentially regulate the expression of at least half of the genes encoding the proteins in the predictive 8-protein panel.

We identified an integrated proteomic biomarker panel capable of separating CD and UC patients. Through further integration of confounder variables along with using other supervised and unsupervised approaches, subsequent analyses may further refine the molecular heterogeneity among CD and UC patients. Our results demonstrate the need for large datasets to identify relevant clusters of patients with IBD, since the diagnosis exhibits a high degree of clinical heterogeneity.

*Equally contributed

Nathalie Auger and Marianne Bilodeau-Bertrand describe their absolutely enormous epidemiological study of 3 decades of data from Quebec, Canada identifying birth-defects for offspring of almost 22,000 mothers with IBD.

This talk discusses the importance of sex and body image in relation to IBD and surgery. We will consider how disease and surgery affect all aspects of sex, and crucially we will examine how conversations about sex should be managed.

Educational Objectives:
1. To understand how IBD can affect patients' body image and sexual pleasure

2. To consider how clinicians feel about discussing sex and address our own anxieties

3. To develop techniques and confidence in discussing sex in clinical consultations

4. To appreciate when sex should be discussed, particularly around surgery

To discuss the possibilities for achieving a 'cure' from surgical intervention in both Crohn's Disease and Ulcerative Colitis

To discuss the definition of a 'cure' in this context 

Crohns:
To explore which patients with Crohn's disease may be at low risk of recurrence post-surgery and who may achieve a cure in the medium or long-term

To refine the role of withdrawing post-operative medical therapy in Crohn's to achieve disease- and medication-free survival

To explore emerging evidence and novel biomarkers to help stratify patients who may achieve excellent post-surgery results

Ulcerative Colitis:
To discuss the emerging potential for appendicectomy to treat/cure UC

To explore resectional and reconstructive options in UC and discuss whether these offer a 'cure' for patients