Inflammatory bowel diseases may lead to many non-neoplastic intestinal and extra-intestinal problems. 
The main intestinal complications comprise infections, obstruction, perforation fistulas etc, whereas the main extra-intestinal manifestations include skin conditions, liver and biliary diseases, eye complications, systemic infections and other systemic conditions.

Learning objectives: 
- which are the main non-neoplastic intestinal complications
- which are the main non-neoplastic extra-intestinal complications
- example and presentation of interesting histological cases

Discussion of non pharmacological strategies to maintain remission
Review of evidence for dietary intervention
Pre and probiotic therapy
Complementary therapies
Modifying the faecal microbiota
Techniques to modify stress
Vagal nerve stimulation

The efficacy of risankizumab (RZB), an interleukin 23 p19 inhibitor, in patients with Crohn’s disease (CD) has been reported. Normalisation of high-sensitivity C-reactive protein (hs-CRP) and faecal calprotectin (FCP) are intermediate treatment targets in CD. Here, we evaluated changes in these objective inflammatory biomarkers and clinical outcomes with RZB treatment.

In 2 phase 3, randomised, double-blind studies (ADVANCE, NCT03105128; MOTIVATE, NCT03104413), patients with moderately to severely active CD received 12-week intravenous (IV) RZB induction therapy or placebo (PBO). Patients with clinical response to RZB IV induction were rerandomised in a 52-week maintenance study (FORTIFY, NCT03105102) to receive subcutaneous (SC) RZB or PBO (ie, RZB withdrawal). Induction analyses included patients who received either 600 mg RZB IV or PBO for 12 weeks. Maintenance analyses included patients who received 360 mg RZB SC every 8 weeks or withdrawal (PBO SC) for 52 weeks. Outcomes assessed were normalisation of hs-CRP and FCP concentrations at week 12 of induction and at week 52 of maintenance in patients with elevated biomarkers at baseline (hs-CRP > 5 mg/L and/or FCP > 250 μg/g), clinical biomarker response (defined as enhanced clinical response [≥ 60% average daily stool frequency (SF) decrease and/or ≥ 35% average daily abdominal pain score (APS) decrease] and ≥ 50% reduction in hs-CRP or FCP), and clinical biomarker remission (defined as clinical remission per CD Activity Index or SF/APS criteria and normal hs-CRP or FCP) during maintenance treatment. Nonresponder imputation was used for missing data.

Greater proportions of patients receiving RZB vs PBO achieved normalisation of hs‑CRP and FCP at the end of the 12-week induction period and the 52-week maintenance period (P < .0001 for all; Table). Among patients with clinical response to RZB IV induction and entered maintenance, rates of clinical biomarker response were maintained through week 52 in patients receiving 360 mg RZB SC and declined over time among patients in the withdrawal (PBO SC) arm (Figure A). Rates of clinical biomarker remission increased over time in patients receiving 360 mg RZB SC. At week 52, clinical remission and normalisation of hs‑CRP or FCP was achieved by 41% of patients receiving RZB vs 28%–29% of patients in the withdrawal (PBO SC) arm (Figure B-C). The safety profile of RZB in CD was previously reported.

Normalisation of objective biomarkers of inflammation in CD was achieved with RZB induction and maintenance therapy. Improvements in both clinical outcomes and biomarker levels were sustained with continuous RZB maintenance therapy and decreased over time in patients discontinuing RZB.

To explore the role and scope of the IBD nurse.
To emphasise the importance of the impact and perspective of IBD in our patients.
To overview the UK IBD standards and how they enhance the provision of quality of care for all patients with IBD.
To provide an overview of the N-ECCO Consensus statements and the different levels in IBD nursing.

Objectives:
•To discuss why should we perform a nutritional assessment in patients with IBD
•To demonstrate how to perform a nutritional assessment
•To emphasize who and when should be screened 
•To understand the importance of working together in a multidisciplinary team

1. To provide an overview of some of the nutrition and dietary management options for IBD
2. To highlight the role of the IBD nurse in relation to nutrition and dietary management of IBD

1. To establish a standard terminology for the elaboration of trusted reports in endoscopy, surgery and histopathology
2. To provide i interpretation guidance for dysplasia and cancer, surgical indication and strategies including margins and extent of resection, assessment of disease activity.
3. To standardise the  interpretation of biopsies and specimens.

4.To prove useful these recommendations in daily care of IBD patients

Disruption of immune cell trafficking via integrins is a proven and effective mechanism for treating inflammatory bowel disease. When α4β7 integrin is inhibited through pharmacological intervention, immune cells destined for the gut tissue become sequestered in blood circulation and these alterations can be detected through several methods. MORF-057 is a novel, oral, selective, small molecule inhibitor of α4β7 integrin developed for treating IBD. MORF-057 demonstrated favorable tolerability, pharmacokinetic and pharmacodynamic profiles including saturating receptor occupancy and corresponding evidence for proof of biology based on effects on circulating cells during a Phase 1 clinical trial in healthy volunteers (Ray, ECCO 2021). Here we demonstrate an exposure:response relationship of α4β7 related biomarkers examined among MORF-057 treated non-human primates (NHPs) as a means for pre-clinical testing of inhibitors of this pathway.

Single-cell RNA sequencing (scRNAseq) was performed on NHP CD45⁺ blood cells to determine baseline populations potentially impacted through exposure to MORF-057. 40 Naïve cynomolgus monkeys were enrolled over 5 separate studies and dosed orally BID with MORF-057 over 2-7 days using several dose levels to examine biomarker dynamics over a wide range of exposures. Peripheral blood was sampled at various timepoints (n= 125) and assayed using: mass spectroscopy, flow cytometry (FACS), and mRNA quantification to determine MORF-057 exposure levels, on-target receptor occupancy (RO), immune cell subset changes, and CCR9 mRNA levels.

MORF-057 C_trough ranged from 3.3-429 ng/ml. In samples tested for RO, MORF-057 achieved >95% saturation of α4β7 even with the lowest C_trough of 4.5 ng/ml. MORF-057 treatment led to significantly sustained increases in circulating β7high CD4⁺ T memory cells detectable as early as 24h post-exposure. A maximal effect where β7high cells accounted for approximately 60% of the T memory population was achieved at saturating receptor occupancy (Fig., left). CCR9 mRNA values demonstrated increases upon drug exposure (Fig., right).

In NHP, acute changes in circulating β7high T memory cells was a sensitive biomarker demonstrating a dose-dependent response to MORF-057 exposure. CCR9 mRNA levels also showed similar exposure related changes reflecting its expression on a subset of β7high cell types. Analysis of scRNAseq shows expression of α4β7 on other cell types beyond T memory cells including: NK, NKT, B cells, plasmablasts, monocytes, and eosinophils. Pharmacodynamic changes in NHP are consistent with human Phase 1 data in healthy volunteers.

Limited data are available on the use of Vedolizumab (VDZ) in paediatric Crohn’s Disease (CD) and Ulcerative Colitis (UC). We evaluated the effectiveness and safety of VDZ to induce remission at week 14 in the prospective, multicenter VEDOKIDS study.

We enrolled children (age 0-18 years) with CD or UC commenced on VDZ with a standardized dosing of 177mg/BSA up to 300mg at 0, 2, 6 and q8 weeks thereafter. Non-responders had their dose escalated to q4wks at the discretion of the local physician. Explicit demographic, clinical and safety data were prospectively recorded via REDcap. Clinical remission was defined as steroid- and EEN-free remission (i.e. wPCDAI<12.5 or PUCAI<10) without the need for new medications. Complete remission was defined as clinical remission with normal CRP and ESR. Predictors of response were explored by Logistic regression.

128 children were enrolled, 60 (47%) with CD, and 68 (53%) with UC (58 (45%) males, mean age 13.8±3.6, 93 (73%) failed previous anti-TNF, median disease duration 2.3 years (IQR 0.9-4.7)). Using the ITT principle, clinical and complete remission rates for CD at week 14 were 30% and 20%, respectively, and for UC 50% and 38%, respectively (Fig 1). Clinical remission rates of those receiving VDZ as first line biologics versus second line were 57% and 34%, respectively (p=0.019; Fig 2); the corresponding complete remission rates were 49% and 23% (p=0.004).
In the UC group, disease activity at baseline measured by the PUCAI predicted clinical remission at week 14 (OR=0.95, 95%CI 0.93-0.98; median baseline PUCAI 15 (IQR 0-30) in those achieving remission and 45 (20-55) in those who did not; p=0.002). ESR (OR=0.94, 95%CI 0.89-0.98; p=0.009) and a trend towards extensive disease (L3 vs. L1 and L2; OR 0.14, 95%CI 0.18-1.036, p=0.054) predicted clinical remission in CD.

During the 14 weeks, 113 adverse events (AE) were recorded in 58 children: 28 AEs were possibly related to VDZ, all of which were mild-moderate and only 3 (11%) led to discontinuation of VDZ (leukocytoclastic vasculitis, myalgia and dyspnea). There were 18 serious AEs, only one was graded as possibly related to VDZ (headache). There were 18 non-serious cases (19%) of upper respiratory infections (pharyngitis, tonsilitis, parotitis, and otitis media) and one Campylobacter jejuni which was graded as serious.

In this prospective multicenter study, VDZ was safe and effective for inducing remission in a refractory cohort of paediatric IBD, more so in UC. Disease severity and extent at baseline may predict clinical response.

MDT discussion / panel discussion Q&A

IBD Multidisciplinary Team (nurses, dietitians, pharmacists, psychologists, etc.)

1. To review the clinical key predictors of poor outcome in IBD
2. To understand the progress made in predicting the future for a given IBD patient
3. To learn how to communicate prognostic factors to to the patients

Genetics plays a key role in the pathogenesis of inflammatory bowel disease (IBD). With the expanding use of next-generation sequencing, >70 different monogenic disorders associated with IBD have been identified, and most of them present in the first years of life. Recently, several patients with severe IBD were identified to harbor pathogenic mutations in Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) gene, which regulates necroptosis, a necrotic cell death mechanism. We present the clinical features, genetic analysis and immune work-up of three patients with infantile-onset IBD resulting from novel RIPK1 mutations.

Whole exome sequencing was performed in three patients with severe infantile-onset IBD, along with sanger sequencing for conformation. Mass cytometry time of flight was conducted for in-depth immunophenotyping, including cytokine secretion analysis following lipopolysaccharide (LPS) or Phorbol myristate acetate with ionomycin (PMA-I), on one of the patient’s peripheral blood mononuclear cells, and compared to control subjects and patients with Crohn’s disease.

All patients, born to consanguineous Muslim families, presented with severe colitis and multiple perianal fistulas in the first months of life, without severe or atypical infections. One of the patients had a partial response to high doses of inlfliximab and azathioprine, while another one failed to respond to adaliumab and later to low dose anakinra, an IL-1 receptor antagonist. Genetic studies identified novel and pathogenic genetic variants in the RIPK1 gene in all patients, that were confirmed by Sanger sequencing. Using mass cytometry time of flight unbiased clustering analysis, we identified peripheral immune dysregulation in one of these patients, characterized by an increase in IFNγ CD8⁺ T cells along with a decrease in monocytes, dendritic cells and B cells. Moreover, RIPK1-deficient patient’s immune cells exhibited decreased IL-6 production in response to LPS across multiple cell types including T cells B cells and innate immune cells.

Mutations in RIPK1 should be considered in very young patients presenting with colitis and perianal fistulas. Given RIPK1’s role in both immune cells (and specifically in inflammasome activation), and epithelial cells, it is unclear whether immunosuppressive medications (including IL1 blockade) as well as allogeneic hematopoietic stem cell transplantation can suppress or cure the hyper-inflammatory response in these patients. Additional studies in humans are required to better define the role of RIPK1 in regulating intestinal immune responses, and how treatment can be optimized for patients with RIPK1 deficiency.  

The presentation will focus on how to monitor patients' symptoms due to IBD, how to use the main scores and how to use the patients' reported outcomes in clinical practice.

Educational objectives:

1) To understand how important are symptoms in the monitoring of IBD patients
2) To make on overview on the main clinical scores
3) To present the recent evidence on patients' reported outcomes

Risankizumab (RZB), a selective interleukin-23 inhibitor, demonstrated clinically meaningful improvements in endoscopic outcomes in patients with moderate to severe Crohn’s disease (CD) during two phase 3 induction trials (ADVANCE and MOTIVATE) and the maintenance study (FORTIFY). Here, we compared the efficacy of RZB in inducing and maintaining improvements in endoscopic outcomes in patients with CD who demonstrated intolerance and/or inadequate response (IR) to biologic therapies (with prior bio-failure) versus those who demonstrated IR to conventional therapies only (without prior bio-failure).

Data included in this subgroup analysis included pooled data from patients randomized to receive intravenous (IV) RZB 600mg (N=527) or placebo (PBO) IV (N=362) every 4 weeks (wks) for 12wks during induction (ADVANCE+MOTIVATE), and data from patients receiving subcutaneous (SC) RZB 360mg (N=141) or withdrawn from RZB IV to receive PBO SC (withdrawal [PBO SC], N=164) every 8wks for 52-wks during maintenance. At Wks 12 and 52, endoscopic response, endoscopic remission, ulcer-free endoscopy (absence of ulceration), and deep remission (Wk52 only) were evaluated both in the overall population and in subpopulations of patients with and without prior bio-failure. (Endpointsare defined in Table footnotes). Safety was assessed throughout the studies.

Approximately three-quarters of randomized patients included in this subgroup analysis had prior bio-failure (ADVANCE+MOTIVATE: 75.4%; FORTIFY: 73.8%). Higher rates of endoscopic response, endoscopic remission, and ulcer-free endoscopy were observed at Wk12 among patients receiving induction with RZB IV versus PBO IV. Subgroup analysis demonstrated treatment effects with risankizumab in patient subpopulations with and without prior bio-failure, with greater adjusted differences versus PBO in patients without prior bio-failure (Figure). At Wk52, endoscopic response, endoscopic remission, ulcer-free endoscopy, and deep remission rates favored RZB SC compared to withdrawal (PBO SC). Again, treatment effects were observed in patients with and without prior bio-failure, with greater adjusted differences versus withdrawal (PBO SC) in patients without prior bio-failure. RZB maintenance treatment was well-tolerated and no new safety signals were observed. The safety profile of RZB has been reported previously.^1,2

Induction and maintenance therapy with risankizumab achieved higher rates for endoscopic endpoints in patients with moderate to severe Crohn’s disease versus placebo, regardless of prior bio-failure status. However, numerically higher efficacy rates were observed in patients without prior bio-failure.

1 D’Haens, G. et al. in DDW 2021 2 Ferrante, M. et al. in UEGW 2021

Perianal fistulas are a common complication of Crohn’s disease (CD) affecting approximately 25% of patients, often predicting a more complicated disease course. Dysregulated immune responses and epithelial-to-mesenchymal transition (EMT) are hypothesised to contribute to fistulizing disease; however, they have been poorly studied. In this study, we investigated the immune phenotype of patients with perianal fistulizing disease and its relationship with tissue remodelling.

Immune cells were isolated from fistula curettage samples (n=31) and paired peripheral blood from patients with perianal Crohn’s (pCD) or idiopathic fistulizing disease. Multiparameter flow cytometry was performed to evaluate lymphocyte populations including invariant natural killer T-cells (iNKTs), gamma-delta (γδ) T-cells, CD161⁺ mucosal-associated invariant T-cells (MAIT), CD4⁺ T-cells and CD8⁺ T-cells. Gene expression profiling of fistula (Crohn’s n=11, idiopathic n=11) and rectal tissue (Crohn’s n=9, idiopathic n=9) was performed by RNA-sequencing. Cellular deconvolution of transcriptomic data using CIBERSORTx was performed to define the cellular phenotype of perianal fistulas. Cytokine treated intestinal epithelial organoids were used to probe the impact of selective cytokines on disease relevant pathways in perianal fistulas, using gene-set enrichment analysis (GSEA).

Perianal fistulas were characterised by expansion of iNKTs and CD4⁺ T-cells when compared to peripheral blood. Deeper analysis of the phenotype of these populations revealed enrichment of CD8^- CD4^- CD161⁺ iNKTs producing interleukin-22 (IL22), and CD4⁺ CD161⁺ T-cells producing interleukin-13 (IL13) and IL22. Surprisingly, pCD and idiopathic fistulas displayed similar immunophenotypes. Fistulas exhibited distinct transcriptional profiles to rectal tissue, although the phenotype of pCD and idiopathic fistulas appeared similar. Pathways related to the extracellular matrix (ECM) and EMT were more activated in fistulas compared to rectum. Gene-set enrichment analysis and cellular deconvolution identified an increase in the abundance of iNKTs, activated memory CD4⁺ T-cells, activated NK cells and neutrophils in fistula versus rectal tissue. IL13, IL22 and TNFα responsive transcripts were enriched in fistula tissue, and in the case of IL22, was shown to regulate key matrisome components. 

Despite the proven efficacy of vedolizumab (VDZ), only 29% and 36% of the Crohn’s disease (CD) patients present corticosteroid-free clinical- and endoscopic remission, respectively. Therefore, predictive biomarkers for treatment success would be of extreme value. Previous studies have identified aberrant DNA methylation associated with CD-specific phenotypes, suggesting that the methylome may be useful for classification and prediction of VDZ treatment response. Here, we sought to identify such DNA methylation biomarkers that can predict clinical- and endoscopic response to VDZ in CD patients.

We prospectively recruited adult CD patients that initiated VDZ treatment following a baseline colonoscopy in two cohorts: a discovery and validation cohort. Peripheral blood DNA methylation profiles were measured prior to treatment (T1), and after a median of 22 weeks (T2) using the Illumina Infinium HumanMethylation EPIC BeadChip array. Response (R) was defined as the strict combination of endoscopic- (≥50% reduction in SES-CD score) and steroid-free clinical response (≥3 point drop in HBI and HBI ≤4 AND no systemic steroids) and/or biochemical response (≥50% reduction in C-reactive protein (CRP) and fecal calprotectin or a CRP ≤5 g/mL and fecal calprotectin ≤250 µg/g). Twenty-one patients had deep remission (DR), defined as a combined endoscopic- (SES-CD≤2) and steroid-free clinical remission (HBI ≤4, no systemic steroids). Biomarker identification and classification analyses were performed using stability selection gradient boosting.

In total, 64 CD patients were enrolled (discovery 16R/14NR and validation 20R/14NR). Both cohorts were comparable for age, sex and smoking status. Forty-nine (77%) patients had previously failed an anti-TNF agent. All patients had measurable serum vedolizumab concentration at T2 (median 14.5 (6.9 – 21.3) µg/mL).  Through classification analysis at T1, we were capable of discriminating R from NR with high predictive performance (25 CpGs, AUC 0.88, F1-score of 0.84, PPV of 0.91 and NPV of 0.85).  When analysing the methylome of patients in deep remission, we identified 23 CpGs with high predictive performance upon independent validation (F1-score 0.80, PPV of 0.71 and NPV of 0.86). Investigating the CpGs of interest implicated genes involved in endothelial cell-cell adhesion and integrin dependent T-cell homing, corroborating VDZ’s mode of action.

We demonstrate two novel 25- and 23-feature panels of epigenetic biomarkers that accurately predict response or deep remission to vedolizumab respectively. Similar analyses on infliximab, adalimumab and ustekinumab are currently ongoing as part of the EPIC-CD study.

Inflammatory bowel disease (IBD) exhibits heterogeneity at genetic, phenotypic, and therapeutic levels [1]. Although several studies have investigated genetic effects on IBD subtypes and drug adverse events [2,3], few have comprehensively explored the phenotypic and genetic determinants of IBD drug efficacy in a sufficiently powered cohort.

We used data from 32,199 patients in the UK IBD BioResource to investigate the effects of clinical phenotypes and demographics on drug efficacy and combined this with genome-wide genetic data for a subset of 11,536 individuals (Table 1). Drug efficacy was defined using a combination of clinician reported efficacy and persistence on drug without treatment escalation. Anti-TNF, thiopurine, steroids, and mesalazine were explored. We estimated phenotypic effects on drug efficacy using multivariable logistic regression and the genetic effects by genome-wide logistic regression. To explore whether drug efficacy and IBD disease susceptibility share a genetic basis, we estimated the proportion of variance in drug efficacy explained by known IBD risk variants [4]. Associations with Bonferroni corrected P-values < 0.05 were defined as statistically significant in phenotypic analyses and a genome-wide significance threshold of P=5x10^-8 was adopted for genetic analyses.

Drug efficacy was generally lower in patients with Crohn’s disease (CD) compared to those with other subtypes (OR ranges from 0.40 to 0.79), but anti-TNF showed a higher efficacy rate (OR = 1.21) in CD patients. Increasing age at diagnosis was associated with evidence of increased efficacy of thiopurine and mesalazine (Table 2). We found evidence of a genetic contribution to variation in drug efficacy for most drugs studied. However, known IBD risk variants showed little contribution (Figure 1). Using genome-wide association testing, we identified three loci showing a significant association with drug efficacy; two were related to steroid response and one to thiopurines (Table 3). None of these was an IBD disease susceptibility locus (P > 0.05).

Using a large, well-characterised cohort we found both genetic and phenotypic determinants of drug efficacy. Three loci were reported to be associated with drug efficacy in the first phase of the genetic analysis; at least 4,200 extra genotyped samples will be included before the ECCO meeting, thus increasing the power to detect additional loci. Our results suggest the genetic causes of drug efficacy and disease susceptibility are largely independent. These findings may provide opportunities for exploring the biology of drug efficacy and improving medication prioritization in IBD patients.

Reference
1. PMID: 16819502
2. PMID: 26490195
3. PMID: 30806694
4. PMID: 28067908

Educational Objectives:

1. Definition of point of care testing (POCT)

2. Patient´s view: why would I prefer POCT?

3. Fecal alprotectin (FC) – prototypic fecal marker of inflammation

4. Clinical studies assessing FC in POCT

5. Role of therapeutic drug monitoring

6. Effect of Covid-19 on POCT development

7. Lipocalin-2: a new fecal marker of inflammation

8. Outlook and challenges for POCT

Perianal Crohn's disease (pCD) may present with a variety of lesions that include anal skin tags, anal canal lesions including fissures, ulcers, fistula and abscesses, strictures and cancer. pCD is disabling and aggressive phenotype that negatively impacts on the quality of life of affected patients. Perianal fistulas are common manifestations of pCD, with an incidence of 11 cases per 1000 patient-years. Successful treatment of pCD remains still a struggle for both physicians and patients. Significant advances in the management of pCD have occurred in the last two decades, resulting in the concept of a collaborative multidisciplinary approach using the latest medical therapies combined with modern surgical or endoscopic techniques. The use of antibiotics in the treatmentof pCD has limited evidence and antibiotics are currently used in combination with other therapies to prevent abscess formation and improve the rate of fistula closure. Thiopurines in pCD lacks of prospective trials, and evidence supporting their use should be carefully interpreted. Although anti-TNFs have revolutionized the prognosis for patients with pCD in the modern era, their effectiveness in the long term is limited: over 60% may relapse after one year of treatment and less than one third mantain sustained remission over time. Optimisation of anti-TNF treatment in pCD includes associaton with an antibiotic for the induction of fistula remission, combination with thiopurines to achieve appropriate anti-TNF trough level and a low likelihood of anti-drug antibodies. The use of vedolizumab and ustekinumab in pCD after anti-TNFs failure is mainly supported by one randomized phase IV trial (vedolizumab) and a number of real life reports (vedolizumab and ustekinumab), suggesting that they could be beneficial in patients who have failed to respond to anti-TNFs. Finally, in case of refractory pCD, a number of mesenchymal stem cell (MSC)-based therapies have been reported. In particular the use of darvadstrocel in refractory pCD is supported by phase 3 trial, showing that local treatment with adult allogeneic expanded adipose tissue-derived mesenchymal stem cells may succeed in 50% of treated patients after 6 months.

Learning Objectives:
1. Aspects of risk stratification
2. Utility of drugs that may alter the natural history (reducing rates of surgeries and complications)
3. Timing of intervention
4. Evidence base data  comparing different classes
5. Economic consideration/medical economics including the utility of biosimilars