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This presentation will provide an overview of current surgical management of IBD with a focus on abdominal and perianal manifestations and treatment of colitis ulcerosa and Crohn's disease, capitalizing on the most recent ECCO guidelines.

Learning Objectives:
1. Indications for exit strategy
2. Management of exit strategies with biologics
3. Similar option with other drugs

Genome-wide association studies (GWASs) have identified 243 loci associated with inflammatory bowel disease (IBD). However, the mapping of additional disease loci and causal variants is still limited by sample size. Larger GWAS can provide further insights into causal biology.

We performed a GWAS meta-analysis of 33 cohorts, totalling 54,439 IBD patients (N=30,574 with Crohn’s disease (CD), 21,193 with Ulcerative Colitis (UC)) and 37,054 European controls. Genotype imputation was undertaken using the TOPMed diverse population panel and association tests were performed using REGENIE. These results were meta-analysed with summary statistics from 4 additional studies, a Danish cohort, the UK Biobank, deCODE, and FinnGen, totalling 73,030 IBD patients and 1 million controls, Fig1.

We identified 174 novel genome-wide significant signals (32 associated with CD, 36 with UC, 106 with IBD, Fig2).

Of these, 79 are located >1Mb from any known GWAS loci. We also identified two new population specific genetic associations, Fig3.

Six new loci contain genes implicated in monogenic syndromes that include colitis: CARMIL2, DOCK8, G6PC3, HPS4, NCF1, PIK3CD. Several new loci alter the expression of nearby genes, suggesting that aberrant expression of these genes underpins the association. For instance, a new variant associated with decreased risk of IBD increases the expression of VSIR in colon Fig4.

VSIR knockout mice have increased expression of IL23 and develop chronic inflammation in multiple tissues. Fine-mapping analyses identified likely causal missense variants at three new loci. DOK2 (OR_CD=1.3, 27p=2x10^-12) encodes a protein expressed in macrophages and T cells. Loss of Dok2 in mice causes severe DSS-induced colitis with reduced IL17A and IL22 expression. The same variant has been recently associated with CD in a sequencing study. SHARPIN (OR_CD=1.2, p=1x10^-16) is part of the linear ubiquitin chain assembly complex that modulates activation of the NF-κB pathway. Loss-of-function (LOF) mutations in other proteins in the complex are associated with immunodeficiency and systemic autoinflammation. CARMIL2 (OR_UC=1.2, p=1x10^-10) is required for NF-κB signalling in both B and T cells. LOF mutations are associated with primary immunodeficiencies and paediatric forms of IBD.

The greatly expanded sample size in our latest GWAS meta-analysis has enabled the identification of low frequency variants with larger effects on IBD susceptibility than the more common variants typically identified by previous GWAS. The biological overlap between Mendelian and complex forms of IBD is demonstrated by the discovery of common non-coding variants associated with complex forms of IBD that dysregulate the function of a Mendelian IBD gene.

For patients with ulcerative colitis (UC), both subjectively and objectively reported measures are equally important treatment goals. We explored clinical, biological, HRQoL remission and endoscopic improvements as a combined endpoint (CE) from SELECTION (NCT02914522), a phase 2b/3 double-blind trial which assessed the efficacy and safety of filgotinib, a once-daily, oral, Janus 1 kinase preferential inhibitor, for the treatment of UC.

In SELECTION, patients with moderately to severely active UC were randomized 2:2:1 to 200mg filgotinib (FIL200), 100mg filgotinib, or placebo (PBO) for an 11-week induction phase followed by a 47-week maintenance period in patients who achieved clinical remission or response.¹ We defined a CE as achieving all of the following: 1) clinical remission  defined as partial Mayo Score (excluding endoscopy domain) ≤2 and no sub-score >1), 2) biological remission defined as faecal calprotectin <150 µg/g, 3) Inflammatory Bowel Disease Questionnaire (IBDQ) remission defined as IBDQ >170 and 4) endoscopic improvement defined as Mayo endoscopic sub-score ≤1. We evaluated the CE among patients treated with FIL200 vs placebo in induction (week 10) and maintenance (week 58) phases. Among those achieving the CE, we analysed MCID improvement during induction and decline during maintenance on generic QoL instruments (36-item short-form questionnaire and EuroQol 5-dimension [EQ5D]).^2,3,4

The overall population included 381 biologic-naïve and 401 biologic-experienced patients undergoing induction, of which 297 subsequently entered maintenance. A higher proportion of patients receiving FIL200 achieved CE than PBO by week 10 in the biologic-naïve induction cohort (17.6% vs 4.41%, p<0.001) and by week 58 in the maintenance cohort (22.1% vs 7.14%, p=0.002) (Table 1). Biologic-naïve CE achievers had higher MCID improvement across all generic QoL scales and domains (Table 2).Patients achieving CE in maintenance experienced a lower proportion of MCID decline in EQ5D utility, and visual analogue scale.

Treatment with filgotinib resulted in a higher proportion of patients with combined clinical, biological, HRQoL remission and endoscopic improvements. Among patients achieving this combined composite endpoint, clinically meaningful improvements were observed in their overall quality of life. Holistic assessment of several subjective and objective measures may help achieve better outcomes in UC.

1. Feagan BF, et al. Lancet 2021;397:2372–84.
2. User’s manual for the sf-36v2 health survey. Quality Metric, Inc; 2009.
3. Stark RG, et al. Inflamm Bowel Dis. 2010 Jan;16(1):42–51.
4. Irvine EJ. J Pediatr Gastroenterol Nutr. 1999 Apr;28(4):S23–27. 

Learning Objectives:
1. Prevalence and management of EIM
2. Identification of muco-cutaneous EIM and therapy
3. Classification and therapy of rheumatological EIM

4. Classification, prevalence and management of EIMs
5. Identification and therapy of muco-cutaneous EIMs
6. Identification, classification and therapy of musculoskeletal EIMs

Lara Hart discusses her team’s work capturing faecal calprotectin values in a large cohort of patients with clinically quiescent ulcerative colitis undergoing colonoscopy, and reports test performance for predicting ongoing endoscopic or histologic disease activity.

Julien Verdier reports the work of the team at INSERM, Paris, analysing microRNA expression in faeces and considers the significance of the differences they observed between patients with active disease and controls.

Educational objectives:
1. To understand the rationale for FMT as a treatment for IBD.
2. To be updated on trial data for FMT in IBD.
3. To understand some emerging predictors of efficacy for FMT in IBD.
4. To understand the infrastructural needs for FMT as a therapy.
5. To understand the evolving regulatory landscape and governance issues for FMT.

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