Investigating the genetics of IBD multiplex families

Ho-Su Lee © Ho-Su Lee

Background & aim of research

This research aimed to investigate the genetic architecture of Inflammatory Bowel Disease (IBD) multiplex families (including at least three affected first-degree relatives), and to identify the underlying genetic factors that contribute to the familial aggregation of IBD.

Role of DNA methYlation and geNe expression alterations in development of eArly-onset priMary sclerosIng cholangitis in ulCerative colitis – DYNAMIC

Sudipto Das © Sudipto Das

Background & aim of research

Primary Sclerosing Cholangitis (PSC) is a progressive choleostatic disease and up to 80% of patients also have Ulcerative Colitis (PSC-UC). This presents a clinical challenge owing to the diagnostic difficulty and the increased risk for development of cancer. The aim of this study was to identify the transcriptomic and epigenetic alterations regulating the phenotype of this disease.

The role of autophagy in limiting IBD-associated AIEC-induced intestinal inflammation

Shai Bel © Shai Bel

Background & aim of research

While the aetiology underlying the development of Inflammatory Bowel Diseases (IBD) is unclear, evidence points to an interaction between host genetics, such as mutations in autophagy genes, and environmental factors, such as bacterial infections. Multiple studies have identified an adherent-invasive Escherichia coli pathotype (AIEC) only in patients with IBD. It is thought that AIEC exploits the intestinal inflammation in patients with IBD to attach to intestinal epithelial cells, intensifying the pre-existing inflammation. Studies in vitro have shown that functional autophagy is crucial to eliminate AIEC infection. Here, we aimed to identify how autophagy protects the host from AIEC-associated pathologies in vivo.

Marc Ferrante © ECCO

Yves Panis © ECCO

Pauline Rivière © Pauline Rivière

For two years, a group of 25 IBD specialists, including gastroenterologists, surgeons and scientists, have been working to build a research framework for postoperative recurrence (POR) in patients with Crohn’s Disease. Even though more biological therapies are now available, ileocaecal resection is still a frequent event and POR management remains a challenge for both patients and IBD specialists.

Robin Dart © ECCO

Iris Dotan is a gastroenterologist and mucosal immunologist based at Rabin Medical Center, Israel. She is chair of the International Organization for the Study of Inflammatory Bowel Disease (IOIBD) and is well known to ECCO Members through her previous membership of SciCom, her speeches at ECCO Congress and her permanent presence on the Hearts and Minds dancefloor. During a break at the ECCO Congress in Copenhagen, I sat down with Iris to discuss her career, how mentorship has been important to her and, for anyone who has been on a Zoom call with her in the last 3 years, the origins of the beautiful painting she is usually seen sitting in front of.

Vedolizumab for the treatment of chronic pouchitis

Travis S, Silverberg MS, Danese S, et al., EARNEST Study Group

N Engl J Med 2023;388:1191–1200. doi:10.1056/NEJMoa2208450.

Introduction

Proctocolectomy is a curative treatment for medically refractory Ulcerative Colitis (UC). However, a significant number of patients prefer to have continuity of their bowel and undergo a restorative ileal pouch–anal anastomosis (IPAA), after having had an initial subtotal colectomy. Unfortunately, pouchitis is a most common complication in patients with an IPAA: 81% of patients experience pouchitis in their lifetime, with 40% experiencing it in their first year of pouch formation [1]. Multiple factors associated with pouchitis include mutations in NOD2/CARD15, genetic polymorphisms of interleukin-1 receptor antagonists [2–4], tumour necrosis factor allele 2 and toll-like receptor 1 [5].

The cause of pouchitis is multifactorial, including abnormal immune reaction to newly formed IPAA, change in the vascularity and anatomy of the bowel, faecal stasis and many other postulated factors. Single-cell analysis of CD45+ haematopoietic cells in the colon and pouch of UC patients has also highlighted genetic pathways that might contribute to the inflammation and disease severity seen in this condition [6]. However, the aetiology of pouchitis remains poorly understood and this may explain why treatment of this condition has emerged as an important area of unmet research need in the field of IBD. The treatment currently ranges from probiotics, antibiotics, steroids and immunomodulators through to use of biologics. Unfortunately, 50% of patients develop recurrent pouchitis, and up to 20% develop chronic pouchitis. Typically, cases of medically refractory pouchitis have been treated with anti-tumour necrosis factor (anti-TNF), vedolizumab and ustekinumab, but the evidence base for this approach has been very limited, typically comprising only case series and retrospective studies. Until recently, there had been no double-blind, randomised placebo-controlled trial supporting use of any therapeutic in pouchitis. Therefore, there has been significant interest in the study by Travis et al., reporting the first placebo-controlled trial for treatment of pouchitis, with use of vedolizumab. The findings from this trial help to provide evidence supporting the use of gut-selective vedolizumab for patients living with an IPAA.

Ustekinumab improves health-related quality of life in patients with moderate-to-severe Crohn's disease: Results up to week 104 of the STARDUST trial

Panes J, Vermeire S, D’Haens GR, et al., STARDUST Study Group

United European Gastroenterol J 2023 May 4. doi: 10.1002/ueg2.12384. Online ahead of print.

Introduction

The concept of treat to target (T2T) in Crohn’s Disease (CD) involves optimising therapy until a predetermined clinically relevant endpoint is met. In recent years, this endpoint has most commonly been a short-term biomarker response or endoscopic healing, but this has typically been juxtaposed with long-term patient reported outcomes (PROs) such as health-related quality of life (HRQoL) [1]. The international STRIDE-2 guidelines emphasise the need for monitoring at frequent intervals to ensure that treatment targets agreed at the commencement of any therapy are actually being achieved. One of the big unknowns of such strategies, requiring frequent monitoring, has been their cost-efficiency. However, concerns about cost have been balanced by arguments that adequate monitoring may allow earlier and more appropriate initiation of advanced therapies, which may then result in better longer-term outcomes [2].

STARDUST (NCT03107793) was a phase 3b, open-label, randomised controlled trial that compared ustekinumab (UST) T2T with standard-of-care (SoC) treatment strategies in adult patients with moderate to severe CD. The primary results from this trial have previously been reported, and it is notable that endoscopic and biomarker endpoints were not statistically different between the two treatment strategies [3]. However, it is also worth noting that while more patients in the T2T arm received q4w (4-weekly) dosing of UST (18.4% vs 0%), more patients in SoC received q8w (8-weekly) dosing (61.5% vs 38.8%). The original STARDUST trial included 440 patients, of whom 336 completed the first year of treatment and 323 (T2T, n=147; SoC, n=176) were subsequently enrolled to the long-term extension (LTE) period until week 104 (2-year mark). In this study, Panes et al. report on the HRQoL outcomes from patients in the LTE study from the STARDUST trial.

Efficacy of filgotinib in patients with ulcerative colitis by line of therapy in the phase 2b/3 SELECTION trial

Dotan I, Feagan BG, Taliadouros V, et al.

J Crohns Colitis 2023 Mar 16. doi:10.1093/ecco-jcc/jjad039. Online ahead of print.

Introduction

In recent years, there has been significant optimism in the field with the arrival of newer licensed therapies for patients living with IBD [1]. Alongside the welcome arrival of new therapeutics, there has also been an appreciation that many (but not all) patients may have preferences for oral medications [2]. In particular, targeting Janus kinases (JAKs) with oral small molecule treatments has proved to be a promising strategy. Indeed, tofacitinib, a pan-JAK inhibitor, was shown to have efficacy in patients with Ulcerative Colitis (UC), even in some instances where there had been loss of response or non-response to all prior licensed biologic options [3]. With growing understanding of the pathways involved in UC, preferential inhibition of JAK1 has been investigated in the field of IBD, including with the JAK1 inhibitor, filgotinib. This is a medication already licensed for some rheumatological conditions and it was recently assessed in the context of UC in the phase 2b/3 SELECTION trial – with the results having previously been published, and demonstrating superiority of filgotinib over placebo in UC [4]. In this current study, Dotan et al. assess efficacy of filgotinib based on prior treatment exposure and number of lines of therapy for instances of previous exposure to biologic therapy, based on a post-hoc analysis of data from the SELECTION trial. This study contributes to our understanding of how to sequence and position a new advanced therapy, in the context of a growing armamentarium of treatment options for patients living with UC.

Dear Y-ECCO Friends,

Although it still feels as though ECCO’23 has only just exited our rear-view mirrors, I’m sure many of you have moved onto preparing your abstract submissions and it’s worth remembering that the abstract submission window for ECCO’24 will soon be open! However, before getting started with that (there’s still plenty of time, after all) I would very much encourage you to take a look at the recently published IBD Communication Toolbox. Whatever type of ECCO Membership you hold, I can assure you that there’s something there for everyone.

At the 18^th Congress of ECCO in Copenhagen in 2023, many exciting projects on artificial intelligence (AI) were presented. Most of these projects focused on the role of AI in endoscopy. As a pathologist, I asked myself the following question: What about the role of AI in the histological evaluation of IBD?

The pathologist plays an important role in establishing the diagnosis and in assessing therapy response. Given that in many parts of the world IBD prevalence is still rising and histological remission may soon become a treatment target, the workload for pathologists is expected to increase. Therefore, as it promises to guide and thereby reduce time spent on biopsy assessment, AI is an interesting tool for pathologists. Moreover, it may aid the mission of H-ECCO to “raise standards of IBD pathology reporting” by mitigating problems associated with inter-observer variability.