Point-of-care intestinal ultrasound in IBD patients: Disease management and diagnostic yield in a real-world cohort and proposal of a point-of-care algorithm

Bots S, De Voogd F, De Jong M, et al.

J Crohns Colitis 2022;16:606–615.

Introduction

Intestinal ultrasound (IUS) is an inexpensive, non-invasive, safe and repeatable, dynamic cross-sectional imaging technique for IBD. It has been demonstrated to be accurate and reliable both for initial diagnosis of IBD and for follow-up monitoring [1]. Huge advantages of IUS are that it does not need any prior preparation of the patient and provides a real-time result. IUS can be performed in various hospital settings, which makes it the only point-of-care (POC) imaging technique available today [2].

The impact of POC IUS on daily decision making and the evolution in its use over the years were evaluated in this retrospective study, which included two consecutive cohorts of IBD patients in a real-world outpatient setting. The first cohort of patients, included between January 2016 and July 2018, was compared with a second cohort collected between October 2019 and December 2019.

Guselkumab plus golimumab combination therapy versus guselkumab or golimumab monotherapy in patients with ulcerative colitis (VEGA): A randomised, double-blind, controlled, phase 2, proof-of-concept trial

Feagan BG, Sands BE, Sandborn WJ, et al.

Lancet Gastroenterol Hepatol 2023;8:307–20.

Introduction

Despite a growing armamentarium of advanced therapies for Ulcerative Colitis (UC), fewer than 40% of patients maintain clinical remission at 12 months [1]. Combination therapy utilising dual biologic or small molecule agents can be considered in highly selected, medically refractory cases; however, robust data to support dual therapy in routine clinical practice are still lacking [2]. Inhibitors of TNF-α and IL-23 have demonstrated efficacy in the treatment of UC [3,4]. Data emerging from animal studies have suggested that their use in combination reduces colitis synergistically and may be more efficacious than treatment with either monotherapy [5].

This randomised double-blinded controlled phase 2 trial, named the VEGA trial, was conducted across 54 sites internationally and aimed to determine the efficacy and safety of combination therapy with guselkumab (GUS), an IL-23 p19 antagonist, plus golimumab (GOL), a TNF-α inhibitor, compared with either monotherapy in UC.

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.

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.

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.

Filgotinib for the treatment of small bowel Crohn’s disease: The DIVERGENCE 1 Trial

D’Haens GR, Lee S, Taylor SA, Serone A, Rimola J, Colombel JF; DIVERGENCE 1 Study Group.

Gastroenterology 2023;165:289–92.e3. doi: 10.1053/j.gastro.2023.03.234.

Introduction

Despite an increasing number of therapeutic options for patients with Crohn's Disease (CD), one-third of individuals develop intolerance or lose response to current pharmacological treatments, and up to half of patients require surgery within ten years of diagnosis. One of the reasons often highlighted for such figures has been the increasing understanding that different sub-types of CD may require different treatment approaches. Indeed, multiple clinical and molecular studies in recent years have demonstrated the differences between ileal and colonic CD in terms of pathophysiological mechanisms [1], as well as clinical features such as disease progression and treatment efficacy. In fact, although there is a lack of reported data on the comparative efficacy of biologics in achieving segment-specific healing in CD [2], evidence from observational studies and post-hoc analyses of interventional trials has shown that deep ulcers in the ileum are more challenging to heal than those located in the colon [3], with rates of endoscopic healing after one year of therapy ranging from 19% to 38% [4].

Faecal microbiota transplantation with anti-inflammatory diet (FMT-AID) followed by anti-inflammatory diet alone is effective in inducing and maintaining remission over 1 year in mild to moderate ulcerative colitis: a randomised controlled trial

Kedia S, Virmani S, Vuyyuru SK, et al.

Gut 2022;71:2401–13. doi: 10.1136/gutjnl-2022-327811.

Introduction

Microbiota are known to play a role in the pathogenesis of both Ulcerative Colitis (UC) and Crohn’s Disease (CD). Various lifestyle factors, including rural living, absence of antibiotic exposure and larger family size, have been associated with greater microbial diversity and lower risk for development of IBD [1, 2]. Conversely, dietary patterns and constituent elements of the diet have been linked to dysbiosis and increased risk of IBD [3, 4]. Despite these associations, the causal relationship between microbiota disturbance and IBD pathogenesis/disease flares remains unclear.

Current therapeutic strategies for IBD primarily focus on targeting the dysregulated immune response. However, these approaches have limitations, including a “ceiling effect” of current treatments and a high risk of relapse following withdrawal of therapy [5]. Consequently, there has been a growing interest in exploring alternative interventions, including through modulation of the gut microbiota or manipulation of dietary factors. Most of the evidence for such therapeutic approaches has focused on CD, including with the use of exclusive enteral nutrition [6]. In UC, microbiota modification has been attempted by faecal microbiota transplantation (FMT) in cohort studies and in randomised controlled trials. However, heterogeneous protocols, methods, donors, doses and intervals of FMT have all likely contributed to the conflicting evidence base for FMT in UC. Notably, however, a recent meta-analysis has suggested an overall clinical and endoscopic benefit of FMT, at least in the short term, in the treatment of UC [7].

Anti-integrin αvβ6 autoantibodies are a novel biomarker that antedate ulcerative colitis

Livanos AE, Dunn A, Fischer J, et al.

Gastroenterology 2023;164:619–29. doi: 10.1053/j.gastro.2022.12.042.

Introduction

Biomarkers for the prediction of disease onset and disease course in Ulcerative Colitis (UC) represent an ongoing and important area of unmet need. However, discovery and validation of such biomarkers has been complicated by the wide heterogeneity in disease presentation and variability in disease course [1]. Despite many initial biomarker discovery efforts in UC focusing on biopsy-based approaches, it has increasingly been recognised that non-invasive blood-based biomarkers would likely have more clinical utility, including because of their ease of collection and high rates of patient acceptance [2, 3].

Previous studies have discovered a novel autoantibody against integrin αvβ6 (anti-αvβ6) in the serum of UC patients, with strong discriminative ability for diagnosis of UC. Integrin αvβ6 plays a critical role in maintaining epithelial barrier integrity and suppressing epithelial inflammation [4–7].

Intestinal barrier healing is superior to endoscopic and histologic remission for predicting major adverse outcomes in Inflammatory Bowel Disease: The Prospective ERIca Trial

Timo Rath, Raja Atreya, Julia Bodenschatz, et al.

Gastroenterology 2023;164:241–55

Introduction

Mucosal healing (MH) in both Crohn's Disease (CD) and Ulcerative Colitis (UC) has been recognised as an important treatment target for many years. Indeed, the 2021 update of the Selecting Therapeutic Targets (STRIDE) consensus reaffirmed MH as the top priority among long-term treatment objectives [1]. Nonetheless, it is important to note that endoscopic inflammation may not always mirror the histological picture. Histological healing is an emerging endpoint in IBD. This is particularly true in UC, in which it represents a deeper level of recovery with some early evidence for correlation with better long-term outcomes; for CD, however, findings have been more controversial [2, 3]. Despite the increasing focus on histology, histological scoring systems are complex, with only two validated ones, both in the setting of UC, i.e. there is no validated scoring system in the context of CD.

Upadacitinib induction and maintenance therapy for Crohn’s disease

Loftus Jr EV, Panes J, Lacerda AP, et al.

N Engl J Med 2023;388:1966–80. doi: 10.1056/NEJMoa2212728.

Introduction

The management of Crohn’s Disease (CD) is dependent on many factors, including disease activity, site of involvement and the need to tailor treatment for each individual patient [1]. Moreover, features such as obstruction, fistulation, strictures and abscesses can all add to the complexity of CD management. While surgery has played a large role in the management of these patients, it is by no means a cure and the risk of relapse and repeat surgeries remains high [2, 3]. Accordingly, there continues to be a large unmet need for the development of novel medications that target distinct mechanisms of action in order to provide symptomatic and endoscopic control for patients with active disease. In parallel with this need to develop new medications, there has been an increasing desire for fast-acting medications, and movement towards oral administration, which may help both to reduce costs for hospitals and patients and to enhance aspects that are important to patients, such as quality of life and work productivity [4, 5].