Genome‐wide association studies (GWAS) have identified several susceptibility loci believed to predispose individuals to Inflammatory Bowel Disease (IBD) [1]. However, to translate the discovery of these risk loci into meaningful improvements in disease management or prevention, it is vital to understand how risk variants impact upon disease development and inflammatory processes [2]. In this regard, a non-coding risk locus on chromosome 21q22 had previously been linked to multiple immune-mediated inflammatory diseases, including IBD, primary sclerosing cholangitis (PSC), axial spondyloarthropathy and Takayasu’s arteritis; however, no causal gene was identified [3–6]. Stankey and colleagues sought to use functional genomics to identify the causal gene and investigate its role at cellular and metabolic levels, with the goal of revealing potential therapeutic targets.
Postoperative recurrence (POR) in Crohn’s Disease (CD) remains a significant clinical challenge. Surgical resection is often necessary to manage complications such as strictures, fistulas and abscesses, and disease recurrence is common in many patients without prophylactic treatment. Despite advances in surgical and medical management, recurrence rates remain alarmingly high. Endoscopic recurrence can occur in up to 90% of patients within one year of ileocolonic resection if left untreated , while clinical recurrence, typically defined in clinical trials using the Crohn’s Disease Activity Index (CDAI), occurs in up to 40% of patients within 12 months of surgery [1]. These rates underscore the importance of developing effective strategies to prevent disease recurrence and enhance long-term patient outcome. Ileocolonoscopy is the gold standard for diagnosing postoperative recurrence, as it defines the presence and severity of morphological recurrence. Both European and American guidelines recommend endoscopic monitoring within 6–12 months after surgery to evaluate for POR and guide treatment decisions, regardless of pharmacological prophylaxis [2, 3].
Current guidelines suggest using clincial predictors of early postoperative recurrence after ileocolonic resection to guide treatment. These potential predictors include smoking status, prior intestinal surgery, absence of prophylactic treatment, penetrating disease at index surgery, perianal location, granulomas in the resection specimen and myenteric plexitis. For patients with at least one of these risk factors, prophylactic treatment is strongly advised, with thiopurines or anti-TNFs historically being used as the preferred options to reduce the risk of recurrence [2]. Vedolizumab, a gut-selective integrin antagonist, has emerged as a promising alternative. D’Haens and colleagues conducted the first placebo-controlled clinical trial to date to assess the efficacy and safety of vedolizumab in reducing both the incidence and the severity of POR in patients with CD.
The therapeutic landscape for Inflammatory Bowel Disease (IBD) is rapidly evolving, with the introduction of new advanced therapies. Despite these advances, there is an absence of head-to-head clinical trial data to support decision-making regarding the choice and sequencing of drugs – with evidence often being extrapolated from indirect comparisons between single-agent clinical trials or observational studies [1]. This is well highlighted by the fact that there is often a lack of data to support choice of medication after first-line use of anti-tumour necrosis factor (TNF) agents. Ustekinumab is a humanised IgG1 monoclonal antibody that selectively binds to the p40 subunit and was approved for the treatment of Crohn’s Disease (CD) several years ago. Risankizumab, which was approved more recently, is also an IgG1 monoclonal antibody, but it selectively binds to the p19 subunit. Both p19 and p40 are components of the interleukin-23 (IL-23) proinflammatory cytokine, which plays a crucial role in skin, joint and gastrointestinal inflammation [2]. Peyrin-Biroulet and colleagues sought to undertake a direct head-to-head comparison of ustekinumab with risankizumab for patients with CD after failure of anti-TNF therapy.
Safety and efficacy of autologous haematopoietic stem-cell transplantation with low-dose cyclophosphamide mobilisation and reduced intensity conditioning versus standard of care in refractory Crohn's disease (ASTIClite): an open-label, multicentre, randomised controlled trial
A large number of patients living with Inflammatory Bowel Disease (IBD), including Crohn’s Disease (CD), show persistent disease activity and bowel damage despite medical or surgical therapy [1]. Haematopoietic stem-cell transplantation (HSCT) is a procedure able to “reset” the immune system by replacing autoreactive lymphocytes. A total of 232 patients (data from case series, observational studies and one clinical trial) had previously undergone HSCT for CD. Although there were promising clinical results, there were also some significant associated risks, including life-threatening side effects and mortality [2]. In a previous randomised controlled trial, called ASTIC, HSCT did not demonstrate superiority over standard therapy when an extremely high bar was set for the primary endpoint, i.e. induction of sustained disease remission in CD (defined as medication-free clinical remission for 3 months without any evidence of disease activity at endoscopy or imaging). Apart from the lack of efficacy demonstrated for the primary endpoint, the HSCT arm was also hampered by a significant burden of side effects [3].
Ulcerative Colitis (UC) is characterised by episodes of recurrent inflammation affecting the colonic mucosa. Accurate assessment of disease activity and prediction of clinical outcomes are crucial for effective management. Traditionally, histological examination has been the gold standard for evaluating mucosal inflammation, but it is time-consuming and subject to inter-observer variability. Recent advances in artificial intelligence (AI) may offer a potential solution. Iacucci and colleagues explored the application of machine learning in diagnosing histological remission and predicting clinical outcomes in UC patients.
Patients with colonic inflammatory bowel disease (IBD) face an elevated risk of colorectal cancer (CRC) compared to the general population.[1, 2] Colonoscopic surveillance has been shown to be associated with a reduction in CRC and CRC-related mortality in these patients.[3] Current guidelines recommend initiating surveillance 8-10 years after disease onset, with follow-ups every 1-5 years based on individual risk factors.[4–6] These factors include disease duration, severity, associated primary sclerosing cholangitis (PSC), family history of CRC, and other risks. The risk factors for CRC in IBD patients are dynamic, comprising both modifiable (inflammation, dysplasia detection, disease extent) and non-modifiable (age, family history, PSC) elements that change over time and with treatment, exerting varying influences, including protective effects, on the risk of developing CRC.[7]
A biomarker-stratified comparison of top-down versus accelerated step-up treatment strategies for patients with newly diagnosed Crohn’s disease (PROFILE): a multicentre, open-label randomised controlled trial
There is debate on the optimal management of newly diagnosed active Crohn’s Disease (CD). The most commonly used treatment strategy around the world is a “step-up” treatment approach. This involves initial use of steroids at diagnosis to induce remission, followed by introduction of immunomodulators such as azathioprine to maintain that remission. Subsequently, if this treatment fails to control inflammation, patients are escalated to advanced therapies such as anti-TNF biological agents. When performed rapidly, this can be referred to as “accelerated step-up” treatment, and indeed in many countries this accelerated step-up approach is considered standard of care (conventional) treatment. An alternative treatment strategy is a more “top-down” approach , where there is early introduction of an advanced therapy, typically an anti-TNF agent.
Inflammatory Bowel Diseases (IBD), comprising the two most common subtypes of Crohn's Disease (CD) and Ulcerative Colitis (UC), are chronic inflammatory conditions of the gastrointestinal tract. Tumour necrosis factor (TNF) inhibitors, particularly infliximab, have been pivotal in the management of moderate to severe IBD. While effective, intravenous administration of infliximab typically involves regular visits to hospital-based infusion centres. Particularly from a patient convenience point of view, many individuals would prefer to administer medication at home without the need to attend infusion centres and without the need for intravenous administration. The development of a subcutaneous (SC) formulation of infliximab (CT-P13) aims to enhance patient convenience and adherence by allowing self-administration at home [1–3] . In the LIBERTY trials, Hanauer and colleagues sought to examine the efficacy and safety of CT-P13 SC as maintenance therapy in IBD, in two randomised, placebo-controlled phase 3 trials.
At present, disease activity in Inflammatory Bowel Disease (IBD) is primarily monitored using faecal calprotectin, serum C-reactive protein (CRP) and endoscopic examination [1]. Whilst these are powerful tools, all three approaches have notable limitations. Faecal calprotectin testing requires a patient either to provide a stool sample whilst attending clinic or to return with a sample at a later date. Serum CRP requires a blood sample to be taken by a healthcare professional and endoscopy is invasive. Interleukin (IL)-6, whilst not routinely used in clinical settings to monitor disease activity, is known to play a role in IBD pathogenesis by increasing T-cell resistance against apoptosis, resulting in chronic inflammation [2].
Increased versus conventional adalimumab dose intervals for patients with Crohn’s disease in stable remission (LADI): a pragmatic, open-label, non-inferiority, randomised controlled trial
van Linschoten RCA, Jansen FM, Pauwels RWM, et al.
Adalimumab is an effective and safe treatment for Crohn’s Disease (CD). However, both patients and healthcare professionals may wish to mitigate medication exposure due to potential safety and economic concerns in the long term. Since a high relapse rate follows drug discontinuation, treatment de-escalation without actually stopping the medication may allow for decreasing drug exposure while maintaining efficacy. In two observational studies, de-escalation from a 2-week to a 3-week adalimumab dosing interval was successful in most of the patients, though reversal to a 2-week dosing interval was required in about 30% due to insufficient disease control [1, 2]. The Lengthening Adalimumab Dosing Interval (LADI) study is a pragmatic, open-label, multicentre, non-inferiority, parallel, randomised controlled trial conducted in the Netherlands and specifically designed to address this knowledge gap [3].
