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].
Withdrawal of immunomodulators or TNF antagonists in patients with inflammatory bowel diseases in remission on combination therapy: A systematic review and meta-analysis
Combination therapy with anti-TNF inhibitors (ATI) and immunomodulator (IMM) therapy remains an efficacious treatment strategy for disease control in moderate to severe Inflammatory Bowel Disease (IBD). This conclusion was largely based on the findings of landmark trials, SONIC and UC SUCCESS, which showed combination therapy to be far superior to monotherapy in achieving durable clinical and endoscopic remission in IBD [1, 2].
However, combination treatment with ATI and IMM can lead to increased risk of infection and malignancy. Whilst withdrawal of combination treatment once the patient is in disease remission can reduce the risk of treatment-related complications as well as the cost to health services, there remains a risk of relapse of previously controlled disease. At present there is no consensus amongst global clinical guidelines as to the appropriate duration of use of combination therapy. Thus, clinicians often find decisions related to withdrawal of treatment quite challenging.
The gut microbiota of patients with Inflammatory Bowel Disease (IBD) may have a role in disease aetiology and course [1]. Patients with IBD often have dysbiotic microbiota, with lower microbial diversity and cell counts, with both absolute and relative abundance of commensal microorganisms [2, 3]. Conversely, during remission following anti-inflammatory therapy, the gut microbiota has been observed to shift to a more eubiosis-like composition [3–6]. Furthermore, lower proportions of taxa with pro-inflammatory properties and mucus-degrading bacteria, as well as higher proportions of short-chain fatty acid-producing bacteria, have been associated with a higher likelihood of favourable outcomes with medical treatment [3, 5, 6]. In this study, Caenepeel and colleagues monitored changes in intestinal microbiota and stool features in order to develop and validate a predictive model to assist clinicians in determining a patient-specific therapeutic strategy.
The SONIC trial yielded seminal findings showing that the combination of infliximab and azathioprine is more effective than either treatment alone for the maintenance of remission in patients with Crohn’s Disease (CD) [1]. In recent years, despite the availability of an increasing number of biologics and small molecules to treat CD, a ceiling of therapeutic efficacy has been reached [2]. Therefore, there has been a resurgence of interest in whether this therapeutic ceiling “effect” can be overcome with new treatment combinations. In the EXPLORER study, the efficacy and safety of triple combination therapy was assessed using two biologics with different modes of action in association with methotrexate for the treatment of CD.
Higher intra-abdominal visceral adipose tissue mass is associated with lower rates of clinical and endoscopic remission in patients with inflammatory bowel diseases initiating biologic therapy: Results of the Constellation Study
Despite an expanding therapeutic arsenal, a considerable proportion of patients with Crohn's Disease (CD) and Ulcerative Colitis (UC) fail to achieve or sustain therapeutic responses [1, 2]. Mechanisms contributing to this failure, particularly with respect to biologic therapy, are only partially understood [3]. Uncovering the mechanisms behind loss of response may help to enhance the efficacy of existing treatment options or to develop alternative options for the future.
Some investigations have noted an association between obesity, high intra-abdominal visceral adipose tissue (IA-VAT) mass and unfavourable outcomes in individuals with Inflammatory Bowel Disease (IBD). However, these observations have been constrained by their methodology and have to date focused only on patients having treatment with anti-tumour necrosis factor alpha (anti-TNF-α) agents [4–6], limiting their scope.
The Constellation Study by Yarur and colleagues aimed to investigate the relationship between IA-VAT in patients with IBD and the response to biologic drugs with multiple different mechanisms of action.
Patients will often ask, “What causes Inflammatory Bowel Disease?” Frustratingly, we remain unable to answer this seemingly simple question, beyond the often-quoted paradigm that unknown environmental factors trigger inflammation in genetically susceptible individuals. Although our understanding of the immune response in IBD has reached phenomenally detailed levels of resolution, the nature and identity of the initial environmental triggers of IBD have continued to remain a mystery. The strong relationship between socioeconomic development and IBD incidence is tantalising evidence of a definable environmental toxin and various substances such as processed food additives have recently been highlighted as potential suspects [1]. However, searching for the causative agent is like looking for a needle in a haystack as the candidate list includes literally every small molecule in existence!
Submucosal injection of the RNA nucleotide GUT-1 in active ulcerative colitis patients: A randomized, double-blind, placebo-controlled phase 2a induction trial.
Atreya R, Kuhbacher T, Waldner M, et al.
J Crohns Colitis 2023. doi: 10.1093/ecco-jcc/jjad162. Online ahead of print.
Despite an increasing number of therapeutic options for Ulcerative Colitis (UC), many patients still have disease which progresses over time, and there has been renewed interest in and improved understanding of the chronic fibrosis and remodelling that occurs in UC [1–3]. In particular, there has been a growing appreciation of both the importance of the extracellular matrix (ECM) for remodelling in UC and the potential to target the ECM with new therapeutic agents [4]. One such target is carbohydrate sulphotransferase 15 (CHST15). This is a type II transmembrane Golgi protein that biosynthesises highly sulphated disaccharide units (E-units) of chondroitin sulphate, which binds to various functional proteins and pathogenic microorganisms. Targeting this molecule in mouse models has previously been shown to offer promising signals for ameliorating colitis [5]. Based on this promising pre-clinical data, blockade of CHST15 has emerged as a potentially promising therapeutic target, and such blockade can be achieved by a silencing RNA oligonucleotide molecule called GUT-1 (previously called STNM01). A prior phase I clinical trial demonstrated the safety of GUT-1 in patients with Crohn’s Disease [6]. Accordingly, Atreya and colleagues now sought to evaluate the safety, as well as the efficacy and mode of action, of GUT-1 in patients with UC as part of a phase IIa placebo-controlled, clinical trial.
