Acute severe ulcerative colitis trials: the past, the present and the future.

Acute severe ulcerative colitis (ASUC), characterised by bloody diarrhoea and systemic inflammation, is associated with a significant risk of colectomy and a small risk of mortality. The landmark trial of cortisone in 1955 was pivotal for two reasons: first, for establishing the efficacy of a drug that remains a first-line therapy today and, second, for producing the first set of disease severity criteria and clinical trial endpoints that shaped the subsequent ASUC trial landscape. Trials in the 1990s and at the turn of the millennium established the efficacy of infliximab and ciclosporin, but since then, there has been little progress in drug development for this high-risk population. This systematic review evaluates all interventional randomised controlled trials (RCTs) conducted in patients hospitalised with severe UC. It provides an overview of the efficacy of treatments from past to present and assesses the evolution of trial characteristics with respect to study populations, eligibility criteria and study designs over time. This review details ongoing RCTs in this field and provides a perspective on the challenges for future clinical trial programmes and how these can be overcome to help deliver novel ASUC therapies.

Ulcerative colitis.

Ulcerative colitis is a lifelong inflammatory disease affecting the rectum and colon to a variable extent. In 2023, the prevalence of ulcerative colitis was estimated to be 5 million cases around the world, and the incidence is increasing worldwide. Ulcerative colitis is thought to occur in people with a genetic predisposition following environmental exposures; gut epithelial barrier defects, the microbiota, and a dysregulated immune response are strongly implicated. Patients usually present with bloody diarrhoea, and the diagnosis is based on a combination of clinical, biological, endoscopic, and histological findings. The aim of medical management is, first, to induce a rapid clinical response and normalise biomarkers and, second, to maintain clinical remission and reach endoscopic normalisation to prevent long-term disability. Treatments for inducing remission include 5-aminosalicylic acid drugs and corticosteroids. Maintenance treatments include 5-aminosalicylic acid drugs, thiopurines, biologics (eg, anti-cytokines and anti-integrins), and small molecules (Janus kinase inhibitors and sphingosine-1-phosphate receptor modulators). Although the therapeutic options are expanding, 10-20% of patients still require proctocolectomy for medically refractory disease. The keys to breaking through this therapeutic ceiling might be the combination of therapeutics with precision and personalised medicine.

Effectiveness and Safety of Ustekinumab in Inflammatory Bowel Disease: A Systematic Review and Meta-Analysis.

INTRODUCTION: Ustekinumab, an interleukin-12 and interleukin-23 antagonist, is licensed for the treatment of Crohn's disease (CD) and ulcerative colitis (UC) after the phase III trial programs demonstrated efficacy over placebo. However, these findings may not be directly transferable to the real-world due to the stringent inclusion criteria of clinical trials. METHODS: We conducted a systematic review and meta-analysis of the safety and effectiveness of ustekinumab in inflammatory bowel disease (IBD). A systematic literature search was conducted via Medline and Embase from inception to April 21, 2020. Observational studies assessing ustekinumab's safety and effectiveness by reporting response, remission and/or adverse events (AE) in either CD or UC were included. Two reviewers independently assessed risk of bias and extracted study data. Random-effects meta-analysis was performed to pool rates of clinical response, remission, and safety data. RESULTS: Following deduplication, 2147 records were identified of which 41 studies (38 CD, 3 UC) comprising 4400 patients were included for quantitative analysis. Pooled clinical remission rates for CD were 34% (95% CI, 26%-42%) following induction and 31% (95% CI, 25%-38%) at one year. For UC, post-induction clinical remission rates were 39% (95% CI, 23%-56%). Serious AEs were reported in 5.6% of patients. Pregnancy outcomes were similar to the general population. One-third of patients with active baseline perianal disease responded or had fistula healing with ustekinumab. CONCLUSIONS: In the most comprehensive systematic review and meta-analysis to date, and the first to include UC, ustekinumab was shown to be effective and safe in the real-world treatment of IBD.

Positioning biologics and new therapies in the management of inflammatory bowel disease.

PURPOSE OF REVIEW: Since the advent of anti-tumour necrosis factor agents, knowledge of their optimal use and their pitfalls has grown exponentially. However, the range of therapeutic agents available to clinicians and patients is expanding, creating challenging decisions about which drugs to use at any given time point. The present review aims to provide a framework within which positioning decisions can be made in the context of limited comparative effectiveness data. RECENT FINDINGS: The present review will summarize the current literature emphasizing how best to use biologic agents, and will provide suggestions as to how they should be positioned. Recent trials comparing efficacy and safety will be considered as will their strengths and weaknesses. SUMMARY: On reading this review, clinicians should have an understanding of the optimal use of currently approved biologic agents and tofacitinib and how they might be positioned in relation to one another.

Target Trial Emulation: Improving the Quality of Observational Studies in Inflammatory Bowel Disease Using the Principles of Randomized Trials.

The past decade has seen a substantial increase in the number of randomized controlled trials (RCTs) conducted in inflammatory bowel disease (IBD). Randomized controlled trials are the gold standard method for generating robust evidence of drug safety and efficacy but are expensive, time-consuming, and may have ethical implications. Observational studies in IBD are often used to fill the gaps in evidence but are typically hindered by significant bias. There are several approaches for making statistical inferences from observational data with some that focus on study design and others on statistical techniques. Target trial emulation is an emerging methodological process that aims to bridge this gap and improve the quality of observational studies by applying the principles of an ideal, or "target," randomized trial to routinely collected clinical data. There has been a rapid expansion of observational studies that have emulated trials over the past 5 years in other medical fields, but this has yet to be adopted in gastroenterology and IBD. The wealth of nonrandomized clinical data available through electronic health records, patient registries, and administrative health databases afford innumerable hypothesis-generating opportunities for IBD research. This review outlines the principles of target trial emulation, discusses the merits to IBD observational studies in reducing the most common biases and improving confidence in causality, and details the caveats of using this approach.

Target trial emulation uses observational data to mimic the principles of an ideal or "target" randomized trial. This framework offers several opportunities to strengthen the quality of observational research in inflammatory bowel disease by reducing common sources of bias.

Navigating the complexities of drug development for inflammatory bowel disease.

Inflammatory bowel disease (IBD) - consisting of ulcerative colitis and Crohn's disease - is a complex, heterogeneous, immune-mediated inflammatory condition with a multifactorial aetiopathogenesis. Despite therapeutic advances in this arena, a ceiling effect has been reached with both single-agent monoclonal antibodies and advanced small molecules. Therefore, there is a need to identify novel targets, and the development of companion biomarkers to select responders is vital. In this Perspective, we examine how advances in machine learning and tissue engineering could be used at the preclinical stage where attrition rates are high. For novel agents reaching clinical trials, we explore factors decelerating progression, particularly the decline in IBD trial recruitment, and assess how innovative approaches such as reconfiguring trial designs, harmonizing end points and incorporating digital technologies into clinical trials can address this. Harnessing opportunities at each stage of the drug development process may allow for incremental gains towards more effective therapies.

Biomarkers in inflammatory bowel disease: a practical guide.

Inflammatory bowel disease (IBD), comprising ulcerative colitis (UC) and Crohn's disease (CD), is a costly condition in terms of morbidity and healthcare utilization, with an increasing prevalence now approaching 1% in the Western world. Endoscopic assessment of IBD remains the gold standard for diagnosis, evaluation of treatment response and determination of post-operative recurrence, but is expensive and invasive. Biomarkers can facilitate non-invasive disease assessment, with C-reactive protein and faecal calprotectin as the most widely available biomarkers in current clinical practice. This narrative review summarizes the evidence for their use in both UC and CD and offers practical guidance for healthcare providers taking into account the limitations of biomarker interpretation. We present evidence for the future use of novel biomarkers in IBD and discuss how biomarker discovery could deliver the goal of precision medicine in IBD.

Biomarkers in inflammatory bowel disease: a practical guide Inflammatory bowel disease (IBD) is a term used to describe two conditions, ulcerative colitis (UC) and Crohn's disease (CD). These two diseases cause inflammation of the bowel, which can lead to diarrhoea, abdominal pain and bleeding from the back passage. The best way of assessing how active a patient's IBD is, is by performing a camera test called a colonoscopy. However, having a colonoscopy is inconvenient, comes with some risks to the patient, and uses a lot of healthcare resources. 'Biomarkers' are proteins detectable in body fluids (such as blood, poo and urine) which can give information to medical staff about how active a patient's disease is, without the need for colonoscopy. In this article, we give guidance about how best to use these tests, and when they might not be so useful. We also discuss new biomarkers and ways in which they could be used in the future to predict which treatments patients might respond to best.

JAK inhibitors for inflammatory bowel disease: recent advances.

Inflammatory bowel disease (IBD) commonly requires immunosuppressive treatments to induce and maintain durable remission. Janus kinase inhibitors (JAKis) are a novel group of orally administered, small molecule drugs that work by attenuating multiple cytokine signalling pathways to mediate dysregulated immune responses involved in the pathogenesis of IBD. Tofacitinib, filgotinib and upadacitinib have demonstrated efficacy against placebo and are licensed for the treatment of moderate to severe ulcerative colitis; upadacitinib is the only JAKi also currently approved for the treatment of Crohn's disease. Safety concerns stratified by age have led to class-wide regulatory restrictions for JAKi use across all inflammatory diseases. It is important for gastroenterologists managing patients with IBD to be aware of the key pivotal trial outcomes, to identify appropriate patients in whom to commence a JAKi, and to understand the safety considerations and ways to mitigate these risks in the patients they treat. This review provides a contemporaneous overview of this emerging therapeutic class and provides a practical guide for healthcare practitioners for initiating and monitoring JAKi in IBD.

Amoebic colitis masquerading as inflammatory bowel disease for a decade.

Nil.

Review article: Externally derived control arms-An opportunity for clinical trials in inflammatory bowel disease?

BACKGROUND: One of the greatest challenges in the current IBD clinical trial landscape is, perhaps, the recruitment and retention of eligible participants. Seamless testing of promising investigational compounds is paramount to address unmet needs, but this is hindered by a number of barriers, particularly patient concerns of placebo assignment. AIMS: To review the use of novel trial designs leveraging externally derived data to synthetically create control groups or augment existing ones, and to summarise the regulatory position on the use of external controls for market authorisation. METHODS: We conducted a PubMed literature search without restriction using search terms such as 'external controls' and 'historical controls' to identify relevant articles. RESULTS: External controls are increasingly being used outside the context of cancer and rare diseases, including IBD, and increasingly recognised by regulatory bodies. Such designs, particularly in earlier phase trials, can inform key nodes in drug development and permit evaluating efficacy of interventions without combating the ethical and numerical enrolment challenges described. However, the lack of randomisation and blinding subjects them to significant bias. Groups require robust statistical and computational approaches to ensure patient-level data across groups are adequately balanced. CONCLUSIONS: While this approach has several pitfalls, and is not robust enough to replace traditional randomised, placebo-controlled trials, it may offer a compromise to address key research questions at a more rapid pace, with fewer patients, and lower cost.

An update on the safety of long-term vedolizumab use in inflammatory bowel disease.

INTRODUCTION: Vedolizumab (Entyvio) is a humanized monoclonal antibody that disrupts the interaction between α4ß7 integrin on circulating T-lymphocytes and MAdCAM-1 on the vascular endothelium to prevent their egress to sites of gut inflammation. It has proven therapeutic efficacy for the treatment of moderate-to-severe Crohn's disease, ulcerative colitis, and pouchitis. AREAS COVERED: This narrative review assesses the safety profile of vedolizumab from the registration trial programs, open-label extension studies, observational real-world data, and pooled safety analyses. This includes an evaluation of the long-term overall safety in special populations typically underrepresented in clinical trials. EXPERT OPINION: Vedolizumab is an effective therapy for inflammatory bowel disease with a well-established safety profile. No unexpected long-term safety signals have been identified. Safety data in pregnancy, in pediatric and elderly populations, in patients undergoing surgery, and in patients with a prior history of cancer are reassuring. Due to its safety merits, we propose that vedolizumab is an excellent candidate for advanced combination treatment with an anti-cytokine approach using another biologic or novel small molecule inhibitor. This is important in patients with medically refractory IBD, in patients at high risk of developing disease-related complications, or in patients with concomitant uncontrolled immune-mediated inflammatory diseases.

JAK inhibitors for the treatment of inflammatory bowel disease: results of an international survey of perceptions, attitudes, and clinical practice.

BACKGROUND: Janus kinase inhibitors (JAKi) are small molecule drugs with demonstrated efficacy in inflammatory bowel disease (IBD). However, widespread utilisation may be hindered by safety concerns. AIMS: This is the first study assessing risk-benefit perceptions and clinical practices of those using JAKi for IBD. METHODS: A prospective, cross-sectional study was conducted using a 23-item survey distributed to IBD healthcare providers worldwide. RESULTS: Of 385 respondents from 48 countries, 72% were tertiary-centre based and 50% were gastroenterologists with ≥10 years experience. JAKi were commonly used outside market authorisation (31%), though many (17%) were unconfident discussing JAKi risk-benefit profile and 7% had never prescribed JAKi. If venous thromboembolism risks were present, 15% preferentially referred for surgery than initiate JAKi; 21% would do this even if the patient was already anticoagulated. For patients relapsing on dose reduction, 8% would switch treatment rather than dose escalate. Conversely, 45% felt that cardiovascular safety concerns from post-marketing studies were irrelevant to IBD. Despite the lack of detailed, long-term safety data, safety profiles of JAK1-selective drugs were perceived to be favourable to tofacitinib by most (62%). CONCLUSION: The study indicates that while clinical practice appears to be in keeping with international guidance, a significant minority remain deterred by safety concerns.

Are All Janus Kinase Inhibitors for Inflammatory Bowel Disease the Same?

Ulcerative colitis and Crohn's disease are chronic, progressive inflammatory bowel diseases (IBDs) and are without a known cure. Janus kinase (JAK) is a family of cytosolic tyrosine kinases that mediate signal transduction in response to extracellular stimuli. Abrogating the proinflammatory cytokine signaling cascades using JAK inhibitors (jakinibs) has been shown to be highly effective in the treatment of numerous inflammatory diseases, including IBD. Jakinibs currently licensed for moderate-to-severe IBD include the first-generation, nonselective tofacitinib and the second-generation JAK1-selective inhibitors filgotinib (licensed outside of the United States) and upadacitinib; several other jakinibs in the therapeutic pipeline are in various stages of clinical development. The jakinib class of small-molecule drugs share numerous commonalities such as their oral administration, nonimmunogenicity, short half-life, rapid onset of action, and the same class-wide regulatory restrictions owing to safety concerns. However, jakinibs differ on several fronts, translating into important clinical practice points for health care providers managing IBD patients. This article provides an overview of the jakinib class in IBD, examines how each drug differs in terms of pharmacology as well as efficacy and safety, and offers perspectives on challenges that remain and future opportunities.

Patient and Public Involvement in Research: Lessons for Inflammatory Bowel Disease.

Participatory research, also referred to as patient and public involvement, is an approach that involves collaborating with patients affected by the focus of the research, on the design, development and delivery of research to improve outcomes. There are two broad justifications for this: first, that it enhances the quality and relevance of research, and second, that it satisfies the ethical argument for patient inclusion in decisions about them. This synergistic and collaborative effort, which bridges the divide between researchers and participants with the lived condition, is now a mainstream activity and widely accepted as best practice. Although there has been a substantial increase in the literature over the past two decades, little has been published on how participatory research has been used in inflammatory bowel disease [IBD] research and little guidance as to how researchers should go about this. With an increasing incidence and prevalence worldwide, combined with declining study enrolment in an era of perennial unmet need, there are a multitude of benefits of participatory research to IBD patients and investigators, including research output that is informed and relevant to the real world. A key example of participatory research in IBD is the I-CARE study, a large-scale, pan-European observational study assessing the safety of advanced therapies, which had significant patient involvement throughout the study. In this review, we provide a comprehensive overview of the benefits and challenges of participatory research and discuss opportunities of building strategic alliances between IBD patients, healthcare providers and academics to strengthen research outcomes.

Positioning intestinal ultrasound in a UK tertiary centre: significant estimated clinical role and cost savings.

Objective: Intestinal ultrasound (IUS) is an inexpensive, non-invasive method of diagnosing and monitoring inflammatory bowel disease (IBD). We aimed to establish the proportion of lower gastrointestinal endoscopies (LGIEs) and magnetic resonance enterographies (MREs) that could have been performed as IUS, the potential pathology miss-rates if IUS was used and the associated cost savings. Methods: All MREs and LGIEs performed for either assessment of IBD activity or investigation of possible IBD, performed at a single UK tertiary centre in January 2018, were retrospectively reviewed against predetermined criteria for IUS suitability. Case outcomes were recorded and cost of investigation if IUS was performed instead was calculated. Results: 73 of 260 LGIEs (28.1%) and 58 of 105 MREs (55.2%) met the criteria for IUS suitability. Among potential IUS-suitable endoscopy patients, one case each of a <5 mm adenoma and sessile serrated lesion were found; no other significant pathology that would be expected to be missed with IUS was encountered. Among IUS-suitable MRE patients, no cases of isolated upper gastrointestinal inflammation likely to be missed by IUS were found, and extraintestinal findings not expected to be seen on IUS were of limited clinical significance. The predicted cost saving over 1 month if IUS was used instead was £8642, £25 866 and £5437 for MRE, colonoscopy and flexible sigmoidoscopy patients, respectively. Conclusion: There is a significant role for IUS, with annual projected cost savings of up to almost £500 000 at our centre. Non-inflammatory or non-gastrointestinal pathology predicted to be missed in this cohort was of limited clinical significance.

How achievable are STRIDE-II treatment targets in real-world practice and do they predict long-term treatment outcomes?

Objective: The second iteration of the Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE-II) initiative recommends use of the Simple Endoscopic Score for Crohn's disease (SES-CD) as a treatment target for patients with CD. We aimed to assess whether the STRIDE-II endoscopic endpoints are achievable and whether the degree of mucosal healing (MH) affects long-term outcomes. Design/method: We performed a retrospective observational study between 2015 and 2022. Patients with CD who had baseline and follow-up SES-CD scores after biological therapy initiation were included. The primary outcome was treatment failure, defined as the need for: (1) change of biological therapy for active disease (2) corticosteroid use (3) CD-related hospitalisation or (4) surgery. We compared rates of treatment failure with the degree of MH achieved. Patients were followed up until treatment failure or study end (August 2022). Results: 50 patients were included and followed up for median 39.9 (34.6-48.6) months. Baseline characteristics: 62% male, median age 36.4 (27.8-43.9) years, disease distribution (L1: 4, L2: 11, L3: 35, perianal: 18). The proportion of patients achieving STRIDE-II end-points were: SES-CD≤2-25 (50%) and >50% reduction in SES-CD-35 (70%). Failure to achieve SES-CD≤2 (HR 11.62; 95% CI 3.33 to 40.56, p=0.003) or >50% improvement in SES-CD (HR 30.30; 95% CI 6.93 to 132.40, p<0.0001) predicted treatment failure. Conclusion: Use of SES-CD is feasible in real-world clinical practice. Achieving an SES-CD≤2 or a greater than 50% reduction, as set out by STRIDE-II, is associated with reduced rates of overall treatment failure including CD-related surgery.

Anogenital Crohn's Disease and Granulomatosis: A Systematic Review of Epidemiology, Clinical Manifestations, and Treatment.

BACKGROUND AND AIMS: Metastatic Crohn's disease is an extraintestinal cutaneous manifestation characterised by non-specific inflammatory lesions anatomically separate from the gut; genital involvement is rare. We conducted a systematic review of anogenital Crohn's disease and granulomatosis, to provide a synthesis of epidemiology, clinical features, and treatment outcomes. METHODS: A systematic search of the literature was conducted via MEDLINE, EMBASE, and the Cochrane database from inception to December 1, 2020. Two investigators extracted and analysed study data. Response and remission were defined as partial improvement or complete resolution of symptoms and examination findings, respectively. RESULTS: Of 9381 screened studies, 185 articles, [410 cases: 273 female, 137 male] were included. The predominant clinical features were oedema, ulcers, fissures, and hypertrophic lesions. Adults and children present similarly. Luminal Crohn's disease was diagnosed in nearly 80% of cases including 45-80% patients without gastrointestinal symptoms (time to inflammatory bowel disease [IBD] from anogenital Crohn's disease diagnosis [range] -43 to 11 years). Antibiotics, corticosteroids, thiopurines, and anti-tumour necrosis factor [TNF] therapy were the most frequently prescribed agents. At final follow-up, non-response, response, and remission rates were 37/304 [12%], 267/304 [88%], and 114/304 [38%], respectively. Oedema was associated with a poor response to topical therapy. Greater response rates to anti-TNF therapy were seen in patients prescribed concomitant immunomodulation [24/25, 96% vs 67/90, 74%, p = 0.02]. CONCLUSIONS: We provide an illustrative summary of the clinical presentation and treatment effectiveness of this rare, under-recognised condition, and a proposed algorithm for approach and management. Prospective studies with longer follow-up are required to define optimal treatment strategies.

Ustekinumab for the treatment of moderate to severe ulcerative colitis: a multicentre UK cohort study.

Objective: Ustekinumab is an interleukin-12/interleukin-23 receptor antagonist licensed for the treatment of ulcerative colitis (UC). Clinical trial data were promising; however, real-world data are limited. We assessed the safety and effectiveness of ustekinumab in UC in a real-world setting. Design/method: This was a multicentre, retrospective, observational cohort study between February 2020 and January 2022. Disease activity was assessed using the Simple Clinical Colitis Activity Index (SCCAI). Clinical remission was defined as a SCCAI≤2. The primary endpoints were rates of corticosteroid-free remission (CSFR) at week 16 and at week 26. Objective outcomes, including faecal calprotectin (FCAL), were also collected. Results: 110 patients with UC (65% male; median age 40 (IQR range 29-59); 96% with prior biologic and/or tofacitinib exposure) had a median follow-up of 28 weeks (IQR 17-47). CSFR was 36% (18/50) at week 16% and 33% (13/39) at week 26, corresponding with a significant fall in SCCAI from 6 (IQR 4-8) at baseline to 3 (IQR 0-5) at week 26, p<0.001. By week 16, there was improvement of median FCAL measurements, which fell from a baseline of 610 µg/g (IQR 333-1100) to 102 µg/g (IQR 54-674) at week 16. At the end of follow-up, 15% (17/110) had discontinued treatment; 13 patients due to primary non-response or loss of response, and 1 patient for family planning. Treatment was discontinued in three patients due to adverse events. Conclusion: In the largest real-world study to date, ustekinumab was effective with a reassuring safety profile in a refractory cohort of patients.