Nuru Noor:Department of Medicine, University of Cambridge School of Clinical Medicine, UK
Citation: EMJ Gastroenterol. 2026; https://doi.org/10.33590/emjgastroenterol/9FS0VEWRJ
The 5-year follow-up of PROFILE1 provides what you describe as some of the most robust evidence to date that the course of Crohn’s disease can be modified. What do the longer-term data tell us that the original trial could not?
The original trial focused on sustained remission, including clinical and biochemical remission, and endoscopic remission at the end of 1 year. Indeed, we saw the highest levels of remission reported in any Crohn’s disease trial in the early effective ‘top-down’ therapy arm.2 It is important to clarify that early treatment, ‘top-down’ treatment, and others terms get used a lot but can often mean different things. In PROFILE, the early ‘top-down’ treatment arm consisted of intravenous infliximab in combination with an immunomodulator, started as soon as possible after diagnosis. Despite the large benefit seen at the end of Year 1, a key question has been whether there would be a sustained benefit of early treatment in the longer-term. Now, the 5-year data show that patients treated with early effective therapy from diagnosis also have substantially reduced risks of abdominal surgery, progression to complicated disease phenotypes, and fewer hospital admissions, all being what we call disease modification outcomes.3 This provides strong evidence that the course of Crohn’s disease can be modified if we start early effective therapy, from the point of diagnosis.
PROFILE showed that early effective treatment from diagnosis can reduce complications and improve long-term outcomes. How should these findings change the way clinicians approach a patient who has just been diagnosed with Crohn’s disease?
When a patient is diagnosed with moderate or severe Crohn’s disease, historically there was always a concern about whether they would need treatment or not, and whether they might be overtreated with early use of advanced therapies. We have shown that moderate or severe Crohn’s disease is not a benign condition. Without treatment, it inevitably progresses for the majority of patients. PROFILE, and other recent studies, provide really helpful data for clinicians and patients to show that the clock is ticking at the point of diagnosis, and that the safest and most effective treatment strategy for patients is to control inflammation as effectively as possible, as soon as possible.
What do we need to demonstrate before we can confidently say that an intervention is genuinely modifying the course of Crohn’s disease, rather than simply controlling disease activity while treatment continues?
This is a good question. The concept of disease modification has been used for many years, but it is only in recent years that we have had an international consensus from the International Organization for the Study of Inflammatory Bowel Disease (IOIBD) about what this might mean in inflammatory bowel disease (IBD). Specifically in Crohn’s disease, the international consensus felt that hard, objective outcomes would be needed to provide evidence of disease modification, including reduced risk of abdominal surgeries, reduced progression to more complicated phenotypes, and reduced hospital admissions. There are other potential disease modification outcomes reported, such as reduced used of corticosteroids, although as most people will recognise, there is a lot more subjectivity associated with this outcome. While other studies have previously suggested signals for possible disease modification in Crohn’s disease, PROFILE is the first study to robustly show that early effective intervention reduced all these key disease modification outcomes, providing perhaps the strongest evidence to date that it is possible to alter the natural history of Crohn’s disease.3
You have highlighted the need for more pragmatic, investigator-led trials in IBD. What kinds of questions can these studies help answer that conventional drug-development trials may not, and why are these questions important for clinical practice?
This is a question very close to my heart. It is important to state that commercial trials are extremely important to generate data to support regulatory submissions and licensing of novel therapies and mechanisms of action. Such trials have to be explanatory and meet very strict regulatory standards. However, these commercial trials often have narrow eligibility criteria, highly artificial trial protocols, and are often conducted in specialised IBD centres. On the other hand, pragmatic trials are typically much more inclusive, and can also broaden the understanding of treatments beyond the narrow eligibility criteria of explanatory, Phase III trials. Pragmatic trials typically aim to inform healthcare policy or practice, and crucially they can allow evaluation of treatment strategies.4 Increasingly, we are learning that the way we use our treatments and management strategies might be just as important as having more treatments, and maybe even more so.
Your recent work has explored adaptive platform trials, Bayesian approaches, and more efficient trial designs. How could these innovations help us evaluate multiple treatment strategies more quickly and generate evidence that is more relevant to individual patients?
In clinical trials, there is a desire for more efficiency. That word is used frequently, but has different meanings to different people. Efficiency in clinical trials typically refers to faster answers for patients and clinicians, smaller and cheaper trial programmes, and more patient-centred protocols. These are some of the big challenges we face in IBD clinical trials today. Adaptive trials, Bayesian approaches, and master protocols, including platform trials, help offer solutions to many of these challenges. We are slowly seeing some of the innovations being used in IBD nowadays, but if we want more efficiency, then we need to accelerate our use of these more novel trial designs and methods.
PROFILE has the potential to change treatment practice, but changing clinical practice can be harder than generating the evidence. What are the biggest barriers to implementing early effective treatment for Crohn’s disease across routine healthcare systems?
This is arguably the most important aspect of any research: how can the findings be used to improve outcomes and care for patients around the world? Too often we see research studies published in big journals and then no translation to benefitting patients. This gap is a major problem. Although we reported efficacy and safety findings, cost is a major barrier in many countries. So, we also completed a formal health economic analysis, which showed that early treatment is not only safer and more effective for patients, but crucially also cheaper for healthcare services and payers.5 This has been important to help convince payers to fund early initiation of treatment for patients. Guidelines have also often been criticised for being slow to adjust, but we have seen an almost immediate uptake of the PROFILE findings in guidelines. Indeed, all major international guidelines, including the European Crohn’s and Colitis Organisation (ECCO), the British Society of Gastroenterology (BSG), the American Gastroenterological Association (AGA), and the American College of Gastroenterology (ACG) now all recommend early initiation of effective therapy as the standard of care for patients presenting with moderate or severe Crohn’s disease, and they all cite PROFILE as being one of the major sources of evidence for this recommendation.6-9 However, even despite updates to guidelines, we see that changing clinical practice can still be difficult. We are working closely with patients and patient groups, as well as clinicians, to work even more on helping overcome the implementation gap, so that as many patients can benefit from this research as possible.
With the field moving towards disease modification, more innovative trial designs, and increasingly personalised treatment strategies, what is the most important unanswered question in Crohn’s disease research now?
There are still so many important questions to answer in Crohn’s disease. An important area relates to prevention and possibly even a cure. We have seen that the best outcomes reported for patients today are from studies where treatment is started as soon as possible after diagnosis. This has driven interest in whether it might be possible to deliver even better outcomes by intervening before diagnosis, in what is termed ‘pre-clinical Crohn’s disease’. The ongoing INTERCEPT project10 represents a major step in this direction, aiming to determine if Crohn’s disease can be modified even before it manifests clinically. INTERCEPT and other related projects are very exciting and will hopefully provide insights into our long-term aspiration for prevention and cure. However, it is important to state that there are numerous uncertainties regarding pre-clinical disease management, including what would be the safest, most effective, and most acceptable interventions for patients, and at what different stages of pre-clinical Crohn’s disease might these interventions be used. So, in summary, there has been lots of progress, but there is still lots of work for us all to do to help improve the lives of people living with Crohn’s disease and to address these ongoing, unanswered questions.
