Thoughts on preventing IBD, curing IBD and eliminating disease flares.
“Not to assume it’s impossible because you find it hard. But to recognize that if it’s humanly possible, you can do it too.” Marcus Aurelius
There is a lot of talk about finding a cure for IBD. What might this look like? IBD is more than just Crohn’s disease and ulcerative colitis … it is a spectrum of heterogenous of clinical, environmental, microbiological, immunology and molecular pathways that combine to present in different ways in every single person who becomes unwell. Currently we apply the same treatment pathways to nearly all patients, sub-divided by relatively crude parameters. Therapeutics are certainly getting better and the drug pipeline looks very healthy. And for some (many) people we’re now doing a really great job — inducing deep remission (where symptoms AND inflammation go away), normalising life and preventing long-term complications.
But we have a problem. All new medicines for IBD seems to be hitting a ceiling at about 30–40% remission rates. Potential game-changes such stem-cell and faecal transplants once promised cures, but in reality they have fallen a long way short. Most drugs are characterised in placebo-controlled trials so it is difficult to know which work better than others in certain situations.
But, we do now at least have multiple different agents that work by different mechanisms of action. Surely then it’s just up to us to work out which drug to give which patient? And yes, it would be great to take some of the guesswork out of this. But, it will require a substantial effort to systematically address this in very well characterised prospective cohorts with detailed molecular phenotyping. If that works how close does that get us? And that is genuinely an unanswered question. Will we get closer with combinations of different drugs? Targeting multiple pathways at once? For now, cost probably precludes this model … small molecules that can be manufactured more cheaply than monoclonal antibodies may change that.
If we can accurately stratify patients at diagnosis by their RISK profile and their underlying disease BIOLOGY and then get them on the right drug (or combination) the first time? Minimise time with damaging active inflammation, minimise drug toxicity, maximise quality of life. We know already that using effective drugs earlier in disease maximises benefit: “the inflammatory window of opportunity” #timeisgut
This is the current paradigm. And with such a healthy drug pipeline it will continue to effect step-wise improvements. But it will not lead to a cure.
What about prevention? What would that look like? We’d need to first have a really good idea about what causes Crohn’s disease and ulcerative colitis. We are getting better at understanding this … altered immune responses to gut microbiome / environmental stimuli in genetically susceptibility individuals.
But we can’t yet use any of these details to predict who will get IBD. But if we could? We’d then need to figure out what to do about it. How would we negate the risk? Tablets? Microbial manipulation? Targeted dietary therapies? How individually tailored would they need to be? (probably very). How long would the “at risk” state last? (probably indefinitely unless we could find a way to ‘reset’ the immune risk). Big studies like GEM (www.gemproject.ca) are part of the answer here. Prospectively followed cohorts who are healthy at the time of sampling. Either pick an at risk group (in GEM the subjects were young healthy first degree relatives of people with Crohn’s disease) or simply follow a very large cohort of healthy young people. Age is important here. The big biobanks (like UK Biobank) are great for picking up diseases of ageing (e.g. cancer and heart disease and dementia) but not so useful for immune-mediated diseases that affect young people. This is a challenge for the research community and the funding bodies to rise to together.
OK, cure and prevent remain worthy, but lofty goals. Yet they look to be a long way off. And what we’re doing just now, with all the best intent, falls a long way short of ideal. Put simply we’re failing too many people with IBD who need something different soon.
So here’s my thinking. If we can’t prevent IBD the prevalence will continue to rise across the world (urbanisation and westernisation is clearly driving this). We then need to
1) raise awareness (this is going well, but much but work to do)
2) ensure rapid diagnosis and specialty referral
3) phenotype and stratify to induce remission
4) “treat to target” to ensure resolution of symptoms and underlying disease activity … and then …
5) prevent disease flares.
Along this journey it is my belief that we should make clinical research the norm and not the exception. Where there is equipoise between two treatments patients should be offered a clinical trial so we can collect the data. Where there is uncertainty about treatment strategies, we should randomise different approaches and collect the data. Systematic of data collected in real-time should become normal practice. To enable this we need to offer robust solutions for data collection. The technology is now available to do this. There is rapidly becoming no excuse. Healthcare professionals can no longer say they are too busy to help with research when clinical research is deeply embedded into treatment pathways. This is a change in mind-set. This is a challenge. But it is one we must rise to. And to maximise benefit we need clinical, academic and commercial partners working in close collaboration.
Of course, this is then where the PREdiCCt programme of work fits in (www.predicct.co.uk). First step, characterise who gets disease flares, and when, and then work out what causes them and how to prevent them.
Get people well, keep them well, stop the disease from flaring.
This will require medical therapy for many but not for all. It may become much clearer when we understand the underlying clinical and molecular characteristics that define those patients in favourable remission state (i.e. one that is at low risk of flaring). Then we can target therapeutic interventions, for example to ‘normalise’ the microbiome (perhaps by tailored dietary therapies).
And in the meantime, I think it is really important we empower patients by providing them with a curated version of their medical notes, with robust symptom and disease activity tracking and hyper-personalised sign-posting. Integrated digital health care solutions, mobile apps, point-of-care testing, wearables, machine learning, AI algorithms. Within PREdiCCt we are testing some of this technology. We are developing platforms for research on a very large scale. To realise the ambitions stated above.
And so, there is lots to do. But there are reasons to be optimistic. Join us in this journey. We prepare to stand up and be judged by our actions not by our intentions.
“Everything that is not forbidden by laws of nature is achievable, given the right knowledge.” David Deutsch
“Those who are governed by reason desire nothing for themselves which they do not also desire for the rest of humankind.” Baruch Spinoz