Friday 19th May 2017

A few words of hope to the millions of people around the world living with Crohn’s disease and ulcerative colitis. A rallying cry to the many healthcare professionals looking after people with inflammatory bowel disease.

Already IBD affects more than 1 in 200 individuals in the Western world; this number continues to increase. Across the traditional ‘developing’ world, IBD is beginning to emerge with alarming speed. Global epidemiological trends paint a very clear picture – IBD is becoming a true pandemic.

Whilst we still do not know what causes IBD, we are getting much better at understanding how the different pieces of the jigsaw fit together – genes, environment and the gut microbiota. After more than a decade of gene discovery and working with some of the cleverest people I know (and perhaps who exist – the ‘analysts’), the genetic architecture of IBD is understood better than almost any other complex disease or phenotype. Well in excess of 200 IBD susceptibility genes to date, plus massive on-going whole genome-sequencing experiments. Has this delivered clinical utility? Not yet; at least not living up to initial promise. But biological insights – stackloads …. And many of these druggable targets. Gene discovery today = new IBD therapy in the future.

The environment and the microbiota have lagged behind gene discovery. In many ways the science is more complex; standardization rife with complexity; and of course temporal fluctuations dominate the landscape. Nonetheless this is the direction in which I and many others have turned our efforts. Large prospective cohort studies in people with IBD and healthy populations are critical to this effort. Studies such as the GEM project and PREdiCCt are leading the way here.

On the clinical front the biggest impact has come from large national and international efforts to improve standards across the board. ECCO has led the way with the development of IBD guidelines covering all aspects of care. These have been made widely available and adopted by many national studies wholesale (often after careful translation). In the UK, the IBD Audit has, over 4 cycles, clearly demonstrated the ability of targeted interventions to drive forward quality improvement.

Moves towards increasingly personalized or precision therapy in IBD have gathered force. Unfortunately our ability to predict disease course from diagnosis onwards remains severely hampered. What has improved dramatically over time are monitoring efforts backed by increasingly robust clinical data. We are now in a position whereby we can make our best guestimate as to the best first-line therapeutic strategy for an individual. But accepting that we will get this wrong much of the time, increasingly sophisticated monitoring strategies (incorporating clinical symptoms, CRP, calprotectin, colonoscopy and MRI) allow us to detect on-going gut inflammation

Mucosal healing is associated with better outcomes (reduced hospitalization and surgeries). We now know from the CALM study a treat-to-target method improves clinical outcomes at 12 months. We can no longer simple monitoring on the basis of clinical symptoms – the disconnect with underlying gut inflammation is too great. The message is clear – monitor and ACT on the results of the monitoring. Important clinical outcomes that matter to the individual patient are better.

Treatment options for patients with IBD in 2017 are better than ever. As an IBD doctor in the clinic, the options available mean increasingly few patients are left without effective therapies. As a result we are keeping more patients out of hospital, preventing operations and reducing bowel damage. OK so not all of this is evidence based just yet, but I can tell you that this is definitely the feeling from me and many others on the ground.

The introduction of biosimilar infliximab has slashed the costs to <40% of the original. That’s approximately 5000 Euros for a year’s therapy … not quite as cheap as beer, but not far off. Therefore the access to therapy for patients across the world has increased. We can now afford to use these therapies much higher in the therapeutic algorithm, earlier in the disease course, and this we know improves outcomes. Biosimilar adalimumab is coming at the end of 2018. It’s a complex area but our experience so far has been overwhelmingly positive.

We’ve been using vedolizumab (anti-integrin therapy) for nearly 2 years now and ustekinumab (anti-p40 / IL12 therapy) has now also appeared in the clinic. Many patients who were stuck on ineffective therapies, requiring repeated surgical interventions or simply living with an inexcusably poor quality of life due to active inflammatory disease are now on drug therapies that work.

But this still isn’t enough for too many people living with IBD for whom existing therapies either don’t work or are poorly tolerated. Thankfully the IBD drug pipeline looks more robust and healthier than ever. Small molecule JAK inhibitors, anti-SP1 therapies, anti-IL23 antibodies, SMAD7 antisense (Mogersen) are just a few of the exciting new therapies expected to hit the clinic with the next 1-5 years. With so many different mechanisms of action and with so few head to head studies, treatment algorithms are going to get very complicated very quickly. And this presents a big challenge to the clinical community – to work out how best to use these drugs, on whom and for how long – and to use them responsibly; the new drugs will not be cheap. But this is challenge we should relish. For far too long we have had an extremely limited therapeutic toolkit; thankfully this is now increasingly something of the past.

So …

  • IBD is a disease of truly pandemic proportions with staggering global healthcare costs
  • We are getting closer at understanding the true cause of IBD, but not to a cure
  • Whilst we are no good at predicting disease course we are increasingly good at disease monitoring; treat-to-target = better outcomes
  • New drugs have hit the clinic; biosimilars are a good thing
  • The pipeline is very rosy

But, we have many on-going and urgent challenges. To address these we need to, amongst other things (this is not meant to be an exclusive or a definitive list):

  • Work co-operatively and collaboratively and make large datasets free to access (the International IBD Genetics consortium and the UKIBDGC Bioresource are leading the way here
  • Translate gene discovery to biological insight to drug discovery
  • Deploy the same scientific and analytical rigor learnt through genetic studies to large scale, prospective studies of environmental factors and the microbiome
  • Learn how to robustly monitor temporal trends in the environment and microbiota
  • Adopt large-scale prospective clinical registries to robustly assess long-term clinical outcomes
  • Bring the promising drug pipeline to the clinic

To achieve this we should invest in scientifically rigorous, carefully designed and appropriately powered studies. We should desist from supporting small scale research that yields little insight and is difficult to reproduce. ‘science’ for ‘science’s’ sake should in my mind be something of the past. In many parts of the world this will require major educational efforts that the like of ECCO and UEG should lead. This should I think particularly apply to poorly designed in vitro and in vivo experiments. And we should support large-scale efforts to develop clinical grade functional assays to tell us which biological pathway is dominant / defective in an individual patient to optimally target new therapies.

There is a huge amount to be positive about on World IBD Day in 2017. The shift in the clinical landscape is palpable on the ground. The excitement palpable in the scientific community. So my message to those people living with IBD is this … we are not there yet, but we are getting there, please bear with us … we will do everything we can to get you well and back to a completely normal quality of life.

charlielees

Author charlielees

Dr Charlie Lees is a gastroenterologist at the Western General Hospital in Edinburgh. He trained at University College London and subsequently in Edinburgh, with doctoral studies at the University of Edinburgh. He works as a full-time NHS consultant whilst maintaining a full research programme and a portfolio of local and international speaking activities. He specialises in the management of people with inflammatory bowel disease and is pursuing a range of innovative digital solutions to transform patient care and education. Following a decade of gene discovery in IBD, Dr Lees’ current research interests focus on the role of environmental factors, including diet, and the microbiota on disease flare and natural history. He is Chief Investigator of the PREdiCCt study, currently recruiting 3000 people with IBD in clinical remission from across the UK. PREdiCCt aims to discover how diet, environmental factors, the gut microbiota and host genetics influence disease flare. He also leads the UK arm of the GEM study, a major international study investigating the underlying cause of Crohn’s disease.  Charlie has been centrally involved with the European Crohn’s and Colitis Organisation over the last 10 years, and is the Chief Scientist Office Scottish Specialty Lead for Gastroenterology. HE co-chairs the International IBD Genetics Consortium management committee and sits on the British Society of Gastroenterology IBD Research Committee. In 2009, he was awarded the prestigious UEG European Rising Star in Gastroenterology Award.

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