Precision medicine for inflammatory bowel disease

Dr Hayley Carr discusses inflammatory bowel disease and current research into improving patient care using genetics-driven precision medicine.

Welcome back to Making science work for health, the PHG Foundation podcast that explains the most promising developments in science and their implications for healthcare.

In each episode, host Ofori Canacoo discusses with a PHG Foundation policy analyst, the underpinning science, the ambitions for improving population health and the impact it could have on patients, on society and on the people delivering your healthcare.

You can read Hayley's briefing on precision medicine for inflammatory bowel disease here.

If you would like to find out more about what was discussed in this episode, you can find additional information on our website, phgfoundation.org.

If you have any further questions about the topic then you can email us at intelligence@phgfoundation.org. 

Transcript

Ofori: 0:12

Welcome to 'Making science work for health'. The PHG Foundation's podcast exploring developments in genomics and related emerging health technologies. Social media and the many digital news outlets now mean more of us than ever are aware of the progress being made by teams of intrepid scientists and researchers around the world. Many of the latest advances feature genomics and 'omics related technologies. The field in which the PHG Foundation has 25 years of experience, helping policy makers get to grips with practical on the ground delivery. 'Making science work for health' aims to strip away the gloss and explain what new science means for patients, health professionals, and members of society. My name is Ofori Canacoo, part of the communications team at the PHG Foundation and host of 'Making science work for health'. For this episode, we're discussing inflammatory bowel disease and the use of precision medicine to aid in patient healthcare for the condition. Joining me for this episode is Dr. Hayley Carr, policy analyst at the PHG Foundation. Hello, Hayley.

Hayley: 1:12

Hi.

Ofori: 1:12

Would you like to tell us a little bit about yourself?

Hayley: 1:15

Yes, so I am a policy analyst in the science team here at PHG. I've been here for around a year now, and I've worked on several topics during this time, including what we're going to discuss today, which is the use of precision medicine for inflammatory bowel disease, or IBD. Before working here I did a PhD looking at rheumatoid arthritis, which is quite a similar disease to IBD, in that it's another complex autoimmune disease. So this has been an area of interest for me.

Ofori: 1:53

Okay. First off, we are talking about inflammatory bowel disease. Is this the same thing as irritable bowel syndrome?

Hayley: 2:01

No, they are sometimes confused because they do have similar symptoms, which can include diarrhea and abdominal pain, but they do have different characteristics. So IBS is more associated with digestive issues and also some neurological factors, whereas IBD, as you might expect, is characterized by more inflammation of the gut. Although the exact causes of both of these diseases are currently unknown, IBD also is less common than IBS, but is generally more severe.

Ofori: 2:37

Okay, so what exactly is IBD?

Hayley: 2:40

So, IBD actually encompasses several diseases with the key theme being that the gut becomes inflamed in all of them. The most common of these are Crohn's disease and ulcerative colitis. But even within a specific disease, people's symptoms and outcomes can vary quite widely. So patients go through periods of what's called relapse and remission. So when they are in remission, they feel quite well and have quite few symptoms, and then they'll sometimes have what's called a disease flare, which is the relapse, and this is where they get the symptoms associated with the disease. And the time that's spent in remission and the severity of the flares can vary between patients and also varies over the time course of the disease for an individual patient.

Ofori: 3:34

So, how much of a problem is IBD then?

Hayley: 3:36

So, it's estimated to affect around 500,000 people in the UK, so a really significant number of people. And although it's not immediately life threatening for them, it is a chronic and lifelong condition that can have a significant impact on their lives. It is also worth noting that although IBD is not immediately life threatening, it can increase your risk of other complications that are. So, for example, an individual with IBD is at increased risk of getting colorectal cancer and this risk increases the longer a person has lived with IBD and also the more poorly controlled their disease is.

Ofori: 4:17

You said earlier that we don't currently know what causes IBD?

Hayley: 4:21

Yes, that's right. We do know that there are quite a few factors involved in this. Genetics is one of these. For example, we know that more than one in four of those with ulcerative colitis actually have a family history of the condition. But there are also several environmental factors that increase risk, and these can include things like stress and pollution. Another big contributor is changes to the gut microbiota, which are the microbes that live in your guts. And so we believe that these factors work together and lead to the abnormal immune responses we see in IBD.

Ofori: 4:58

So what can a patient who suspects they have IBD or who has been experiencing IBD symptoms expect from a visit to the GP?

Hayley: 5:06

Diagnosis for IBD is based, generally on patient reporting and then a series of tests that will be done by the GP. And these generally include things like physical examinations and blood and stool tests. And if from this there's a suggestion of gut inflammation, they'll then get referred to a specialist gastroenterology team. And this is where more specialized tests are made where they can make a more clear diagnosis. And these tests will generally include an endoscopy, which basically looks directly in the gut.

Ofori: 5:42

When do patients tend to get diagnosed?

Hayley: 5:45

So, this can vary quite a lot. It tends to be when they're anywhere between, kind of, 15 and 40 years old. And then from there they have IBD for the rest of their life. So, this can have a really significant lifelong impact on them, particularly when they are diagnosed at these young ages.

Ofori: 6:03

And are there treatments currently?

Hayley: 6:05

There are quite a few treatment options available, although there is notably no known cure currently. So, this means that doctors do have to make decisions about which treatments to give patients, and this will be based on a number of factors, including what specific disease the patient has, so whether they actually have Crohn's or ulcerative colitis, for example, as well as the severity of their disease and also their specific symptoms. And this aims to manage the disease while minimizing side effects of the treatment. There is also a framework that clinicians follow to try to achieve this. So, IBD patients with a new diagnosis generally start on treatments called anti-inflammatories, and these have fairly few side effects and work for a good percentage of patients. So for example, in ulcerative colitis, the main anti-inflammatories used are aminosalicylates, and these work for around seven out of every ten patients.

Ofori: 7:09

That sounds quite positive?

Hayley: 7:11

Overall yes, but that still leaves around 30% of patients who don't respond well to these initial treatments, and there are around half a million people with IBD in the UK. So, that actually leaves quite a lot of patients for whom alternatives are necessary.

Ofori: 7:29

So what are the next options?

Hayley: 7:31

The next step then is to move onto immunosuppressants, which work by dampening the immune system to reduce the inflammation in the gut. But by doing this, you can put patients at greater risk of infection, and so they are associated with more side effects than the anti-inflammatories. If these also don't work, then the third broad category of treatments and the most aggressive are biologics and these also work to reduce the immune response. But while immunosuppressants broadly dampen the immune response, biologics target specific immune processes by blocking specific proteins that drive the inflammation. However, biologics can be associated with quite nasty side effects, and they are also the most expensive treatment choice, which is a consideration. So someone with IBD will generally require these treatments for the rest of their life, and they may also need supplementary treatments, for example, steroids to get their disease flares under control.

Ofori: 8:40

So at the moment, it seems a bit trial and error. Would that be fair to say?

Hayley: 8:43

To some extent you are right, but I think this is more often the case than you would think in medicine today and this current approach, which is termed a step-up approach, does have logic as well as a lot of scientific evidence behind its use. And in fact, even the main rival to this step-up approach, which is termed the top-down approach, is still ultimately based on trial and error.

Ofori: 9:11

What is this top-down approach?

Hayley: 9:14

So this basically involves reversing the current treatment pathway, so starting on the most aggressive treatments, the biologics, and then as their disease comes under control, you deescalate down to immunosuppressants and then down again to anti-inflammatories. So some advocates suggest that this top-down approach would help to improve outcomes for IBD patients with very severe disease, as it means that you would give them the more aggressive treatments earlier, which might get their disease under control. However, this also requires giving the more aggressive treatments to those with milder disease when they might actually be able to control their disease with anti-inflammatories that have fewer side effects and are also cheaper. Generally, the problem with both of these approaches is that we can't accurately predict what an individual patient's outcome will be or how they will respond to a given treatment.

Ofori: 10:17

And this leads us to the PHG Foundation briefing, which you researched and wrote, Hayley, on the hopes for a precision medicine approach for IBD patients.

Hayley: 10:26

Yes. So, currently all patients follow the same general approach, which is based on research and current evidence, but is associated with varying levels of success between patients. So, precision medicine, on the other hand, aims to tailor the treatment based on that individual patient. So, you'll collect information about them, including things like their symptoms and their clinical factors. So, age of onset or disease severity, for example. And then you also use other biomarkers that give information about their disease. So, for example, this could include their genetic information, and the hope is that you can combine all of this information together and come up with a solution specifically for that patient. So, this means giving them the right treatment at the right time and also at the right dose for them that results in minimal side effects and controls their disease, rather than following the same general approach for everyone. If this works, it could reduce a lot of the uncertainty faced by IBD patients currently, some of whom, as we've mentioned before, have to trial several treatments before finding one that actually works for them. And they also obviously have to deal with poorly controlled disease all during this time.

Ofori: 11:50

So, precision medicine is about using information from the patient to inform the treatment of that patient.

Hayley: 11:57

Essentially, yes, that's right.

Ofori: 12:00

In the briefing, you mentioned one approach that can provide some of this information. Pharmacogenomics? What does this involve?

Hayley: 12:08

So, pharmacogenomics broadly involves testing individuals for specific genetic changes that alter their response to a given treatment. So, this can be used to predict whether a patient will respond or not to a treatment, and also whether the treatment is likely to trigger side effects.

Ofori: 12:28

Has this been used in IBD?

Hayley: 12:30

It hasn't directly been used yet. There is a variant in the TPMT gene that predicts side effects in response to a particular drug, but in this instance, the level of protein are tested rather than the gene itself. There is also another example that's been found in research but not yet implemented, which is a variant in the NUDT15 gene. And this has been associated with side effects actually in response to the same drug as the TPMT variant. So, if this was used in the clinic, you could test for the variant, and if someone had it, you would know there'd be a risk of these side effects and therefore you could use a different drug or you could alter the dose. One particular benefit of genetics is that you can test for multiple variants at the same time, so in the future it's not inconceivable that there could be a test that gives information about how a patient will respond to multiple IBD treatments, which would allow for a more informed treatment approach.

Ofori: 13:34

Are there other ways that genetic information can help achieve precision medicine?

Hayley: 13:38

Yeah. So, another potential approach that may help work towards precision medicine aims to look more at the prediction of a patient's outcome. So this is trying to predict how severe their disease will be or how quickly it will progress, for example. And I think this is particularly exciting for IBD, as patients do have very varying disease courses and we can't currently accurately predict who will have severe or milder disease at the moment.

Ofori: 14:10

Have we seen this being used in practice in any capacity?

Hayley: 14:13

So, not really in the clinic yet, but there is one test that's in clinical trials at the moment, which is called PredictSURE IBD. And this aims to stratify patients according to the prediction of the severity of their disease. But this is, as I said, currently being tested in a clinical trial, which is called the PROFILE trial.

Ofori: 14:35

How does this test work then?

Hayley: 14:37

PredictSURE IBD is a blood test that tries to predict how at risk a patient is of having severe or progressive disease. So it tests for a gene expression signature in immune cells that are found in the blood, and this is associated with their disease activity.

Ofori: 14:56

Okay, so for those who don't know, testing for gene expression signatures involves looking at a group of genes to see whether they are switched on or not, and to what extent?

Hayley: 15:05

Yes, and this can give clues as to which processes are happening within the patient at the time of testing.

Ofori: 15:13

So how would this be expected to help patients?

Hayley: 15:16

So, the idea for PredictSURE IBD is that people at high risk of severe disease could follow the more aggressive top-down approach, which is what I described before, where they start with the biologics and then deescalate once their disease is under control. On the other hand, the people at low risk could continue to follow the current step-up approach. So, this means you avoid giving these aggressive treatments to those who will have a milder disease course and don't need it, but are able to give them instead to those who will get more severe disease and hopefully enable them to get their disease under control earlier on.

Ofori: 15:54

Currently, patients aren't able to routinely access such tests on the NHS. Is that correct?

Hayley: 15:59

Yes. So before any test or treatment can be made routinely available through the NHS, there needs to be a decision on its clinical and also its cost effectiveness based on evidence that it improves patient care and outcomes. So, for these kinds of novel and innovative tests, there needs to be sufficient evidence that it can accurately predict which patients are at risk of severe disease, and also who will have more mild disease, and then show that this information can be used to inform treatment choices, which in turn improves patient outcomes. So there continues to be significant research efforts that aim to provide the answers to these questions.

Ofori: 16:43

And what about the outlook for using precision medicine for other complex diseases?

Hayley: 16:48

For precision medicine more generally, more work needs to be done to identify new biomarkers and also to develop new and better outcome prediction tests to make sure that we are actually capturing the information that is most useful to inform these treatment approaches. These then need to be tested in clinical trials, like the PROFILE trial to make sure that they do actually improve patient outcomes. Beyond this, healthcare professionals will need training in how to order and interpret these kinds of tests so that they can get the maximum benefit out of them for their patients. And there will also need to be things like economic assessments done to make sure that precision medicine actually represents value for money compared to current approaches that are used. So, I think precision medicine for IBD has been a really interesting topic to look into, and this is partly because it's quite a good example. So, precision medicine could be used in a number of other complex diseases as well. So, for example, rheumatoid arthritis where I did my PhD would be another good example. However, there's still quite a bit more work to be done, and as we've discussed, which needs doing to make sure that this is actually a realistic approach that does lead to patient benefit. Overall, I think precision medicine is a really exciting area, but it might actually be a while until we see all patients benefiting from this approach.

Ofori: 18:17

Brilliant. Thank you, Hayley. That's all been very insightful. Would you like to tell us what you are working on next?

Hayley: 18:23

Yeah, so I'm actually working on several projects at the moment. One of these is looking at host genomics for infectious disease. So, this is broadly looking at human or host genetic profiles to see how they influence response to a particular infectious disease, and then also looking at how this information can be used to improve patient care.

Ofori: 18:48

Wonderful. Well, we look forward to having you back on to talk about all of that. Hayley, once again, thank you for joining us.

Hayley: 18:54

Thank you.

Ofori: 18:57

Well, that brings us to the end of the episode. If you liked it, please leave us a rating and review and make sure to subscribe. If you would like to find out more about what was discussed in this episode, there are useful links included in the podcast description. You can also find additional information on our website, phgfoundation.org. And if you have any further questions about the topic, then you can email us at intelligence@phgfoundation.org. Thank you for listening, my name is Ofori Canacoo, and I look forward to bringing you a new topic in the next episode.