̽��ֱ�� of Cambridge - Crohn’s and Colitis UK

New prognostic test could enable personalised treatment of inflammatory bowel disease

cjb250 — Fri, 03 May 2019 07:12:05 +0000

Ulcerative colitis and Crohn’s disease – collectively known as inflammatory bowel disease (IBD) – are chronic conditions that involve inflammation of the gut. Symptoms include abdominal pain, bloody diarrhoea, weight loss and fatigue. There is currently no cure, but there are a growing number of medicines that aim to relieve symptoms and prevent the condition returning; however, the more severe the case of the IBD, the stronger the drugs need to be and the greater the potential side effects.

Researchers at the Department of Medicine, ̽��ֱ�� of Cambridge, and Cambridge ̽��ֱ�� Hospitals NHS Trust previously showed that a genetic signature found in a certain type of immune cell known as a CD8 T-cell could be used to assign patients to one of two groups depending on whether their condition was likely to be mild or severe (requiring repeated treatment). However, isolating CD8 T- cells and obtaining the genetic signature was not straightforward, making the test unlikely to be scaleable and achieve widespread use.

In the latest study, published in the journal Gut, the researchers worked with a cohort of 69 patients with Crohn’s disease to see whether it was possible to develop a useful, scaleable test by looking at whole blood samples in conjunction with CD8 T-cells and using widely-available technology.

̽��ֱ��team used a combination of machine learning and a whole blood assay known as qPCR – a relatively simple tool used in NHS labs across the country – to identify genetic signatures that re-created the two subgroups from their previous study.

̽��ֱ��researchers then validated their findings in 123 IBD patients recruited from clinics in Cambridge, Nottingham, Exeter and London.

“Using simple technology that is available in almost every hospital, our test looks for a biomarker – essentially, a medical signature – to identify which patients are likely to have mild IBD and which ones will have more serious illness,” says Dr James Lee, joint first author of the study.

“This is important as it could enable doctors to personalise the treatment that they give to each patient. If an individual is likely to have only mild disease, they don’t want to be taking strong drugs with unpleasant side-effects. But similarly, if someone is likely to have a more aggressive form of the disease, then the evidence suggests that the sooner we can start them on the best available treatments, the better we can manage their condition.”

̽��ֱ��accuracy of the test is comparable to similar biomarkers used in cancer, which have helped transform treatment, say the researchers. They found the new test was 90-100% accurate in correctly identifying patients who did not require multiple treatments.

“IBD can be a very debilitating disease, but this new test could help us transform treatment options, moving away from a ‘one size fits all’ approach to a personalised approach to treating patients,” says Professor Ken Smith, senior author and Head of the Department of Medicine.

̽��ֱ��test is now being developed further by PredictImmune, a spinout company co-founded by Professor Smith with support from Cambridge Enterprise, the ̽��ֱ��’s technology transfer arm. ̽��ֱ��team is involved in a £4.2 million trial to see whether using the biomarker to guide treatment at the time of diagnosis can lead to better outcomes for patients.

̽��ֱ��findings have been welcomed by Helen Terry, Director of Research at Crohn’s & Colitis UK, which helps fund the research. “It’s really exciting that we are moving away from a ‘one size fits all’ approach for people with Crohn’s or Colitis. Dr Lee and his team’s latest study is the accumulation of 10 years’ worth of research and we’re now at the stage where this test will be available in the NHS. This could drastically change the lives of people with Crohn’s or Colitis as it means they can be started on the best medication for them sooner.”

Additional funding for the research came from Wellcome, the Medical Research Council and the National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre.

Later this year, Professor Smith and his team are due to move into the new Cambridge Institute of Therapeutic Immunology and Infectious Disease, to be based in the Jeffrey Cheah Biomedical Centre on the Cambridge Biomedical Campus, the centrepiece of the largest biotech cluster outside the United States.

Reference
Biasci, D and Lee JC, et al. A blood-based prognostic biomarker in inflammatory bowel disease. Gut; April 2019; DOI: 10.1136/gutjnl-2019-318343

Scientists at the ̽��ֱ�� of Cambridge have developed a new test that can reliably predict the future course of inflammatory bowel disease in individuals, transforming treatments for patients and paving the way for a personalised approach.

This new test could help us transform treatment options, moving away from a ‘one size fits all’ approach to a personalised approach to treating patients

Ken Smith

Dr James Lee

Kate Gray, aged 31, Amersham, living with Crohn’s

Kate was diagnosed with Crohn’s Disease when she was 14 years old having been unwell with symptoms for quite some time.

This meant she needed surgery. “I was told by my consultant I would only need a little bit of a resection and that it’s unlikely I would be bothered by symptoms for decades, giving me the impression that was probably the end of it.”

Within 9 months of her bowel resection, Kate’s symptoms had returned. She tried various medications, including immunosuppressants and steroids but nothing worked, and she kept getting more unwell. She also had some nasty side effects from the drug mercaptopurine, becoming neutropaenic (low on neutrophils), leading to two admissions to hospital.

This pathway continued throughout Kate’s secondary education and once on the drug infliximab, it reached the point where Kate couldn’t eat solid foods. Her bowel was so strictured and damaged that she was told she needed an ileostomy at the age of 20. In the lead-up to this Kate had a nasal-gastric feeding tube which involved long stints in hospital.

When Kate woke up from her operation, she was told that the damage was much more extensive than thought and she would have a permanent stoma.

Following surgery, Kate was started on the biologic drug, Humira and has been on this weekly ever since. “My stoma’s been amazing and bowel wise, my symptoms have been good for the past decade.”

Kate could have benefited hugely from a prognostic test, making her more aware of disease course and allowing her to try stronger treatments earlier.

“I do sometimes wonder what would have happened if I knew my disease was going to be more severe and not mild, as I was told. It’s likely I would have opted for my ileostomy sooner and would have been keen to try stronger drugs earlier as this might have halted to progression of my Crohn’s. It would also have been good to have known what other symptoms I could have expected with more severe Crohn’s, including issues with my joints, uveitis and Crohn’s on the skin at the site of my surgery scars.”

Kate's story courtesy of Crohn's and Colitis UK

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Crohn’s disease risk and prognosis determined by different genes, study finds

cjb250 — Mon, 09 Jan 2017 16:00:07 +0000

Crohn’s disease is one of a number of chronic ‘complex’ diseases for which there is no single gene that causes the disease. In fact, to date around 170 common genetic variants have been identified that each increase the risk of an individual developing the disease. ̽��ֱ��conventional wisdom has been that there exists a ‘tipping point’: if someone has enough of these genes, they become very likely to develop the disease – and the more of the variants they carry, the more the severe the disease will then be.

However, in a study published today in Nature Genetics, a team of researchers led by the ̽��ֱ�� of Cambridge has shown that this is not the case: genetic variants that affect the progression, or prognosis, of a disease operate independently of those that increase the likelihood of developing the disease in the first place.

“Genetic studies have been very successful at identifying genetic risk factors for Crohn’s disease, but have told us virtually nothing about why one person will get only mild disease while someone else might need surgery to treat their condition,” says Dr James Lee from the Department of Medicine at Cambridge. “We do know, though, that family members who have the disease often tend to see it progress in a similar way. This suggested to us that genetics was likely to be involved in prognosis.”

̽��ֱ��researchers looked at the genomes – the entire genetic makeup – of more than 2,700 individuals, who were selected because they had either had experienced particularly mild or particularly aggressive Crohn’s disease. By comparing these patients’ DNA, the researchers found four genetic variants that influenced the severity of a patient’s condition. Strikingly, none of these genes have been shown to affect the risk of developing the disease.

̽��ֱ��team then looked at all the known genetic risk variants for Crohn’s and found that none of these influenced the severity of disease.

“This shows us that the genetic architecture of disease outcome is very different to that of disease risk,” adds Professor Ken Smith, Head of the Department of Medicine. “In other words, the biological pathways driving disease progression may be very different to those that initiate the disease itself. This was quite unexpected. Past work has focussed on discovering genes underlying disease initiation, and our work suggests these may no longer be relevant by the time a patient sees the doctor. We may have to consider directing new therapies to quite different pathways in order to treat established disease”

One of the genetic variants discovered by the team was in a gene called FOXO3. This gene is involved in modulating the release of the cytokine TNFα – cytokines are proteins released into the blood by immune cells in response to infection or, in the case of conditions such as Crohn’s, to the body erroneously attacking itself. This FOXO3-TNFα pathway is also known to affect the severity of rheumatoid arthritis, another auto-inflammatory disease.

Another of the variants was close to the gene IGFBP1, which is known to play a role in the immune system. This genetic region, too, has previously been linked to rheumatoid arthritis, in a study looking at the presence of a particular antibody in patients – presence of this antibody is associated with more severe disease.

̽��ֱ��third genetic variant was in the MHC region, which is responsible for determining how our immune cells respond to invading organisms. This region has been implicated in a number of auto-immune diseases, including Crohn’s, but the genetic variant that alters Crohn’s disease risk is different to the one that affects prognosis. ̽��ֱ��variant the team identified, which was associated with a milder course of Crohn’s disease, was shown to affect multiple genes in this region, and result in a state that is known to cause weaker immune responses.

̽��ֱ��final variant occurred in the gene XACT, about which very little is known; however, in adults this gene appears to be mainly active in cells in the intestine – the organ affected by Crohn’s disease.

“This discovery has shown us a new way of looking at disease and opens up potential new treatment options, which could substantially ease the burden of Crohn’s disease,” says Dr Lee. “What’s more, we have evidence that some of these prognosis genes will be shared with other diseases, and as such this approach could be used to improve treatment in a number of conditions.”

̽��ֱ��study has been welcomed by Crohn's and Colitis UK, who helped fund the study. "This is an exciting breakthrough which offers new hope for people who suffer every day from Crohn's and Colitis,” says Dr Wendy Edwards, Research Manager at Crohn’s and Colitis UK. “ ̽��ֱ��research sheds new light on why some people with inflammatory bowel disease experience more severe symptoms than others, which has been little understood until now."

As well as its implications for Crohn’s and other diseases, the approach taken by the researchers has suggested that there is value in re-examining previous genetic studies. Around a third of the genomes of Crohn’s disease patients analysed in this study had been collected for a previous study in 2007. By dividing the patients into groups categorised by disease severity, the researchers were able ask new questions – and gain new insights – from the old data.

̽��ֱ��research was mainly funded by Wellcome, NIHR Cambridge Biomedical Research Centre, Crohn’s and Colitis UK and the Evelyn Trust.

Reference
Lee, JC, Biasci, D, et al. Genome-wide association study identifies distinct genetic contributions to prognosis and susceptibility in Crohn's disease. Nature Genetics; 9 Jan 2017; DOI: 10.1038/ng.3755

Researchers have identified a series of genetic variants that affect the severity of Crohn’s disease, an inflammatory bowel disease – but surprisingly, none of these variants appear to be related to an individual’s risk of developing the condition in the first place.

Genetic studies have been very successful at identifying genetic risk factors for Crohn’s disease, but have told us virtually nothing about why one person will get only mild disease while someone else might need surgery to treat their condition

James Lee

Charles Clegg

DNA

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