Current medicine for inflammatory bowel disease (IBD) is poor, characterised by misdiagnoses, late diagnoses, and guesswork. This pain arises from the lack of effective IBD biomarkers. However, this picture is changing with the development of new, reliable precision medicine biomarkers that could significantly advance the care of IBD patients.
Meet Caroline, one of our life-course models for the 5M-diagnosed IBD patients across the globe, and the additional 5M people who we estimate live with IBD, but are currently undiagnosed. Caroline is a citizen of the United Kingdom, a nation with one of the most advanced medical Care Process systems in the World. Despite this, Caroline’s health journey has been a long, painful odyssey, beset with medical mistakes. These have affected not just her, but her whole family.
Caroline’s IBD symptoms first appeared at age 13, when she suffered constant episodes of diarrhoea and experienced significant weight loss. Her general practitioner misdiagnosed her as having irritable bowel syndrome (IBS), a condition experienced by between 10 per cent to 20 per cent of the UK population. The misdiagnosis arose because Caroline tested negative for Faecal Calprotectin (FCP). FCP is now one of the main medical assays used in primary care to identify IBD suspects, having undergone many improvements over the past decade. However, at the time that Caroline was tested, the FCP test was insufficiently reliable. Believing that the root of her illness was psychological, Caroline’s GP referred her to a counsellor who specialised in eating disorders. This further delayed the appropriate diagnosis and treatment.
Caroline’s health did not improve significantly with the counselling. Disillusioned by conventional medicine, Caroline´s parents sought help from complementary and alternative healthcare practitioners. Over the next six years, five different practitioners diagnosed Caroline variously as having IBS, coeliac disease, and Candida overgrowth. It wasn’t until she turned 19 that Caroline tested positive for FCP. At that point her doctor, finally, referred her to a gastroenterologist for further investigation. Through the use of endoscopy and histology on her gut biopsies the specialist diagnosed Caroline as having Ulcerative Colitis (UC). This is one of the two most common forms of IBD, the other being Crohn’s Disease (CD). The long delay in Caroline’s proper diagnosis and treatment meant that she had suffered inflammatory episodes that caused significant destruction to bowel tissue. The damage was so severe that, at age 21, Caroline had to have part of her colon surgically removed. Then, ten years later another consequence of delayed treatment became apparent — Caroline was diagnosed with colorectal cancer (CRC), which is now ranked the second leading cause of sickness and death by cancer across the globe.
IBD manifests as a series of uncontrolled fires, progressively destroying gut tissue and causing a range of distressing symptoms including severe constipation, uncontrolled diarrhoea, episodes of gut inflammation (so-called ‘IBD flares’), abdominal pain, rectal bleeding, rectal ulcers, extreme fatigue, and depression. Currently, there is no cure for IBD. Medics typically manage patients’ symptoms with anti-inflammatory therapeutics and turn to surgery to remove irreparably damaged sections of the gut. Those IBD patients with severe, long-term gut inflammation have significantly increased risk of developing CRC — so Caroline’s chances of getting cancer were greatly elevated by her late diagnosis and treatment.
Caroline’s story is relevant to the growing number of Asians at risk from IBD. Once thought to be a disease of the West, IBD is increasing across Asia – particularly in rapidly-industrialising countries such as China, which now has the highest number of prevalent IBD cases in the World. There is a further problem — Asians typically suffer from a more complex form of IBD than Caucasians, with higher levels of peri-anal complications. Our analysis is that within the next decade IBD will become a very serious health problem across continental Asia, with the most economically advanced countries suffering the highest burden of disease.
Caroline is one of an estimated 10 per cent of IBD patients who were previously misdiagnosed as having IBS. Misdiagnosis is one of seven types of failure in clinical decision-making that we have identified within the patient care pathways for IBD in the UK and every other country we have investigated. The errors occur across all stages of IBD progression, spanning both primary and secondary care. We investigated why these medical mistakes are so common. Our conclusion was that they arose largely from a lack of reliable tests for the detection of changes in IBD-specific chronic inflammation (cI) that occur during disease progression. Instead of measuring cI, most inflammation markers such as hsCRP that are commonly employed by healthcare professionals to monitor IBD actually estimate levels of acute inflammation (aI). This is because aI produces large, highly variable molecular signals that overshadow the smaller, steady signals from cI processes. To use an analogy, cI is like the climate and aI is like the weather — it’s difficult to measure climate change because the weather gets in the way.
Increases in aI signals are indirectly associated with IBD and can be caused by many conditions other than IBD. As a result, the current aI-based IBD biomarkers have low sensitivity and specificity for IBD i.e,. they are imprecise and unreliable because they measure the wrong things.
IBD is not the only condition where aI-based clinical biomarkers are being used to detect a cI-driven disease. Similar phenomena occur with other chronic inflammatory diseases. Consequently, cI in IBD and many other cIDs can increase steadily over many years, but is invisible to patients and their medics. In a significant proportion of cases, IBD-related cI only becomes noticed when the patient’s symptoms are so severe that they’re referred to a gastroenterologist. Regarding FCP, the guidance on that biomarker’s use to distinguish IBD from functional gut disorders in primary care is becoming clearer. However, the diagnosis of patients with gastrointestinal alarm symptoms and identification of IBD suspects is still complex. Given this, there’s an urgent need for better diagnostic tools for IBD. We believe that those could be provided using a precision medicine approach.
The Human Genome Project (HGP) ushered in the age of Precision Medicine (PM). The promise was that knowledge of an individual’s genome would help us to predict what diseases they could get and how to cure them. We now know that an individual’s genome shapes their disease risk profile but does not predetermine health across their life course. Also, our ability to understand how genes relate to health outcomes is still limited. For example, around 240 gene loci are now known to be associated with IBD — but this explains at most 25 per cent of the heritability of IBD variants. There is a further complication. Studies over the past three decades show that genes interact in complex ways with many other factors to shape an individual’s health trajectory. For IBD patients, those factors include environmental parameters, the gut microbiome, food, movement, sleep, circadian and other body rhythms, and both mental and physical stress. Accordingly, today’s version of precision medicine encompasses a multi-disciplinary approach to understanding the complex networks of interactions that underlie the generation and progression of chronic conditions. PM’s original promise has now turned into a premise i.e., knowledge of the aetiology (i.e. causal pathways) for a disease allows us to detect and track its progression in individuals at risk, and could also help us to identify therapeutic targets and develop effective therapies that tackle root causes, not just alleviate symptoms.
The first step in a PM approach to IBD is to realise it’s a syndrome — a collection of diseases with different aetiologies but that share common symptoms that include episodes of gut inflammation. All IBD variants are chronic inflammatory diseases — so understanding the changes in the immune system that occur with their progression over long time periods is central to PM approaches to their management. IBDXTM™, PredictSure IBD™, and GlyHealth-IBD-Escalate™ are three novel IBD PM blood biomarkers that exploit such changes.
IBDX, from GlycoMinds (https://www.glycominds.com/), is a panel of six solid-phase enzyme-linked immunosorbent assay (ELISA) kits, each of which detects the serum level of a specific anti-glycan antibody that is a potential serological biomarker for IBD development. The kits are used in combination to probe a patient’s blood. The resulting multi-marker profiles are used (a) to aid differential diagnosis of IBD vs. non-IBD and CD vs. UC and (b) for Crohn’s disease prognosis. For CD prognosis, the number of positive IBDX antibody results correlates with the probability of Crohn’s Disease progression in the individual. For patients positive for three or more IBDX antibodies, 90 per cent are likely to have complicated disease and 80 per cent are likely to require abdominal surgery.
PredictSURE IBD, from PredictImmune (https://www.predictimmune.com), is another PM IBD biomarker for Crohn’s disease prognosis. The system is a serological test that estimates the level of CD8+ T cell exhaustion, which correlates with the severity of the future disease course. The parameters measured are the expressions of 15 specific target genes plus 2 controls. This is performed using quantitative polymerase chain reaction with reverse transcription (RT qPCR).
GlyHealth-IBD-Escalate (GIE) is a prognostic and predictive biomarker of IBD. The technology is being co-developed by Avenna (www.avenna.com) and Ludger (www.ludger.com) — sister companies based near Oxford in the UK — and the Translational Gastroenterology Unit at the University of Oxford. GIE is based on quantitative measurement of glycomics patterns in an IBD patient’s blood that we have shown correlate with IBD flare progression. The patterns of interest are prodromal signals of developing IBD flares i.e., they can be detected before signs of gut inflammation are visible by endoscopy. The results from retrospective clinical studies are promising, with GIE reliably predicting the likelihood that a newly-diagnosed IBD patient would need treatment escalation within 18 months of testing. Although it’s still early days, the preliminary results for GIE as a potential predictor of an IBD patient’s response to specific anti-inflammatory biologic drugs have been encouraging too. We are now preparing to test the performance of GIE in real-world clinical settings, the first prospective study being with gastroenterologists at the IBD clinic in St. Mark’s Hospital, London which specialises in the care of patients with bowel diseases.
These new PM IBD biomarkers, and others being developed, have the potential to impact two critical areas of IBD care: (a) greatly enhancing clinical decision-making, particularly for treatment personalisation, and (b) helping to move diagnosis and treatment from late to early action. However, like most PM technologies, these have been developed in R&D labs and there are many hurdles to overcome in order to translate them into reliable, everyday medical tools for use in busy clinics. The challenges we as developers face include ensuring that: we can generate convincing evidence that the real-world performance of our biomarkers are as good as we claim; we can thoroughly test the technologies with diverse groups of patients, including people of different ethnicities; we can meet all the regulatory hurdles for medical diagnostics; our biomarkers are straightforward to use; medics will adopt our technologies; we can manufacture and support our technologies at national scales; our technologies are demonstrably cost-effective; and that healthcare payers will reimburse clinics for use of our biomarkers. Of course, these challenges also prevail for every medical technology in widespread use today — so we won’t complain. Fortunately, we can get help and advice for our technology translation journeys from precision medicine accelerator programmes and specialist organisations such as Crohn’s & Colitis Foundation. If we succeed then, in future, patients living with IBD across the globe will, we believe, have much better IBD journeys than that experienced by Caroline.
