Biomarkers in inflammatory bowel disease: a practical guide.

Inflammatory bowel disease (IBD), comprising ulcerative colitis (UC) and Crohn's disease (CD), is a costly condition in terms of morbidity and healthcare utilization, with an increasing prevalence now approaching 1% in the Western world. Endoscopic assessment of IBD remains the gold standard for diagnosis, evaluation of treatment response and determination of post-operative recurrence, but is expensive and invasive. Biomarkers can facilitate non-invasive disease assessment, with C-reactive protein and faecal calprotectin as the most widely available biomarkers in current clinical practice. This narrative review summarizes the evidence for their use in both UC and CD and offers practical guidance for healthcare providers taking into account the limitations of biomarker interpretation. We present evidence for the future use of novel biomarkers in IBD and discuss how biomarker discovery could deliver the goal of precision medicine in IBD.

Biomarkers in inflammatory bowel disease: a practical guide Inflammatory bowel disease (IBD) is a term used to describe two conditions, ulcerative colitis (UC) and Crohn's disease (CD). These two diseases cause inflammation of the bowel, which can lead to diarrhoea, abdominal pain and bleeding from the back passage. The best way of assessing how active a patient's IBD is, is by performing a camera test called a colonoscopy. However, having a colonoscopy is inconvenient, comes with some risks to the patient, and uses a lot of healthcare resources. 'Biomarkers' are proteins detectable in body fluids (such as blood, poo and urine) which can give information to medical staff about how active a patient's disease is, without the need for colonoscopy. In this article, we give guidance about how best to use these tests, and when they might not be so useful. We also discuss new biomarkers and ways in which they could be used in the future to predict which treatments patients might respond to best.

Using clinical cases to guide healthcare.

Evidence-based practice (EBP) has been the gold standard in healthcare for nearly three centuries and aims to assist physicians in providing the safest and most effective healthcare for their patients. The well-established hierarchy of evidence lists systematic reviews and meta-analyses at the top however these methodologies are not always appropriate or possible and in these instances case-control studies, case series and case reports are utilised to support EBP. Case-control studies allow simultaneous study of multiple risk factors and can be performed rapidly and relatively cheaply. A recent example was during the Coronavirus pandemic where case-control studies were used to assess the efficacy of personal protective equipment for healthcare workers. Case series and case reports also play a role in EBP and are particularly useful to study rare diseases such as inflammatory bowel disease in transgender and gender non-conforming individuals. They are also vital in generating and disseminating early signals and encouraging further research. Whilst these methodologies have weaknesses, particularly with regards to bias and loss of patient confidentiality for rare pathologies, they have an important part to play in EBP and when appropriately utilised can significantly impact upon clinical practice.

JAK inhibitors for inflammatory bowel disease: recent advances.

Inflammatory bowel disease (IBD) commonly requires immunosuppressive treatments to induce and maintain durable remission. Janus kinase inhibitors (JAKis) are a novel group of orally administered, small molecule drugs that work by attenuating multiple cytokine signalling pathways to mediate dysregulated immune responses involved in the pathogenesis of IBD. Tofacitinib, filgotinib and upadacitinib have demonstrated efficacy against placebo and are licensed for the treatment of moderate to severe ulcerative colitis; upadacitinib is the only JAKi also currently approved for the treatment of Crohn's disease. Safety concerns stratified by age have led to class-wide regulatory restrictions for JAKi use across all inflammatory diseases. It is important for gastroenterologists managing patients with IBD to be aware of the key pivotal trial outcomes, to identify appropriate patients in whom to commence a JAKi, and to understand the safety considerations and ways to mitigate these risks in the patients they treat. This review provides a contemporaneous overview of this emerging therapeutic class and provides a practical guide for healthcare practitioners for initiating and monitoring JAKi in IBD.

The evolution of informed consent in gastroenterology.

With medical litigation on the rise, physicians require a nuanced understanding of the legalities of consenting patients to reduce their liability while practising evidence-based medicine. This study aims to a) clarify the legal duties of gastroenterologists in the UK and USA when gaining informed consent and b) provide recommendations at the international and physician level to improve the consent process and reduce liability.A bibliometric analysis of the Web of Science database with the MeSH terms "gastroenterology" and "informed consent" yielded 383 articles, of which 228 were excluded due to not meeting the inclusion criteria. Of the top 50 articles, 48% were from American institutions and 16% were from the UK. Thematic analysis showed 72% of the articles discussed informed consent in relation to diagnostic procedures, 14% regarding treatment, and 14% regarding research participation.Both the USA and the UK have progressed from previously paternalistic Natanson case (1960) and Bolam test (1957), respectively, where physicians were held to the standard of a "reasonable and prudent medical doctor". The American Canterbury case (1972) and the British Montgomery case (2015) radically shifted the standard of disclosure during the consent process by requiring physicians to explain all information pertinent to a "reasonable patient".It is our recommendation that a two-pronged approach be taken; a) creation of international guidelines for consenting patients for invasive procedures in gastroenterology, and b) development of internationally standardised endoscopy consent forms containing all the details pertinent to a "reasonable patient".

Using national census data to facilitate healthcare research.

National censuses are conducted at varying intervals across both the developed and developing world and collect detailed data on a wide range of societal, economic and health questions. This immense volume of data has many potential uses in the field of healthcare research and can be utilised either in isolation or in conjunction with other information sources such as hospital records. At a governmental level census data can be used for healthcare service planning by providing accurate population density information but also, through the use of more detailed data collection, by helping to identify high-risk populations that may require increased resource allocation. It can also be a key tool in addressing and improving healthcare inequality and deprivation by both identifying those populations with poorer healthcare outcomes and through helping researchers to better understand the causes of this inequality. Similarly, it has utility when studying the complex causes of disease and assessing the success of strategies designed to tackle these aetiologies. However, the maximum benefit from these various uses can only be realised if the data collection and analysis processes utilised are robust and this requires that census bureaus regularly review and modify their methods in a transparent and thorough way.

Emerging role of colorectal mucus in gastroenterology diagnostics.

Colonoscopy is currently the gold standard for diagnosis of inflammatory bowel disease (IBD) and colorectal cancer (CRC). This has the obvious drawback of being invasive as well as carrying a small risk. The most widely used non-invasive approaches include the use of faecal calprotectin in the case of IBD and fecal immunochemical test in the case of CRC. However, the necessity of stool collection limits their acceptability for some patients. Over the recent years, there has been emerging data looking at the role of non-invasively obtained colorectal mucus as a screening and diagnostic tool in IBD and CRC. It has been shown that the mucus rich material obtained by self-sampling of anal surface following defecation, can be used to measure various biomarkers that can aid in diagnosis of these conditions.

COVID-19 infection causing residual gastrointestinal symptoms - a single UK centre case series.

Although COVID-19 was first recognised as an acute respiratory illness, extra-pulmonary manifestations are increasingly being recognised. Acute gastrointestinal side effects have been well reported with COVID-19 infection and are estimated to affect around 17% of patients. With COVID-19 still being a relatively new illness, the chronic gastrointestinal symptoms are less well characterised. Post-infectious irritable bowel syndrome (IBS) can occur following bacterial and viral infections, and with ACE-2 receptors being shown to be present in the gastrointestinal tract and SARS-Cov-2 RNA being present in stool, SARS-CoV-2 is now appreciated as an enteric pathogen. In our study, we survey acute and chronic gastrointestinal symptoms after COVID-19 infection. We have conducted one of the few UK studies on gastrointestinal symptoms, with the longest follow-up duration of 6 months. We have found that gastrointestinal symptoms are common at 6 months, affecting 43.8% of our patients. Further research is needed to explore whether this represents a new post-COVID-19 IBS, which has not previous been described in the literature, including its clinical course and response to any potential medical therapies.

Associations with pancreatic exocrine insufficiency: An United Kingdom single-centre study.

BACKGROUND: Pancreatic exocrine insufficiency (PEI) is said to be associated with numerous conditions both within and outside the gastrointestinal (GI) system. The majority of research has been concerned with conditions that reduce the volume of functioning pancreatic tissue or prevent adequate drainage to the small bowel, such as chronic pancreatitis, cystic fibrosis, pancreatic cancer and pancreatic resection. However, the evidence base supporting an association with extra-pancreatic conditions, such as coeliac disease, diabetes mellitus and congestive cardiac failure, is heterogeneous. AIM: To strengthen the evidence base by studying all previously reported associations with PEI in a large cohort of outpatients. METHODS: A single-centre retrospective study was performed. General gastroenterology outpatients tested for PEI with faecal elastase-1 (FE1) were identified and information retrieved from the electronic patient record. PEI was defined as FE1 < 200 µg/g. Patients already taking pancreatic enzyme replacement therapy were excluded. Multiple imputation was used to handle missing data. Univariable logistic regression was used to study which presenting symptoms predicted PEI. Multivariable logistic regression was used to explore the relationship between all previously reported associations and PEI. RESULTS: Of 1027 patients were included. 182 patients (17.7%) were diagnosed with PEI. Steatorrhoea [odds ratios (OR): 2.51, 95% confidence intervals (CI): 1.58-3.98] and weight loss (OR: 1.49, 95%CI: 1.08-2.06) were the only presenting symptoms that predicted PEI. Chronic pancreatitis (OR: 7.98, 95%CI: 3.95-16.15), pancreatic cancer (OR: 6.58, 95%CI: 1.67-25.98), upper GI surgery (OR: 2.62, 95%CI: 1.32-5.19), type 2 diabetes (OR: 1.84, 95%CI: 1.18-2.87), proton pump inhibitor therapy (OR: 1.87, 95%CI: 1.25-2.80) and Asian ethnicity (OR: 2.11, 95%CI: 1.30-3.42) were significantly associated with PEI in the multivariable analysis. None of the other historically reported associations with PEI were significant after adjustment for the other variables included in our multivariable analysis. CONCLUSION: PEI is common in patients with chronic pancreatitis, pancreatic cancer, upper GI surgery and type 2 diabetes. Proton pump inhibitor therapy may also be associated with PEI or a false positive FE1.

The investigation and management of pancreatic exocrine insufficiency: A retrospective cohort study.

Pancreatic exocrine insufficiency (PEI) is associated with significant gastrointestinal symptoms, but is readily treated by pancreatic enzyme replacement therapy (PERT). We reviewed our current practice and examined the factors that predict repeating a positive faecal elastase-1 (FE1; <200 µg/g), the repeat FE1 being normal, initiation of PERT and clinical response to treatment. A single-centre retrospective cohort study was conducted. Outpatients with FE1 <200 µg/g between 2012 and 2018 were included. Logistic regression was used to explore the associations with each outcome, with statistical adjustment for confounders. Two-hundred and ten patients were included; 28.1% of patients had their FE1 repeated, 47.5% of whom had a normal repeat result. Patients with initial FE1 <15 µg/g were unlikely to be reclassified on repeat testing. Patients with a confirmatory low FE1, abnormal pancreatic imaging or abnormal nutrition blood tests were more likely to be started on PERT (all p<0.05). Patients with abnormal pancreatic imaging were 10 times more likely to respond to PERT (odds ratio 10.70; 95% confidence interval 1.62-70.70; p=0.01). Augmenting clinical judgement with pancreatic imaging and repeat FE1 testing could improve the rate of PERT prescription and inform the approach to non-response, particularly in cases where there is diagnostic doubt.

Patient perspectives on social-media-delivered telemedicine for inflammatory bowel disease.

In attempts to reduce the spread of COVID-19 among high-risk inflammatory bowel disease patients, many gastroenterology practices have recently gone 'virtual', using telemedicine technologies to care for their patients. In efforts to support this transition and improve approachability, social media platforms have been used to deliver telemedicine services with significant success. However, the patient perspective on this use of social media has largely been ignored. This study provides a baseline patient perspective on social media usage to help inform clinicians on which methods of telemedicine delivery will be best suited to their patient populations.

Gastrointestinal symptoms in acromegaly: A case control study.

BACKGROUND: Acromegaly is a chronic disease caused by a pituitary somatotroph adenoma resulting in excess secretion of growth hormone, which leads to excess secretion of Insulin like growth factor 1 from the liver, causing abnormal soft tissue growth. There is increasing awareness that diseases affecting connective tissue are associated with an increase in functional gastrointestinal symptoms. Data was collected from patients with a confirmed diagnosis of acromegaly to evaluate the intensity, variety and impact of abdominal symptoms in comparison with a control group who were healthy participants recruited from the local fracture clinic. AIM: To evaluate the frequency type and burden of abdominal symptoms in acromegaly in comparison with a control group. METHODS: Medical documentation of patients with a diagnosis of acromegaly treated in one tertiary medical centre between 2010 and 2017 has been analysed. Data was collected from patients with confirmed acromegaly, using the Short Form Health Survey (SF36) and Rome IV Diagnostic questionnaire for Functional Gastrointestinal Disorders in Adults (R4DQ) and compared to a sex- and age-matched control group, to assess the burden of abdominal symptoms. Microsoft Excel and IBM SPSS v 25 were used for data analysis. RESULTS: Fifty patients with acromegaly (24 male and 26 females; age range 23-64 years, mean 43) and 200 controls (96 male and 104 females; age range 18-84, mean 42.4) were recruited. 92% (46 out of 50) of patients with acromegaly reported abdominal symptoms and 78% (39 out of 50) had at least one functional gastrointestinal disorder according to the Rome IV diagnostic criteria, compared to 16% of controls (OR > 1, P < 0.0001). The most commonly reported symptom was constipation (69% acromegaly vs 21% of controls OR > 1, P < 0.0001, 95%CI: 4.4-15.8). 34 out of 50 (68%) respondents met the criteria for functional constipation according to Rome IV. Upper gastrointestinal disorders were also more prevalent in the acromegaly group. There was no statistically significant difference in the prevalence of biliary and anorectal symptoms between the two groups. Patients in acromegaly group scored lower on the mean scores of the eight parameters of SF36 Quality of Life questionnaire (mean scores 60.04 vs 71.23, 95%CI: -13.6829 to -8.6971, OR > 1, P < 0.001) as compared to the control group. CONCLUSION: Upper and lower functional gastrointestinal tract disorders (defined by Rome IV diagnostic criteria) are significantly more prevalent in patients with acromegaly compared with healthy age and sex matched controls in our study. Functional constipation is the most commonly reported problem. Poorer quality of life may in part be attributable to the increased prevalence of abdominal symptoms.

Optical imaging technology in colonoscopy: Is there a role for photometric stereo?

Colonoscopy screening for the detection and removal of colonic adenomas is central to efforts to reduce the morbidity and mortality of colorectal cancer. However, up to a third of adenomas may be missed at colonoscopy, and the majority of post-colonoscopy colorectal cancers are thought to arise from these. Adenomas have three-dimensional surface topographic features that differentiate them from adjacent normal mucosa. However, these topographic features are not enhanced by white light colonoscopy, and the endoscopist must infer these from two-dimensional cues. This may contribute to the number of missed lesions. A variety of optical imaging technologies have been developed commercially to enhance surface topography. However, existing techniques enhance surface topography indirectly, and in two dimensions, and the evidence does not wholly support their use in routine clinical practice. In this narrative review, co-authored by gastroenterologists and engineers, we summarise the evidence for the impact of established optical imaging technologies on adenoma detection rate, and review the development of photometric stereo (PS) for colonoscopy. PS is a machine vision technique able to capture a dense array of surface normals to render three-dimensional reconstructions of surface topography. This imaging technique has several potential clinical applications in colonoscopy, including adenoma detection, polyp classification, and facilitating polypectomy, an inherently three-dimensional task. However, the development of PS for colonoscopy is at an early stage. We consider the progress that has been made with PS to date and identify the obstacles that need to be overcome prior to clinical application.

Biomarker measurement in non-invasively sampled colorectal mucus as a novel approach to colorectal cancer detection: screening and triage implications.

BACKGROUND: Faecal tests are widely applied for colorectal cancer (CRC) screening and considered for triaging symptomatic patients with suspected CRC. However, faecal tests can be inconvenient, complex and expensive. Colorectal mucus (CM) sampled using our new patient-friendly non-invasive technique is rich in CRC biomarkers. This study aimed to evaluate diagnostic accuracy of CRC detection by measuring protein biomarkers in CM. METHODS: Colorectal mucus samples were provided by 35 healthy controls, 62 CRC-free symptomatic patients and 40 CRC patients. Biomarkers were quantified by ELISA. Diagnostic performances of haemoglobin, C-reactive protein, tissue inhibitor of metalloproteinases-1, M2-pyruvate kinase, matrix metalloproteinase-9, peptidyl arginine deiminase-4, epidermal growth factor receptor, calprotectin and eosinophil-derived neurotoxin were assessed using receiver operating characteristic (ROC) curve analysis. RESULTS: Colorectal mucus haemoglobin was superior compared to other biomarkers. For haemoglobin, the areas under the curve for discriminating between CRC and healthy groups ('screening') and between CRC and symptomatic patients ('triage') were 0.921 and 0.854 respectively. The sensitivity of 80.0% and specificities of 94.3% and 85.5% for the two settings respectively were obtained. CONCLUSIONS: Haemoglobin quantification in CM reliably detects CRC. This patient-friendly approach presents an attractive alternative to faecal immunochemical test; however, the two methods need to be directly compared in larger studies.

Colorectal cancer detection by biomarker quantification in noninvasively collected colorectal mucus: preliminary comparison of 24 protein biomarkers.

OBJECTIVES: Noninvasive colorectal cancer detection and screening remain global diagnostic challenges because the existing stool tests either lack sensitivity or are complex and expensive. Moreover, colorectal cancer screening uptake is low due to stool sampling inconvenience. We have developed a simple and patient-friendly noninvasive technique for collecting highly informative colorectal mucus. In this study, we aimed to comparatively assess a range of candidate biomarkers in colorectal mucus samples for colorectal cancer detection. METHODS: The study included 17 patients with colorectal cancer and 35 healthy controls, who provided noninvasively collected colorectal mucus samples. Protein biomarker quantification in these samples by enzyme-linked immunosorbent assays allowed comparing diagnostic performances of 24 candidate biomarkers that comprised haemoglobin, D-dimer, M2-pyruvate kinase, carcinoembryonic antigen, C-reactive protein, calprotectin, eosinophil-derived neurotoxin, protein S100A12, tumour necrosis factor α, clusterin, soluble cytokeratin 18, caspase-cleaved cytokeratin 18, citrullinated histone H3, peptidyl arginine deiminase 4, epidermal growth factor, epidermal growth factor receptor, matrix metalloproteinase 9, tissue inhibitor of metalloproteinase 1, periostin, vascular endothelial growth factor A, vascular endothelial growth factor receptor 1, vascular cell adhesion molecule 1, intercellular adhesion molecule 1 and mucin 2. Tested biomarkers were ranked for colorectal cancer detection efficiency using receiver operating characteristic curve analysis. RESULTS: High area under the curve values between 0.943 and 0.768 were observed for haemoglobin, tissue inhibitor of metalloproteinase 1, M2-pyruvate kinase, peptidyl arginine deiminase 4, C-reactive protein, matrix metalloproteinase 9, epidermal growth factor receptor, eosinophil-derived neurotoxin and calprotectin. CONCLUSION: Quantification of protein biomarkers in noninvasively collected samples of colorectal mucus certainly allows detecting colorectal cancer. Further clinical evaluation of the optimal biomarkers identified by this study is needed.

Challenges in the management of pancreatic exocrine insufficiency.

Pancreatic exocrine insufficiency (PEI) occurs when the insufficient secretion or function of pancreatic enzymes leads to maldigestion, most commonly as a result of chronic pancreatitis and pancreatic cancer. The condition is associated with significant morbidity and reductions in quality of life, even in milder forms. The challenges in approaching this condition include the non-specific presentation of mild to moderate PEI, and the lack of a convenient, accurate diagnostic test in this cohort. Classical symptoms appear late in the disease, and the diagnosis should be considered before steatorrhoea develops. Direct pancreatic function tests are the reference standard for diagnosis, but are invasive and not widely available. The faecal elastase-1 (FE-1) stool test is widely available and has been shown to be as effective as the 13C-mixed triglyceride breath test in more advanced disease. We recommend a pragmatic diagnostic approach that combines clinical history, assessment of nutritional status and measurement of FE-1. The critical first step is to consider the diagnosis. Once the diagnosis is confirmed, pancreatic enzyme replacement therapy should be initiated. The variety of enzyme preparations and recommended dosing regimens can present a challenge when selecting an adequate initial dose. Non-response should be actively sought and addressed in a systematic manner. This article discusses these challenges, and presents a practical approach to the diagnosis and management of PEI.

Health concerns associated with travelling with inflammatory bowel disease (IBD): a questionnaire survey.

When travelling, patients with inflammatory bowel disease (IBD) have a higher risk of morbidity. We identified barriers to travel, specific health concerns and several areas for service improvement among patients. In total, 136 patients were given a 32-question service improvement questionnaire. Of these, 89% travelled abroad, 30% reported that IBD limited travel and 40% said it affected choice of destination. Fourty-seven percent of patients travelled abroad without health insurance and 7% were refused. Seventy-eight percent wanted pre-travel advice from doctors in the future. Popular service improvement options included providing written prescriptions (91%) and management plans (75%). Sixty-three percent of patients were unaware of needing to avoid live vaccines while on immunosuppressants. Ninety-two percent were unaware that high altitudes could precipitate flares; 27% travelled abroad to high-altitude destinations, of which 46% subsequently had flare-ups. Existing IBD travel services remain unknown such as the 'Can't wait' card (72%) and 'IBD passport' (96%). Service improvements in the IBD clinic need to be implemented to facilitate safer travel overseas.

Inflammatory bowel disease detection and monitoring by measuring biomarkers in non-invasively collected colorectal mucus.

BACKGROUND AND AIM: Non-invasive detection and monitoring of inflammatory bowel disease (IBD) is an important clinical challenge. Stool calprotectin is the most popular among available options, but the necessity of stool collection limits its acceptability. This study aimed to evaluate biomarker measurement in non-invasively collected colorectal mucus as a new tool for IBD detection and activity monitoring. METHODS: Calprotectin, eosinophil-derived neurotoxin (EDN), and protein S100A12 were measured in colorectal mucus self-collected following defecation by 58 patients with IBD (before therapy), 50 patients with irritable bowel syndrome, and 33 healthy volunteers. Patients with IBD also collected samples at days 10, 20, and 30 of treatment for disease activity monitoring. RESULTS: Protein biomarker levels were significantly (P < 0.001) higher in IBD patients than in irritable bowel syndrome and control groups. Calprotectin and EDN effectively detected IBD with a respective sensitivity and specificity of 0.76 and 0.92 for calprotectin and 0.83 and 0.94 for EDN. S100A12 was less sensitive. Calprotectin and EDN results were combined in a new test (CALEDN) that had a sensitivity of 0.91 and a specificity of 0.89. Repeated biomarker measurement during IBD treatment demonstrated a steady decline of calprotectin and EDN levels as well as CALEDN values in patients responding to applied therapy and lack of this pattern in non-responders. CONCLUSIONS: Measuring calprotectin and EDN in non-invasively collected colorectal mucus presents a simple and efficient method for IBD detection and monitoring. Excellent performance of EDN for this purpose is reported for the first time. Combining calprotectin and EDN in one test improves IBD detection sensitivity.