Investigating the role of faecal calprotectin in luminal gastroenterology

Providing a sensitive, non-invasive, cheap marker of disease activity inflammatory bowel disease (IBD) comprises an area of ongoing interest and unmet clinical need. In previous years, options included only serum CRP (poorly sensitive and specific), colonoscopy (invasive, costly, perforation risk, inability to view proximal small bowel), CT (costly, ionising radiation risk) and radiolabelled white cell scanning (costly, poor sensitivity). My thesis describes a series of trials performed to establish the role of faecal calprotectin to define current disease activity in IBD patients. Prompted by studies demonstrating the potential role for a novel faecal marker of clinical utility in the context of NSAID enteropathy, we chose to investigate the role of this biomarker, faecal calprotectin (FC), in Crohn’s disease. To facilitate this I used existing cohorts and then generated new cohorts in which to address fundamental and clinically relevant questions of importance. We compared FC to radiolabelled white cell scanning in our first study which initiated and established a mutually beneficial collaboration between luminal gastroenterology and clinical biochemistry. Thereafter we recruited a rigorously phenotyped cohort of Crohn’s disease patients in remission to answer two separate research questions. First, was there a significant intra-individual variability of FC and secondly, would FC sampling in remission predict future relapse over the ensuing 12 months? Thereafter, in a new cohort, we investigated whether we were over-investigating new GP referrals to the GI clinic with only mildly elevated FC values. Finally, and most recently, we sought to investigate whether or not there was any correlation between serum calprotectin and FC in a new unselected GI cohort of patients, thereby potentially obviating the need for our patients to collect stool samples. Our data demonstrated that FC correlated well with radiolabelled white cell scanning in assessment of Crohn’s disease activity, thereby potentially avoiding this costly test as part of disease monitoring. In addition, we defined an acceptable intra-individual variability of FC in Crohn’s disease to support the clinical utility of one off testing using FC. Our prospective dataset revealed that an FC in remission can indeed stratify Crohn’s disease patients to estimate future relapse risk thereby allowing us to personalise medical therapies with more aggressive therapeutics employed in those with Crohn’s disease in remission but with residual high FC. The work we undertook in our primary care dataset revealed an extremely low yield of investigating mildly elevated FC and thus we developed a new shared protocol with our GP colleagues in which serial FC testing is recommended rather than referral to secondary care for such patients. Lastly, our most recent work demonstrated that there was no significant correlation between serum and FC in an unselected GI cohort meaning the search for a GI-specific serum biomarker of inflammation goes on – this is in accord with a variety of other chronic inflammatory diseases in which circulating biomarkers have proven challenging to find and especially to validate. This body of work has been presented nationally and internationally at meetings, and has been published in discipline relevant, peer reviewed medical journals. Moreover, it has supported the adoption of FC into everyday NHS GI practice. We were the first UK hospital to establish an NHS service for this biomarker in 2007 when we performed around 50 assays per month. Currently, the test is in widespread use and the Glasgow Royal Infirmary biochemistry lab now analyses 1400 samples per month. This has become an established non-invasive, cheap, sensitive marker of IBD activity in clinical practice, often avoiding the need for colonoscopy for the purposes of disease activity monitoring. This biomarker is also being used to gauge the success or failure of medical therapies in IBD and is a useful tool to differentiate irritable bowel syndrome from IBD. The clinical utility of the test has allowed GPs to triage referrals and often avoid referrals completely and has engaged patients in the self-monitoring of their IBD