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Predicting relapse in patients with inflammatory bowel disease: what is the role of biomarkers?
  1. D S Pardi,
  2. W J Sandborn
  1. Inflammatory Bowel Disease Clinic, Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, Minnesota, USA
  1. Correspondence to:
    Dr D S Pardi
    Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN 55905, USA; pardi.darrellmayo.edu

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Faecal calprotectin seems to be a relatively sensitive and specific marker of the risk of relapse in ulcerative colitis, but not in Crohn’s disease

Various laboratory biomarkers have been studied in inflammatory bowel disease (IBD) as diagnostic aids, indicators of disease activity or severity, and to predict the risk of relapse in those patients in remission. These biomarkers have enormous potential implications for patient management. For example, therapeutic decisions could be directed more appropriately if a marker could reliably distinguish active IBD from other inflammatory or non-inflammatory causes of symptoms, or if one could distinguish Crohn’s disease from ulcerative colitis. In addition, a simple, inexpensive, sensitive, specific marker could help monitor response in the clinic and in clinical trials. Finally, the ability to reliably predict the risk of recurrence would help direct appropriate therapy to those who would most likely benefit from it and avoid the expense and potential toxicity of chronic maintenance therapy in those who have a low risk of recurrence. In the current issue of Gut, Costa and colleagues1 addressed the latter issue by studying the role of faecal calprotectin as a marker of risk of relapse in ulcerative colitis and Crohn’s disease (see page 364). Calprotectin represents 50–60% of neutrophilic cytosolic protein, is stable in faeces for several days after excretion, and has a relatively easy to perform assay which is available commercially and correlates well with the more difficult and more expensive indium 111-labelled leucocyte excretion2

Costa and colleagues1 studied 38 patients with Crohn’s disease and 41 with ulcerative colitis in remission for a mean of five months. A baseline faecal calprotectin level greater than 150 μg/g had a sensitivity for predicting relapse within the next year of 89% in ulcerative colitis and 87% in Crohn’s disease. The specificity in ulcerative colitis was 82% but only 43% in Crohn’s disease. After multivariate analysis, patients with Crohn’s disease with a baseline faecal calprotectin greater than 150 μg/g had a non-significant twofold increased likelihood of relapse whereas those with ulcerative colitis and an elevated faecal calprotectin had a significant 14-fold increase risk. C reactive protein (CRP) and erythrocyte sedimentation rate (ESR), either as single tests or combined with calprotectin, were not useful for predicting relapse.

The results of this study add to the growing body of literature on biomarkers in IBD in general and faecal calprotectin in particular. In previous studies, faecal calprotectin has been shown to be a sensitive marker of activity in Crohn’s disease and to correlate well with endoscopic and histological disease activity in ulcerative colitis.3,4 Faecal calprotectin also normalises along with endoscopic healing in Crohn’s disease5 and is a very sensitive and specific marker for distinguishing IBD from irritable bowel syndrome (IBS).3 The Costa study suggests that calprotectin is a good marker of relapse risk in ulcerative colitis, but not in Crohn’s disease, related primarily to poor specificity, and therefore poor positive predictive value. However, a previous study of faecal calprotectin as a marker of relapse risk in IBD found a faecal calprotectin level of 50 μg/g to be a sensitive and specific marker of recurrence risk in both ulcerative colitis and Crohn’s disease.6 In this study, patients with a faecal calprotectin level greater than 50 μg/g had a 13-fold increased risk of relapse, and the specificity for predicting relapse in Crohn’s disease was 83%, compared with 43% in the Costa study.6

The reason(s) for the poorer specificity of calprotectin in the current study are not clear. A different cut off value was used, but the higher cut off in the Costa study would be expected to increase specificity rather than decrease it. The definition of remission and relapse were similar in the two studies, and both used an ELISA assay (although the assays were probably at least slightly different). In the previous study, patients were in remission for 1–4 months while in the Costa study they were in remission for 1–12 months. Perhaps the value of calprotectin for predicting relapse in Crohn’s disease decreases the longer a patient is in remission.

Several other clinical indices and biological markers have been studied in IBD. These can be divided into clinical disease activity indices, endoscopic indices, serum markers, faecal markers, and miscellaneous tests. Clinical indices, including the Crohn’s disease activity index (CDAI) and other disease activity indices for Crohn’s disease and ulcerative colitis, are largely subjective and typically cumbersome and have significant interobserver variability. Furthermore, they are not valid in patients with fistulas, stomas, and non-inflammatory causes of symptoms (for example, stenosis, post surgical anatomy). There are also several endoscopic indices of severity. The Crohn’s disease endoscopic index of severity7 has a poor correlation with clinical activity and treatment induced remission, although complete mucosal healing may predict a favourable course. However, this index is complex and not suitable for routine clinical practice.8 The most well known endoscopic index of severity is the Rutgeerts score which is simple and accurately predicts the risk of recurrence after surgical resection.9

A multitude of serum markers have been studied in IBD. Many of these are acute phase reactants (acid α1 glycoprotein (orosomucoid)), CRP, fibrinogen, lactoferrin, serum amyloid A, and α1 antitrypsin.10 In an early study, Brignola and colleagues found that combining acid α1 glycoprotein, α2 globulin, and ESR into an index resulted in 88% accuracy in predicting relapse over 18 months in patients with Crohn’s disease in remission.11 They found no value in baseline levels of haemoglobin, white blood cell count, albumin, iron, or CRP. Other studies have also found limited value for CRP in predicting relapse.1,6,12 Data on other markers such as serum and urinary neopterin levels, serum tumour necrosis factor (TNF) α levels, TNF-α receptor levels, and various interleukins (IL-1, IL-6, IL-8), interleukin receptors (IL-2R, IL-6R), or interleukin receptor antagonists (IL-1ra) are limited or contradictory.9,13

As serum markers of inflammation can be elevated in a variety of conditions, it seems likely that faecal markers of inflammation, in the absence of enteric infection, would be more specific for IBD. Faecal markers can be divided into faecal excretion of leucocytes, serum proteins, or leucocyte products. Faecal excretion of indium 111-labelled white blood cells has a good correlation with colitis but not ileitis and has no correlation with CDAI.14 These issues, together with the cost, radiation exposure, and limited availability of this technology makes measurement of faecal excretion of indium-labelled white blood cells of limited value clinically.

Faecal excretion of various serum proteins has also been studied in IBD. Perhaps the best studied is faecal α1 antitrypsin excretion. However, the data on this protein and its correlation with disease activity and response to therapy are mixed.14 More promising is faecal excretion of various leucocyte products. Faecal lysozyme excretion correlates with disease activity and indium 111 white blood cell excretion in colitis but not in ileitis, and it is also elevated in other gastrointestinal inflammatory disorders, limiting its specificity for IBD.14 Faecal lactoferrin concentration is increased in active IBD compared with inactive IBD, IBS, and healthy controls.14,15 In addition, in patients tapering off steroids, persistent elevations in faecal lactoferrin may predict an increased risk of early relapse and therefore may help guide the rapidity of the steroid taper.15 Finally, faecal lactoferrin levels may rise significantly prior to a clinically evident relapse and thus may be a good marker to predict subsequent IBD flares.15 Other faecal markers, such as elastase, myeloperoxidase, leucocyte esterase, and TNF-α, have less promising data.14

Several miscellaneous tests have also been studied in IBD. Indium 111 white blood cell scanning can identify and localise active disease and distinguish IBD from IBS and fibrotic from inflammatory strictures. However, labelled leucocyte scans cannot distinguish IBD from other causes of intestinal inflammation and are expensive and involve radiation exposure.16

Intestinal permeability can be measured by a variety of methods. Measures of intestinal permeability have 95% sensitivity for identifying active Crohn’s enteritis but only 50% for colitis.17 Intestinal permeability is thought to be a potentially useful measure of response to therapy in Crohn’s disease, particularly in the small bowel.16 In Crohn’s disease, tests of intestinal permeability have a sensitivity of 84–89% and a specificity of 61–76% for predicting relapse within one year but only 53% and 85%, respectively, at four months.8 Furthermore, these tests are somewhat time consuming and difficult, with limited availability and therefore are of questionable clinical value.

Other tests that have been used to measure disease activity or to predict relapse include assaying whole gut lavage fluid for immunoglobulin G, IL-1B, and IL-8.13 However, data on these markers are limited and patient acceptability would likely be low for repeated testing. Others have measured various inflammatory markers, including TNF-α and IL-1B production from stimulated cultured lamina propria mononuclear cells and showed that the degree of production is predictive of relapse over one year.18 However, this technology requires mucosal biopsies and therefore application to small bowel disease would be limited. Furthermore, this technique is relatively difficult requiring cell culture and stimulation.

In summary, the current clinical indices or biological markers of disease activity are for the most part too invasive, too difficult, too expensive, or require radiation exposure. Two possible exceptions are faecal calprotectin and faecal lactoferrin excretion, which are relatively simple and inexpensive. Based on two studies to date1,6 faecal calprotectin seems to be a relatively sensitive and specific marker of the risk of relapse in ulcerative colitis. It also appears to be a sensitive marker of relapse risk in Crohn’s disease but the data on specificity are conflicting at this point. However, these data need to be interpreted cautiously. The number of studies is small, and in both studies using calprotectin to predict relapse risk, most patients were on medical therapy. Calprotectin may behave differently in patients who are on no therapy. Therefore, before faecal calprotectin or any other biological marker of activity can be incorporated into routine clinical practice, other studies in larger and diverse groups of patients will be necessary to clarify its role further.

Faecal calprotectin seems to be a relatively sensitive and specific marker of the risk of relapse in ulcerative colitis, but not in Crohn’s disease

REFERENCES

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  • Conflict of interest Statement

    Drs. Pardi and Sandborn receive research support from TechLab, Blacksburg, Virginia.
    D S Pardi and W J Sandborn

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