Faecal calprotectin for screening of patients with suspected inflammatory bowel disease: diagnostic meta-analysis
BMJ 2010; 341 doi: https://doi.org/10.1136/bmj.c3369 (Published 15 July 2010) Cite this as: BMJ 2010;341:c3369
All rapid responses
Rapid responses are electronic comments to the editor. They enable our users to debate issues raised in articles published on bmj.com. A rapid response is first posted online. If you need the URL (web address) of an individual response, simply click on the response headline and copy the URL from the browser window. A proportion of responses will, after editing, be published online and in the print journal as letters, which are indexed in PubMed. Rapid responses are not indexed in PubMed and they are not journal articles. The BMJ reserves the right to remove responses which are being wilfully misrepresented as published articles or when it is brought to our attention that a response spreads misinformation.
From March 2022, the word limit for rapid responses will be 600 words not including references and author details. We will no longer post responses that exceed this limit.
The word limit for letters selected from posted responses remains 300 words.
Sir,
We have been very interested by the metaanalysis of van Rheenen et al (1).
However, we think that these results present limitations for crohn's
disease (CD). Calprotectine levels depend strongly with the phenotype of
this disease. Costa et al. found sensitivity and specificity around 90%
for predicting relapse in ulcerative colitis but their specificity of
calprotectine in CD was 43%. D'Inca et al. (3) reported that in CD
patients, only case of colonic CD showed a significant correlation between
a positive calprotectine test and a probability of release.
Results for
sensitivity and specificity of calprotectine in IBD patients were better
when only colonic CD were considered. So, bias may be present because
the authors pooled all patients without considering the phenotype of CD.
1- van Rheenen PF, Van de Vijver E, Fidler V.Faecal calprotectin for
screening of patients with suspected inflammatory bowel disease:
diagnostic meta-analysis. BMJ. 2010;341:c3369.
2- Costa F, Mumolo MG, Ceccarelli L, Bellini M, Romano MR, Sterpi C et al.
Calprotectin is a stronger predictive marker of relapse in ulcerative
colitis than in Crohn's disease.Gut. 2005;54:364-8.
3- D'Incà R, Dal Pont E, Di Leo V, Benazzato L, Martinato M, Lamboglia F
et al. Can calprotectin predict relapse risk in inflammatory bowel
disease? Am J Gastroenterol. 2008;103:2007-14.
Competing interests:
None declared
Competing interests: No competing interests
MAdCAM-1 belongs to the immunoglobulin (Ig) superfamily, human MAdCAM
-1 contains two IgSF domains, a transmembrane domain and a 43-residue
cytoplasmic domain. The Ig domains are crucial for binding to ¦Á4¦Â7,
whereas the appropriately O-glycosylated mucin-like structures bind L-
selectin [1,2]. MAdCAM-1 is a cell adhesion molecule that is
constitutively expressed on the high endothelium venules of intestinal
propria, and guides the specific homing of lymphocytes into mucosal
tissues. The proportion of venular endothelium within lamina propria that
expresses MAdCAM-1 is increased at foci associated with inflammatory bowel
disease (IBD), but it is not detected in the majority of normal or
inflamed extra-intestinal tissues, including those with mucosal surfaces
[3]. Recent studies indicates that the up-regulation of MAdCAM-1 on
mucosal have some critical impact on the activity and relapse of IBD.
IBD has traditionally been classified into two subtypes, namely,
ulcerative colitis (UC) and Crohn's disease (CD). Although there are
differents in the underlying cause, both UC and CD are associated with a
massive influx of immune cells into the gut. Up-regulation of
proinflammatory cytokines in IBD leads to increased expression of vascular
adhesion molecules, resulting in a sustained influx of inflammatory cells.
Some of these cells traffic in a gut-tropic manner in response to
increased levels of MAdCAM-1 on mucosal vessels, which promotes
recruitment to the gut lamina propria in IBD [4]. It has been found that
expression of MAdCAM-1 increases with inflammation, especially chronic
inflammation [5]. The crucial role of MAdCAM-1 in IBD makes it an
interesting target for drug development, pioneering studies with
antiadhesion strategies has been clearly shown that the chronic
inflammation was significantly attenuated after treating with anti-¦Á4¦Â7-
integrin monoclonal antibody, MLN-02, formerly LDP-02. Administration of
this antibody markedly improved the clinical and histological scores in
the IBD [6].
It is reasonable to hypothesize that MAdCAM is probable a determinant
of the development of inflammatory bowel disease, it may be a potential
therapic target in inflammatory bowel disease. Therefore, we can direct
against regulation of the coagulation competence with MAdCAM as one of the
primary target. Recombinant adeno-associated viral (rAAV) vectors are
selected as anti-MAdCAM gene vector. Recombinant adeno-associated viral
vectors have gained attention as a potentially alternative to the more
commonly used retroviral vectors. In our opinion, the adeno-associated
viral human anti-MAdCAM gene seems to hold interesting future prospects
for the treatment of IBD by the suitable injection of vein.
Yiyi Sun1, Zhihe Zang1, Xiaohong Xu1, Zhonglin Zhang1, Ling Zhong1,
Wang Zan1, Yan Zhao1, Lin Sun2*
1.Chengdu Medical College, Chengdu 610083, Sichuan Province, China
2.West China Hospital, Sichuan University, Chengdu 610041, Sichuan
Province, China
Corresponding Author: Lin Sun, West China Hospital, Sichuan
University, Chengdu 610041, Sichuan Province, China.
Email: sunlin99@live.cn
Conflict of interest
We declare that we have no conflict of interest.
References
[1] Tan K, Casasnovas JM, Liu JH. The structure of immunoglobulin
superfamily domains 1 and 2 of MAdCAM-1 reveals novel features important
for integrin recognition. Structure 1998; 6:793-801.
[2] Salmi M, Jalkanen S. Molecules controlling lymphocyte migration
to the gut. Gut 1999; 45:148-153.
[3] Briskin M, Winsor-Hines D, Shyjan A. Human mucosal addressin cell
adhesion molecule-1 is preferentially expressed in intestinal tract and
associated lymphoid tissue. Am J Pathol 1997; 151:97-110.
[4] Eksteen B, Liaskou E, Adams DH. Lymphocyte homing and its role in
the pathogenesis of IBD. Inflamma Bowel Dis 2008; 14:1298-1312.
[5] Briskin M, Winsor-Hines D, Shyjan A, et al. Human mucosal
addressin cell adhesion molecule-1 is preferentially expressed in
intestinal tract and associated lymphoid tissue. Am J Pathol. 1997; 151:97
-110.
[6] Van Assche G, Rutgeerts P. Physiological basis for novel drug
therapies used to treat the inflammatory bowel diseases. I. Immunology and
therapeutic potential of antiadhesion molecule therapy in inflammatory
bowel disease. Am J Physiol Gastrointest Liver Physiol 2005; 288:G169-174.
Competing interests:
None declared
Competing interests: No competing interests
calprotectin is a good screening test to increase the likelihood of IBD, including ileal Crohn’s disease
We appreciate the response from Roblin and Phelip, which allows us to
clear up a misunderstanding. In our meta-analysis (1) we evaluated whether
including a test for faecal calprotectin in the diagnostic pathway is
beneficial for patients with suspected but unconfirmed inflammatory bowel
disease. We concluded that the numbers of false negatives (missed cases)
and false positives (cases without inflammatory bowel disease who go on to
have endoscopy) are acceptable when faecal calprotectin is used as
screening test. In the “new” diagnostic pathway only patients with a
calprotectin value above the cut-point continue for endoscopy.
Roblin and Phelip suggest that the diagnostic accuracy of
calprotectin may be lower in a subgroup of patients with undiagnosed ileal
Crohn’s disease. This suggestion implies that the number of missed cases
is higher when the inflammation is located in the ileum. Roblin and Phelip
refer to two papers that were excluded from our meta-analysis based on
wrong patient spectrum and poor methodological quality (2, 3). Both papers
reported the recruitment of patients with confirmed inflammatory bowel
disease and evaluated the value of calprotectin to predict relapse. In
neither of the studies was relapse confirmed with endoscopy. We only
included studies that recruited patients with suspected inflammatory bowel
disease and that compared faecal calprotectin levels with the results of
endoscopy (reference standard).
Triggered by the letter of Roblin and Phelip we searched for other
diagnostic studies published in Medline that reported the location of
Crohn’s disease in combination with endoscopy and calprotectin testing. We
identified six studies with a fully paired design and better
methodological quality than the two cited by Roblin and Phelip. Five
studies recruited patients with confirmed Crohn’s disease (4-8), and one
recruited patients with suspected inflammatory bowel disease (9). The
latter was also included in our meta-analysis. No study showed a
statistically significant difference in calprotectin levels between
proximal and distal sites of Crohn’s disease, although there was a trend
towards a higher degree of faecal calprotectin increase in colonic
involvement.
In our meta-analysis we recommend that in the “new” diagnostic
pathway only patients with a calprotectin value above the cut-point (>
50 to 150 ìg/g) continue for endoscopy. Every increase above the cut-point
(irrespective of the magnitude) indicates a higher likelihood of
inflammatory bowel disease and justifies endoscopic evaluation. A
calprotectin value of 600 instead of 900 ìg/g makes no difference for the
sensitivity and specificity. There is no evidence to support the
suggestion of Roblin and Phelip that patients with ileal Crohn’s disease
will be wrongly excluded from endoscopy when faecal calprotectin is used
for screening. Including a test for faecal calprotectin in the
investigation of suspected inflammatory bowel disease reduces the number
of adults requiring endoscopy by 67%, and the number of children and
teenagers requiring endoscopy with 35%. The backside of this screening
strategy is that diagnosing IBD may be delayed in a small proportion of
the affected patients. We conclude that measuring faecal calprotectin is a
good screening test to increase the likelihood of inflammatory bowel
disease, including ileal Crohn’s disease.
1. van Rheenen PF, Van de Vijver E, Fidler V. Faecal calprotectin for
screening of patients with suspected inflammatory bowel disease:
diagnostic meta-analysis. BMJ. 2010;341:c3369.
2. Costa F, Mumolo MG, Ceccarelli L, Bellini M, Romano MR, Sterpi C
et al. Calprotectin is a stronger predictive marker of relapse in
ulcerative colitis than in Crohn's disease. Gut 2005;54:364-8.
3. D'Inca R, Dal Pont E, Di Leo V, Benazzato L, Martinato M,
Lamboglia F et al. Can calprotectin predict relapse risk in inflammatory
bowel disease? Am J Gastroenterol 2008;103: 2007-14.
4. Sipponen T, Karkkainen P, Savilahti E, Kolho KL, Nuutinen H,
TurunenU, et al. Correlation of faecal calprotectin and lactoferrin with
an endoscopic score for Crohn’s disease and histological findings. Aliment
Pharmacol Ther 2008;28:1221-9.
5. Kaiser T, Langhorst J,Wittkowski H, Becker K, FriedrichAW, Rueffer
A, et al. Faecal S100A12 as a non-invasive marker distinguishing
inflammatory bowel disease from irritable bowel syndrome. Gut
2007;56:1706-13.
6. Bremner A, Roked S, Robinson R, Phillips I, Beattie M. Faecal
calprotectin in children with chronic gastrointestinal symptoms. Acta
Paediatr 2005;94:1855-8.
7. Leach ST, Yang Z, Messina I, et al. Serum and mucosal S100
proteins, calprotectin (S100A8 ⁄ S100A9) and S100A12, are elevated
at diagnosis in children with inflammatory bowel disease. Scand J
Gastroenterol 2007; 42: 1321–31.
8. Schoepfer AM, Beglinger C, Straumann A, Trummler M, Vavricka SR,
Bruegger LE, Seibold F. Fecal calprotectin correlates more closely with
the Simple Endoscopic Score for Crohn's disease (SES-CD) than CRP, blood
leukocytes, and the CDAI. Am J Gastroenterol. 2010 Jan;105(1):162-9.
9. Schroder O, Naumann M, Shastri Y, Povse N, Stein J. Prospective
evaluation of faecal neutrophil-derived proteins in identifying intestinal
inflammation: combination of parameters does not
improve diagnostic accuracy of calprotectin. Aliment Pharmacol Ther
2007;26:1035-42.
Competing interests:
None declared
Competing interests: No competing interests