ORIGINAL ARTICLE
Assessment of Endoscopic Activity Index and Biological
Inflammatory Markers in Clinically Active Crohn’s Disease
with Normal C-reactive Protein Serum Level
Marie-Armelle Denis, MD,* Catherine Reenaers, MD,†,‡, Fernand Fontaine, MD,*
Jacques Belaı̈che, MD, PhD,‡ and Edouard Louis, MD, PhD†,‡
Background: Patients with clinically active Crohn’s disease (CD),
defined by a Crohn’s Disease Activity Index (CDAI) ⬎150, may have
normal C-reactive protein (CRP) serum levels. In such cases, it is
difficult to know whether these patients have really active disease or
rather functional symptoms. This distinction is important to decide the
most appropriate treatment. The aim of our work was to assess intestinal and colonic lesions in such patients and to look for biological
markers potentially associated with endoscopic activity of the disease.
Methods: We included 28 consecutive CD patients with CDAI
⬎150 and a normal CRP level. These patients underwent a full
colonoscopy with Crohn’s Disease Endoscopy Index of Severity
(CDEIS) calculation, fecal calprotectin, blood fibrinogen, acid ␣-1
glycoprotein, and erythrocyte sedimentation rate measurement. The
Harvey–Bradshaw score was also calculated. Serum IL1 beta, IL6,
IL8, sIL2R, and sTNFR2 were measured.
Results: The median CDAI was 181 (151– 485). Almost all (92.9%)
these patients had endoscopic lesions, but the majority had only mild
lesions (CDEIS ⱕ6). No correlation was found between CDEIS and
any of the clinical or biological markers. However, all the patients with
significant endoscopic lesions (defined by a CDEIS ⬎6) had previous
surgical intestinal resection and lesions involving the anastomosis.
Conclusions: Patients with elevated CDAI and normal CRP have
only mild mucosal lesions of CD. Most significant lesions may be
observed at the anastomosis and proximal to it in previously operated patients. None of the biological markers tested was associated
with these endoscopic lesions.
(Inflamm Bowel Dis 2007;13:1100 –1105)
Key Words: Crohn’s disease, CRP, CDEIS, cytokines
Received for publication February 5, 2007; accepted April 6, 2007.
From the *Department of Gastroenterology, Clinique St Joseph, Liège,
Belgium, †GIGA research, University of Liège, Belgium, ‡Department of
Gastroenterology, CHU of Liège, Liège, Belgium.
Supported by a research grant from AstraZeneca Belgium. Edouard Louis
is senior research associate at the FNRS Belgium. Catherine Reenaers is
research fellow at the FNRS Belgium.
Reprints: Prof. Edouard Louis, service de gastroentérologie, CHU de
Liège, Domaine du Sart Tilman, 4000 Liège, Belgique (e-mail:
edouard.louis@ulg.ac.be).
Copyright © 2007 Crohn’s & Colitis Foundation of America, Inc.
DOI 10.1002/ibd.20178
Published online 16 May 2007 in Wiley InterScience (www.interscience.
wiley.com).
1100
C
rohn’s disease (CD) is a chronic intestinal disorder that
may affect every segment of the gastrointestinal (GI)
tract. It is characterized by an inappropriate immuno-inflammatory reaction inducing chronic inflammatory lesions in the
bowel wall.1 Although several genetic factors were identified2– 6 and pathogenic mechanisms elucidated,7 the etiology
remains unknown. The clinical course is characterized by a
succession of relapses and remissions. The recognition of
these different phases is important but sometimes difficult.
The activity of the disease may be assessed using clinical,8,9
endoscopic,10,11 or biological12 scores. Recently, fecal calprotectin measurement also showed its interest in assessing
bowel inflammation13,14 and predicting clinical relapses.15
This highly sensitive marker, however, has lower specificity,
since high calprotectin rates are found not only in CD and
ulcerative colitis (UC) but also in infections, polyps, and
neoplasms.14 Among biological markers, C-reactive protein
(CRP), an acute-phase reactant member of the pentraxin
family, has been the most widely used and is considered to be
a reliable marker of disease activity and response to treatment.12
It is known that the correlation between these various
markers is globally weak and inconstant at an individual
level.16,17 Therefore, it may sometimes be difficult to choose
the best treatment according to these activity scores or markers. Particularly, some patients may have a clinically active
disease, defined by a Crohn’s Disease Activity Index
(CDAI)8 higher than 150, and a normal CRP serum level. In
such cases it is difficult to know whether these patients have
really mildly active disease or rather functional symptoms,
and which treatment can be proposed.
The aim of this study was to assess endoscopic activity
and various biological inflammatory markers in patients with
clinically active CD and normal CRP serum levels. We
further aimed at identifying clinical or biological factors
predictive for significant mucosal lesions in these patients.
MATERIALS AND METHODS
Patients
Between January 2005 and February 2006 we included consecutive CD patients with clinically active disease, defined by
a retrospective CDAI higher than 150 and with normal CRP
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serum levels (ⱕ6 mg/L) (Roche/Hitachi, Roche Diagnostic,
Mannheim, Germany). The study was accepted by the Liège
University Ethical Committee and all patients gave informed
consent.
In addition to the CDAI, the Harvey–Bradshaw score9
was also calculated. Demographic and clinical characteristics
of the patients were retrieved from medical notes and patient
interview. Disease classification was performed using the
Montreal classification.18 Patients with known active disease
in the upper part of the GI tract were excluded (proximal to
the terminal ileum).
Endoscopy
All the patients underwent a full colonoscopy under anesthesia and the CDEIS (Crohn’s Disease Endoscopic Index of
Severity)11 was calculated, within 7 days of the blood and
stool sampling and the CDAI calculation.
Routine Biological Markers
Blood fibrinogen, erythrocyte sedimentation rate (ESR), and
acid ␣-1 glycoprotein were measured in blood samples by
routine procedures. Stool samples were taken for the dosage
of fecal calprotectin (Calprotectin ELISA, Novatec Immun
Diagnostica, Germany).
Blood Cytokines and Soluble Receptors of
Cytokines
Blood samples were taken for centrifugation and serum storage at ⫺20°C until further use. Interleukin-6 (IL6, coated
monoclonal antibody clone 677B6A2, Biosource, Belgium),
Interleukin-8 (IL8, KAC1301, Biosource), Interleukin-1␤
(IL1␤, KAC1211, Biosource), soluble Tumor Necrosis Factor receptor type 2 (sTNFR2, KAC 1771 Biosource) and
soluble Interleukin-2 receptor (sIL2R, KHR0022, Biosource)
were measured in duplicate using a commercial enzymelinked immunosorbent assay (ELISA) according to the manufacturer’s instruction. The recorded result was the mean of
the 2 measurements. When differences between the 2 measurements were greater than 10%, a new measurement was
performed.
Statistics
Statistical analysis were performed using the Instat 2000
Program. Correlation analyses were performed using a nonparametric Spearman test. Comparison of proportions was
carried out using Fisher’s exact test. Continuous variables
were compared using the Mann–Whitney test. CDEIS was
categorized between clinically significant or not endoscopic
lesions according to a threshold of 6 according to a recent
GETAID study.19
A multivariate analysis by logistic regression was performed with the presence of significant endoscopic lesions as
the dependent variable and demographic and clinical charac-
teristics as well as biological parameters as independent variables. P-values were considered statistically significant at
ⱕ0.05.
RESULTS
Clinical, Biological, and Endoscopic Characteristics
Twenty-eight patients were included, with a median age of 46
years (range, 23– 68 years). Characteristics of the patients are
shown in Table 1. When these patients developed a flare of
the disease and were included in the present study, most of
them were on stable therapy with either steroids, mesalazine,
immunosuppressants, or infliximab. Two patients had a history of upper GI tract Crohn’s lesions, but these were controlled by upper GI endoscopy and/or small bowel followthrough and were inactive at the time of the study.
CDAI, Harvey-Bradshaw score, fibrinogen, CRP, acid-␣1 glycoprotein, cytokines, and soluble cytokine receptor
serum levels as well as fecal calprotectin concentrations are
shown in Table 1.
Terminal ileum or neo-terminal ileum (in the case of
previous surgical resection) was reached in all cases. All but
2 patients (92.9%) had endoscopic lesions. However, globally
these lesions were very mild (Fig. 1): the median CDEIS was
3.4 (0 –16) and only 9 patients (32.1%) had a CDEIS ⱖ6.19
Nine patients (32.1%) had strictures and only 2 patients (7%)
had deep ulcerations. In the 12 patients without treatment or
treated with mesalazine, median CDEIS was not different
(2.8; range: 0 –10).
Correlations
CDAI was significantly correlated with Harvey–Bradshaw
score (r ⫽ 0.42; P ⫽ 0.05) and fibrinogen (r ⫽ 0.51; P
⫽ 0.02). Correlation with CRP was borderline for significance (r ⫽ 0.39; P ⫽ 0.07). No significant correlation was
found between CDAI and acid ␣1-glycoprotein, ESR, or any
of cytokines or cytokine-soluble receptors. There was no
correlation either between CDAI and the CDEIS or fecal
calprotectin. CDEIS was not significantly correlated with any
of the biological parameters tested.
Markers Associated with Endoscopic Significant
Lesions
When comparing demographic and clinical characteristics,
clinical activity scores, and biological markers between patients having or not having significant endoscopic lesions as
defined by a thresholds of 6 for the CDEIS, there was no
significant difference except for the previous history of surgical intestinal resection: all the patients (9/9) with a CDEIS
ⱖ6 had a history of intestinal resection as compared to 6/19
patients with a CDEIS ⬍6 (Table 2). The 13 patients without
previous intestinal resection thus all had a CDEIS ⬍6. Multivariate analysis did not disclose any other parameter asso-
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TABLE 1. Characteristics of the Patients (Variables Expressed as Median and Range)
Male gender
Duration of the disease (y)
Age at diagnosis (Montreal)
Disease location (Montreal)
Disease behavior (Montreal)
Medications
Previous intestinal resection
Smoker
CDAI
Harvey–Bradshaw
CDEIS
IL–6 (pg/mL) (normal value: ⬍12 pg/mL)
IL–1 (pg/mL) (normal value: ⬍44 pg/mL)
IL–8 (pg/mL) (normal value: ⬍12 pg/mL)
sIL2R (pg/mL) (normal value: ⬍101 pg/mL)
STNFR2 (ng/mL) (normal value: ⬍2.67 ng/mL)
CRP (mg/L) (normal value: ⬍6 mg/L)
Fibrinogen (g/L) (normal value: 2.3-4.3 g/L)
ESR (mm/h) (normal value: ⬍10 mm/h)
Acid alpha-1 glycoprotein (g /L) (normal value: 0.4-1.3 g/L)
Fecal calprotectin (␮g/mL) (normal value: ⬍ 50 ␮g/mL)
A1 (⬍16 y)
A2 (17-40 y)
A3 (⬎40 y)
L1 (ileum)
L2 (colonic)
L3 (ileocolonic)
L4 (upper GI) ⫹ L2
L4 ⫹ L3
B1 (nonstrict., nonfist.)
B2 (stricturing)
B3 (fistulizing)
B2 ⫹ P (perianal)
B3 ⫹ P
None
5–ASA
Steroids
Methotrexate
Azathioprine
Infliximab
9
10 (1-35)
0
23
5
15
2
8
1
1
16
7
1
2
2
1
11
14
3
6
2
15
14
181 (151-485)
10.5 (7-15)
3.4 (0-16)
12 (12-1231)
44 (44-2452)
12 (12-880)
101 (101-1060)
5.37 (2.67-16.6)
2.9 (0-6)
3.73 (3-5.2)
13 (2-31)
0.91 (0.5-1.33)
91.35 (10-571.2)
CDAI, Crohn’s Disease Activity Index CDEIS, Crohn’s Disease Endoscopy Index of Severity; CRP. C-reactive protein; ESR, erythrocyte sedimentation rate.
ciated with a CDEIS ⱖ6. Particularly, steroid treatment was
not associated with more severe lesions.
DISCUSSION
The clinical activity of CD may sometimes be difficult to
assess. The origin of symptoms such as diarrhea, fatigue, or
abdominal pain may be multifactorial and does not necessarily correlate with the existence of prominent inflammatory
lesions of the GI tract. Facing a patient with symptoms
compatible with active CD, the optimal therapeutic options
are different if the symptoms are mainly driven by active
inflammatory lesions or not. In clinically active CD, serum
1102
CRP measurement helps to confirm and quantify the importance of the inflammation. CRP level is a good predictor of
relapses, remission, and response to treatment.13,20 In the case
of clinically active CD with normal CRP serum levels, it is
essential to correctly assess the existence and the importance
of the specific lesions of CD along the GI tract. The present
work shows that endoscopic lesions in these patients were
globally very mild and that only one-third of the patients had
lesions that could be considered clinically significant.19 However, apart from a previous history of surgical resection,
which was associated with more severe endoscopic lesions,
mainly at the anastomosis, no other demographic, clinical, or
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FIGURE 1. Value of the Crohn’s disease endoscopic index of
severity (CDEIS) in the 28 patients. Median CDEIS was 3.4 (0 –16).
Only 9/28 (32.1%) patients had a CDEIS ⱖ6.
biological marker was predictive of these significant lesions.
The absence of correlation between CDAI, CDEIS, and CRP
or other biological markers in our study is in contrast with
previously published studies carried out in patients with either elevated or low CDAI and blood inflammatory markers.17 This probably reflects the very particular nature of the
population we studied, with low CRP despite elevated CDAI.
The same reason may explain the relatively weak correlation
between Harvey–Bradshaw score and CDAI. Indeed, the
relative importance of subjective symptoms and diarrhea,
which are not necessarily associated with active inflammation, is greater in Harvey–Bradshaw score than in CDAI.
Symptoms suggesting active CD in the absence of
elevation of CRP could reflect several mechanisms: the absence of intestinal lesions and functional symptoms, intestinal
Assessment of Endoscopic Activity Index
lesions not associated with systemic inflammation, or a genetic defect in CRP production or other inflammatory pathways. Our data suggest more arguments for the first 2 hypotheses. Although CRP production may be influenced by
genetic background and one can speculate on a genetically
determined defect of CRP production,21 this genetic influence
has mainly been shown for illnesses associated with low
levels of CRP, measured with techniques detecting ultrasensitive CRP.22 In CD no relationship was found between CRP
level and CRP genotypes.23 Other blood inflammatory markers including several cytokines and soluble cytokine receptors
were also very low in our population, confirming that the low
levels of CRP we observed were probably not due to a
specific defect in CRP production or to activation of other
inflammatory pathways.
The vast majority of the patients had endoscopic lesions
and no mucosal healing. These lesions were thus associated
with very low systemic inflammation. Several characteristics
of these lesions may help to explain the low systemic inflammation: more than half of these patients were treated with
steroids that can suppress systemic inflammation but induce
little mucosal healing,24 those lesions were superficial in most
cases, there were more ileal than colonic lesions, one-third of
the patients had strictures that increase endoscopic activity
score but induce little systemic inflammation, and finally,
most patients with a clinically significant endoscopic score
had anastomotic lesions.
Superficial lesions could be associated with a limitation
of the inflammation into the mucosa, as in UC. It is interesting to note that UC is also characterized by lower CRP serum
levels compared to CD.25 Consistent with this, in our patients
only 2 harbored deeper ulcers. In such situations, mucosal
cytokines measurement in intestinal biopsies could give interesting information about local inflammation phenomenon.
Strictures that were present in one-third of our patients could
also have contributed to explain the globally low systemic
inflammation in this cohort and also the absence of correlation between endoscopic score and other blood inflammatory
markers. However, even when calculating the CDEIS without
taking into account the strictures (data not shown), no correlation was found between this modified score and all of these
other inflammatory markers. More than half of our patients
had pure ileal disease. Ileal lesions are probably associated
with less CRP elevation than colonic lesions.26 A recent
observation from Florin et al27 about clinically active CD
with low CRP levels also found more ileal CD in this group
of patients, although no systematic endoscopy was performed
at the time of CRP measurement in that study. The reason
why ileal lesions induce less CRP is not precisely known.
This could also have influenced our results, although in the
multivariate analysis disease location was not associated with
clinically significant endoscopic lesions.
Fecal calprotectin was mildly to moderately increased
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TABLE 2. Clinical Characteristics and Biological Markers According to Endoscopic Activity of the Disease
IL6 (pg/mL)
IL1 (pg/mL)
IL8 (pg/mL)
sIL2R (pg/mL)
sTNFR2 (ng/mL)
Calprotectin (␮g/mL)
ESR (mm/h)
Fibrinogen (g/L)
Acid alpha-1 glycoprotein (g/L)
CRP (mg/L)
CDAI
H–B
Stricture
Previous intestinal resection
Male gender
Pure ileal disease
Disease duration (y)
Smoker
5-ASA treatment
Immunosuppressive treatment
Steroid treatment
CDEIS ⱖ6 (n ⫽ 9)
CDEIS ⬍6 (n ⫽ 19)
P value
12 (12-1231)
44 (44-44)
12 (12-18)
101 (101-368)
4.7 (2.7-9.7)
76.8 (11.7-324.1)
13.5 (2-30)
3.7 (3-4.3)
0.91 (0.86-0.95)
2.5 (1-6)
178 (156-485)
11 (7-36)
5/9
9/9
2/9
5/9
17.5 (4-23)
5/9
3/9
4/9
5/9
12 (12-225)
44 (44-2452)
12 (12-880)
101 (101-1060)
5.6 (2.9-16.6)
122.1 (10 –571.2)
10 (3-31)
3.6 (3-5.2)
0.92 (0.5-1.33)
2 (0– 6)
182 (151-247.4)
11 (8-15)
4/19
6/19
7/19
10/19
7 (1-35)
9/19
8/19
5/19
9/19
0.73
0.29
0.23
0.76
0.29
0.57
0.81
0.97
0.89
0.4
0.73
0.97
0.09
0.0008
0.67
1.00
0.27
1.00
1.00
0.41
1.00
CDAI, Crohn’s Disease Activity Index CDEIS, Crohn’s Disease Endoscopy Index of Severity; CRP. C-reactive protein; ESR, erythrocyte sedimentation rate.
The threshold of 6 for CDEIS corresponds to clinically significant lesions and has been previously validated.19 Normal values for biological markers are given
in Table 1.
in our cohort but there was no correlation with the intensity
of the endoscopic lesions assessed by the endoscopic score. It
has been suggested that this marker is a better marker for
colonic than ileal lesions. The large proportion of patients
with ileal disease in our study may have contributed to this
absence of correlation. The discrepancy might also have been
due to undetected jejunal or proximal ileal lesions. Two
patients of our cohort had upper GI tract lesion in the past.
However, those were GI lesions and these patients underwent
an upper GI tract exploration that showed no significantly
active disease at the time of the present study. Although the
value of fecal calprotectin is well established to differentiate
between irritable bowel syndrome (IBS) and inflammatory
bowel disease (IBD) patients,14 the correlation between calprotectin level and intensity of mucosal endoscopic lesions in
CD has not been well established.28,29
When looking at the patients with a CDEIS threshold of
6,19 the only predictive factor of endoscopic active disease
was the presence of previous intestinal resection. Indeed, all
the patients without previous surgery had a CDEIS lower than
6, while all the patients with a CDEIS ⱖ6 had undergone
previous surgery. Lesions in these patients were mainly located around and proximal to the anastomosis. A low level of
CRP in these patients with previous ileal resection evolving
1104
toward a stricturing behavior has already been reported.27
Nonspecific factors due to the anastomosis, like proximal
luminal hyperpressure or ischemic peri-anastomotic phenomenon, may be involved in the development of these anastomotic lesions. Still, the implication of such mild lesions in the
symptoms of the patients is questionable, particularly because
we did not observe any correlation between clinical activity
index (CDAI) and endoscopic activity index (CDEIS) or even
a biological marker of mucosal inflammation, the fecal calprotectin. Quite surprisingly, a significant correlation was
found between CDAI and fibrinogen serum level as well as a
borderline correlation with CRP. Therefore, despite their
level within the normal range, this correlation with the systemic inflammatory markers may suggest the implication of
the systemic inflammatory reaction in the elevation of the
CDAI. Besides this, functional symptoms are also most probably involved. Diarrhea may be due to rapid transit time or
biliary salt malabsorption, particularly in patients with previous ileal resection. Abdominal pain may be due to peritoneal
adherence, quite frequent in CD patients, particularly following surgery. IBS may also explain both diarrhea and abdominal pain. A recent study showed that up to 50% of CD
patients may present with IBS.30 Fatigue is a very frequent
symptom in CD.31 Furthermore, this symptom is very diffi-
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cult to treat and tends to persist despite remission of the
disease.
In conclusion, in almost all cases, patients with clinically active CD but normal CRP had active mucosal lesions
at endoscopy, although these were usually mild. Several
factors may explain the low CRP in this group of patients,
including ileal or stricturing lesions, as well as steroid treatment. Within the present cohort, the only clinical or biological factor associated with clinically significant endoscopic
activity was a previous surgical resection. Therapeutic choice
in these patients remains difficult, since there was no correlation between endoscopic activity and clinical activity of the
disease and the impact of medical treatments on very mild
mucosal lesions or on strictures is questionable. However, it
is difficult to fully consider these patients as functional bowel
disorder, not only because they still harbored mucosal lesions, but also because the clinical activity of the disease
correlated with blood markers of inflammation, albeit these
were within the normal range.
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