! ! ! ! ! UNIVERSITAʼ DI PISA
FACOLTAʼ DI MEDICINA E CHIRURGIA
! ! SCUOLA DI SPECIALIZZAZIONE IN RADIODIAGNOSTICA
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PROPOSAL OF A MODIFIED PHENOTYPE-
BASED RADIOLOGICAL CLASSIFICATION:
THE MR CROHNʼS DISEASE SEVERITY
INDEX (MR- CSI)
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Il Relatore
Chiar.mo Prof. Carlo Bartolozzi
!! ! ! Il Candidato
ABSTRACT Aim
To work out a radiological score in the assessment of Crohnʼs disease activity and severity. Materials and methods.
From July 2011 to February 2012, 46 patients with suspected or established Crohnʼs disease underwent small bowel MRI on a 3T scanner. According to radiological findings and disease behaviour phenotype (as proposed in the Montreal classification), patients were divided into 5 classes:
1. absence of disease
2. disease activity (presence of one of following findings: mucosal abnormalities, submucosal edema, mucosal enhancement)
3. presence of substenosis without obstruction a. active disease
b. inactive disease
4. presence of stenosis with obstruction a. active disease
b. inactive disease
5. extramural involvement (fistulas and/or abscess)
Data were correlated with endoscopical findings, CDAI, CRP and ESR. Results
A significant correlation (r= 0.88, p< 0,001) was registered between endoscopical findings and MR score. A good correlation of MRI- CSI was observed with CDAI (r= 0,59, p<0,01); correlation was superimposable (r= 0,59, p<0,01) if subgroups were divided into active/ non active disease. A moderate correlation of MR- CSI was observed with ESR ( 0,49, p=0,001) and CRP (0,47, p=0,001). Correlation appears higher if subgroups were divided into active/ non active disease (0,66 and 0,59 respectively).
Conclusion
MR- CSI is a quick, manageable score, easy- to apply in daily practice; furthermore, MR can be used in the evaluation of CD as an alternative to ileocolonoscopy.
INTRODUCTION
Crohnʼs disease (CD) is a chronic inflammatory bowel disease, with different clinical features and pathological course, characterized by a relapsing and remitting trend. Clinical and pathological findings were initially considered heterogeneous, since CD phenotypes were divided into three groups by the Vienna classification, according to age at diagnosis, disease location and disease behaviour, as inflammatory (non- stricturing, non penetrating, (B1)), stricturing (B2), penetrating (B3); it was argued that CD could show different progression steps [1]. On 2005, the phenotypic classification was modified
through a so called “Montreal classification” (Tab.1) [2]; suddenly it was demonstrated that CD follows a progressive evolution, that leads to structural bowel damage and loss of function [3, 4].
Quantification of CD activity and severity remains a challenge, meanwhile is fundamental in treatment planning and follow up. Symptomʼs based scores, as the CDAI (Crohnʼs Disease Activity Index) and Harvey- Bradshaw index [5, 6] are not completely reliable since do not include any laboratory variables indicative of active inflammation such as C-reactive protein [7]; furthermore, CDAI reliability is operator dependant, needs a learning curve and improves with experience of the physician that processes the score [8].
Serological markers are widely used in clinical practice, but none of them is specific for disease activity or gives information about prognosis or response to therapy.
The C- reactive protein (CRP) is a annular pentameric protein. A wide range of acute and chronic inflammatory conditions like bacterial, viral, or fungal infections, inflammatory diseases, malignancy and tissue injury or necrosis develops acute phase response. These conditions cause release of interleukin-6 and other cytokines that trigger the synthesis of CRP and fibrinogen by the liver; therefore CRP can not be used as a reliable marker of disease activity and severity [9].
Similarly, the erythrocyte sedimentation rate is a non specific measure of inflammation and is the rate at which red blood cells sediment in a period of 1 hour. Even though the low specificity, erythrocyte sedimentation is a component of the PCDAI (Pediatric Crohnʼs Disease Activity Index), an index for assessment of severity of inflammatory bowel disease in children [10].
Ileocolonoscopy and small bowel capsule endoscopy (SBCE) are considered the gold standard in the evaluation of mucosal involvement, but they can not evaluate transmural involvement and extramural complications; moreover, this imaging methods are quite expensive, not widely available, and therefore not regularly used. Nevertheless, it has
been reported that a significant percentage of patients with moderate- severe symptoms did not have significant lesions at endoscopy [11, 12], while patients in clinical remission can still present ulcerative lesions [13].
Small bowel MRI is now widely used in diagnosis and follow up in CD, thanks to its excellent soft tissue contrast resolution, high temporal resolution, panoramic views and lack of exposure to ionizing radiation. A descriptive report is a fundamental tool in communication between radiologists and clinicians and eventually surgeons; several radiological scores have been proposed in the assessment of Crohnʼs disease activity, but none of them is used in daily practice [14- 27].
A linear score activity index, based on morphological parameters in the evaluation of small bowel loop, colonic segments and extramural involvement can be an useful tool in a
synthetic evaluation of the scene and in the post- therapy assessment. Furthermore, a good index would be able to synthetize the presence of stricturing/ penetrating disease and the presence/ absence of superimposed active disease.
Radiological findings have been classified according disease behaviour as shown in Montreal classification.
Aim of this paper is to derive an MR Crohnʼs disease Severity Index (MR-CSI), phenotype- based [2- 4], built up evaluating disease behaviour according to Montreal classification.
MATERIALS AND METHODS
PATIENTS
From July 2011 to February 2012, forty-six patients (mean age: 35 years, range 18- 75 yrs, 32 male) were submitted to MR Enterography (MRE) for suspected diagnosis of Crohnʼs disease in a previously undiagnosed disease, first staging in an established new
diagnosis, or assessment of patients with established disease. All exams were performed on a 3 Tesla scanner (Discovery 750, General Electric, Milwaukee, Wisconsin, USA) .
Endoscopical assessment
Ileocolonoscopy was performed in 29 patients, and was considered the gold standard. Endoscopy was performed within 15 days by the MRE and no changes in therapy were recorded.
Large bowel and ileum were divided into 6 segments: rectum, sigmoid, descending colon, transverse colon, ascending colon- cecum and terminal ileum.
Mucosal wall was examinated and each segment was classified in a linear growing scale as non affected, affected by non ulcerative lesions (pseudopolips, edema, aphtae) and by ulcerative lesions.
Endoscopy was performed in 29 patients; 4 ileocolonoscopy were interrupted at the descending colon because of stenosis. A total of 160 segments was evaluated.
CDAI computation
Three gastroenterologist with at least 5 years of experienced evaluated CDAI in each patient, in order to quantify symptoms; CDAI was drawn up according the parameters developed by Best [5].
Crohnʼs Disease Activity Index was considered inactive if under 150 points, mild between 150 and 219, moderate between 220 and 450 points, and severe if CDAI resulted over 450 [5, 28].
Hematological parameters
CPR and ESR were evaluated within 15 days from MRI examination. Normal value of CPR is <5mg/l.
Mean ESR value is 10 mm/1 h (range 0-25) in both males and females below the age of 40 yrs; this increased with age, to a mean of 18 mm (range 0-35) by 60 yrs in both men and women. [29]
CPR value was calculated in a subset of 38 patients. ESR value was calculated on a subset of 38 patients.
MRI TECHNIQUE
All patients underwent small bowel MRE according to a standard protocol at our institution. Patients were instructed to drink PEG diluted in 500mL of water every 10 minutes prior to the MRI examination, up to a total of 2L. This approach ensures good bowel distention from the jejunum to the distal ileum without significant side effects, such as nausea or vomiting.
The patient was placed in the prone position, in order to improve separation among small bowel loops by increasing abdominal pressure. This also allowed to lower the number of coronal slices to be acquired, thereby reducing imaging time.
A phased-array body coil was used to cover the entire abdomen. After patient centering and acquisition of scout view images, a FIESTA sequence was performed on the coronal and axial planes with and without fat saturation (Adiabatic SPatial Inversion Recovery Enhancement, ASPIRE). Subsequently, coronal Single-Shot Fast Spin Echo (SSFSE) images were acquired after intravenous administration of 20mg of a spasmolytic agent (hyoscine-N-butylbromide: Buscopan™, Boehringer-Ingelheim, Ingelheim, Germany) to improve bowel wall distention and reduce peristalsis; obtained hypomotility was exploited to perform a coronal T2 Propeller sequence with fat saturation.
Finally, a fat suppressed 3D LAVA sequence is performed on the coronal plane after intravenous administration of 0.1mL/kg of 1.0M gadolinium chelate (gadobutrol 1.0M; Gadovist™, Bayer Schering Pharma, Leverkusen, Germany) injected at a flow rate of 2mL/s. Contrast medium administration is followed by intravenous injection of 20mL of 0.9% NaCl saline flush at the same flow rate. Intravenous injection of both paramagnetic contrast material and saline flush was carried out through a 20G needle placed into an antecubital vein using an automatic power injector (Spectris Solaris, Medrad, Indianola, PA). The LAVA sequence was programmed to generate 8-10 dynamic series with an interscan delay of 20s between each consecutive frame for patient breathing to ensure that breath was as reproducible as possible throughout the whole duration of the LAVA sequence. The time delay between the beginning of contrast medium injection and that of the LAVA acquisition was 15 seconds. (TAB.2).
The total MRI examination time ranged from 20 to 30 minutes, also depending on patient compliance.
IMAGE ANALYSIS
All MRE examinations were interpreted by two consultant gastrointestinal radiologists, with at least 200 MRE readings.
Mucosal and transmural abnormalities and extramural involvement was evaluated on a segmental basis (rectum, sigmoid, descending colon, transverse colon, ascending colon- cecum, terminal ileum, ileum, upper small bowel (jejunum).
Active disease was defined as the presence of mucosal abnormalities, submucosal edema, mucosal enhancement.
Bowel stenosis was considered severe in presence of obstruction (an obstruction was identified when there was dilated bowel proximal to a transition point or stricture). Finally, the presence of fistulas and abscess were registered.
On the basis of these data, according to a modified- Montreal classification, a 5- grade score was proposed:
1: absence of abnormalities
2: active disease (presence at least of one of these parameters: mucosal abnormalities; submucosal edema; mucosal uptake)
3: presence of sub- stenosis (luminal narrowing or wall thickening without obstruction) ! a: active disease (according to class 2)
! b: inactive disease
4: presence of stenosis with obstruction ! a: active disease (according to class 2) ! b: inactive disease
5: presence of extramural involvement (fistulas and/ or abscess)
Colonic involvement was evaluated and computed in the final score; collateral findings (even if pathology- related, such as sacro- ileitis) were reported but not evaluated as pejorative element.
Statistical analysis
All statistical analyses were performed with the Wessa P. software (2012), in Free Statistics Software (v1.1.23-r7), Office for Research Development and Education. Two- tailed Spearmanʼs rank-order correlation coefficient (r) served for analyzing correlations between disease phenotype (according localization and behaviour) and endoscopical data.
Pearson correlation was used to correlate MR-CSI and CRP and ESR values.
RESULTS
On the basis of imaging, clinical data and biological parameters, IBD was excluded in 16 patients; two patient confirmed the diagnosis of UC, while 1 patient previously classified as UC discovered a terminal loop involvement and was classified as affected by CD.
Ileocolonoscopy was performed in 29 patients; 12 patients had an established diagnosis of CD, 1 patient receveid a confirmation of a suspected CD (he was previously classified as UC).
Ileocolonoscopy was interrupted in 4 patients (1 sigma, 3 transverse bowel) for stenosis and ulcerations; a total of 166 segments was examined.
Five patients presented 9 involved segments, characterized by non ulcerative lesions; 10 patients presented ulcerative lesions distributed on 20 segments. On total, 29 segments presented mucosal abnormalities in a dataset of 15 patients.
Fourteen ileocolonoscopy were negative.
Correlation between endoscopic activity and qualitative radiological findings are scheduled on Tab. 2.
Disease activity according CDAI was considered mild in 8 patients and moderate in 5 patients. Severe disease was not registered. Inactive disease was registered in 15 patients.
A significant correlation (r= 0.88, p< 0,001) was registered between endoscopical findings and MR score (Fig. 1).
A good correlation of MRI- CSI was observed with CDAI (r= 0,55; p<0,001) (Fig.2).
A moderate correlation of MR-CSI was observed with ESR (0,49, p=0,001) and CRP (0,47, p=0,001) (Fig.3- 4).
DISCUSSION
Drawing up of a radiological score based on imaging findings in CD is based on the necessity to dispose of an objective measure of disease activity and severity. CD is characterized by a relapsing and remitting course; even during remitting period, bowel is not free from lesions, and subclinical inflammation can persist and evolves to fibrostenotic stricture or penetrating disease. These situations can be eligible for surgical resection. Recurrence can occur also after surgery, leading to progressive loss of intestinal function and disability [30].
In this study we provide evidence that a radiological score phenotype- based is highly correlated with endoscopic data; penetrating disease is more frequently associated with ulcerative mucosal lesions, despite its clinical presentation is not always associated with elevated CDAI.
In recent trials, mucosal healing has been considered the principal endpoint instead
symptoms control, and achieving mucosal healing is associated with a more benign course of the disease [31, 32]; on the other hand, ulcerative lesions are linked to increase surgical requirement [33, 34] even if patients in clinical remission can present mucosal
However, ileocolonoscopy can not be considered as unique diagnostic test: it presents poor patientʼs compliance, and is encumbered by several risks, such as perforation; it can be incomplete expecially in patients with colonic stenosis. Furthermore, ileal involvement can not be completely evaluated: ileoscopy and SBCE are expensive and not widely available.
3T MRE demonstrates higher sensitivity and specificity in detecting mucosal abnormalities than 1,5T MRI scanner [35, 36], and can be used in the response treatment evaluation, particularly in the evaluation of mucosal healing [37].
Correlation between MR- CSI and CDAI was good both considering disease behaviour or radiological activity exclusively; however, some discrepancies between radiological
findings suggestive of active disease and disease activity evaluated with CDAI were recordered.
CDAI is a widely used and handy score, but is based only on patientʼs symptoms and is affected by subjectivity; furthermore, it presents several limitations and is not able to provide a careful evaluation in patients who underwent surgery (38) or in case in which fibrotic events are prevailing and stenotic scene leads to occlusion or subocclusion. As reported by Best, the need for a 7-day patient diary has been a major drawback of the CDAI. It is cumbersome, and occasionally is filled in by a patient at one time rather than each day. In addition, the response to rapid clinical changes tends to be buffered by the 7-day collection period. The body weight variable is cumbersome, a minor influence on calculated CDAI values, and at times misleading [7].
Correlation between CRP and MR- CSI appeared moderate; patients classified as 3a (stricturing form and presence of active disease) presented higher CRP values; instead, patients classified in class 2 presented slightly elevated CRP values.
Similarly, ESR presented higher values on class 3a, while class 4a and 5 presented slightly elevated values.
We can hypotize that sub- stenosis is probably just inflammatory- based, while the presence of stenosis and obstruction is more probably based on a fibrotic, irreversible evolution.
Correlation between MR- CSI and hematological parameters resulted higher classyfing patients onto two datasets, active/ non active disease, according the radiological
parameters of activity.
However, it is necessary to underline that the majority of patients was under steroid or biological therapy.
Hematological markers are daily evaluated in hospitalized patients, but in case of
established disease therapies they can result modified; systemic markers of inflammation can fail in evaluating disease activity [39] and they are not reliable in discriminated inactive from mild, moderate, and highly active disease, which would be the target for activity monitoring [40].
Different scores have been proposed in several studies; a good correlation between MR scores and the gold standard has been registered when the evaluation is limited to small bowel loops, while when the colon is included, the agreement results more inconsistent. [41].
The majority of the indexes in this category are constructed by selection of parameters that are associated with the presence of disease activity and/or are indicators of the presence of severe disease. The number of parameters present defines the existence of active disease and level of severity, usually on a limited 3-point or 4-point global scale (i.e., inactive, mild, moderate, or severe). Alternatively, in other studies, a score of severity is assigned to each of the parameters evaluated, and the final value of the index is the sum of the scores of each individual parameter [41].
Our phenotype- based score appears as a manageable, easy- to- apply index; no calculation is required to gain a score, itʼs just the synthesis of the radiologist report. MRI is the ideal examination for small bowel evaluation in CD, owing to its excellent soft tissue contrast resolution, high temporal resolution, and panoramic views. Its lack of exposure to ionizing radiation makes it attractive for repeated assessment of disease activity, and the ongoing development of MRI technology is likely to broaden its diagnostic potential in terms of morphological and functional evaluation of the small bowel in CD patients.
Furthermore, this score can be further implemented and modified, and a radiological
version of Montreal classification can be built up, which includes every phenotypic element that could be radiologically determined.
This score could be useful for daily practice and for scientific approach, in agreement with Montreal classification purpose:
“The recommendations with respect to Crohn's disease and ulcerative colitis were made so that these might be used in clinical practice and also for the purposes of future genetic and serological studies in inflammatory bowel disease” [42]
Fenotipo Montreal 2005
Età di insorgenza A1: <16 anniA2: 16- 40 anni A3: >40 anni Localizzazione L1: ileale L2: colico L3: ileocolico L4: Upper GI Comportamento
B1: non stenosante, non penetrante
B2: stenosante B3: penetrante p: malattia perianale Tab. 1. Montreal classification.
assenza les non ulc ulc
1 13 0 1(colon) 2 0 1 0 3a 0 1 1 3b 1 0 0 4a 0 2 4 4b 0 0 0 5 0 1 4
r= 0,88; p<0,001
0 1 2 3 4 5 6 7 0 1 2 3Titolo
MR - C SI EndoscopyFig. 1. Correlation between endoscopical findings and MR score (r= 0.88; p<0.001) (Note: 4= 3b, 5= 4a, 6=4b, 7=5). 0 1 2 3 4 5 6 7 0 1 2 3 4 MR - C SI CDAI
Fig. 2. Correlation between MR- CSI and CDAI (r= 0.55. p<0.001) (Note: 4= 3b, 5= 4a, 6=4b, 7=5).
0
1
2
3
4
5
6
7
0 20 40 60 80 100 MR - C SI ESR(mm/h)Fig. 3. Correlation between MR- CSI and ESR (r= 0.49; p= 0.001) (Note: 4= 3b, 5= 4a, 6=4b, 7=5). 0 1,0 2,0 3,0 4,0 5,0 6,0 7,0 0 1 2 3 4 5 6 7 MR - C SI CRP (mg/dl)
Fig. 4. Correlation between MR- CSI and CRP (r=0.47; p=0.001) (Note: 4= 3b, 5= 4a, 6=4b, 7=5).
CONCLUSION
MR- CSI is a quick, manageable score, easy- to apply in daily practice; furthermore, MR can be used in the evaluation of CD as an alternative to ileocolonoscopy.
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