You are here
Evolving roles of cross-sectional imaging in Crohn's disease
Digestive and Liver Disease - Available online 20 May 2016, In Press, Corrected Proof
The implementation of cross-sectional imaging techniques for the clinical management of Crohn's disease patients has steadily grown over the recent years, thanks to a series of technological advances, including the evolution of contrast media for magnetic resonance, computed tomography and bowel ultrasound. This has resulted in a continuous improvement of diagnostic accuracy and capability to detect Crohn's disease-related complications. Additionally, a progressive widening of indications for cross-sectional imaging in Crohn's disease has been put forward, thus leading to hypothesize that in the near future imaging techniques can increasingly complement endoscopy in most clinical settings, including the grading of disease activity and the assessment of mucosal healing or Crohn's disease post-surgical recurrence.
Keywords: Computed tomography, Crohn's disease, Magnetic resonance imaging, Ultrasound, Ultrasound elasticity imaging.
In the last three decades cross-sectional imaging techniques have gained increasing relevance in the clinical management of inflammatory bowel diseases (IBD). Patients with Crohn's disease (CD), in particular, benefit from abdominal imaging, given the transmural nature of CD-related inflammation, which frequently associates with extra-mucosal involvement and intra-abdominal complications . Moreover, CD often affects segments of the small bowel, which is less readily reachable by endoscopy than the large intestine. Traditionally, cross-sectional imaging has been employed in the diagnostic work-up of patients with suspected CD of the small intestine and in the detection of CD-related complications ; in such clinical contexts, excellent levels of diagnostic performance have been reported for bowel ultrasound (US), computed tomography (CT) and magnetic resonance imaging (MRI). In a recent systematic review  an overall per-patient sensitivity of 85% (95% CI, 83–87%) and 78% (95% CI, 67–84%) was reported for US and MRI, respectively, in the diagnosis of CD. The corresponding values of per-patient specificity were 98% (95% CI, 95–99%) and 85% (95% CI, 76–90%). More recently, a series of innovative applications has been proposed to expand the traditional role of cross-sectional imaging in CD, to include: the assessment of disease activity, the detection and grading of post-surgical relapses, the assessment of mucosal healing following biological therapy, and the calculation of cumulative CD-related bowel damage. Additionally, abdominal imaging techniques have been employed for the prediction of the therapeutic response to anti-tumor necrosis factor (TNF) drugs and the need for surgical intervention, and, lately, in the distinction of active inflammation from fibrosis in CD-affected areas. In this paper we offer a review of the evolving applications of imaging in CD, with a particular emphasis on the most recent technological advances in cross-sectional imaging.
2. Evaluation of disease activity
From a clinical perspective, the detailed knowledge of Crohn's disease inflammatory status constitutes an essential element to guide both medical and surgical management. Even if routinely used in therapeutic trials, clinical disease activity scores, including Crohn's Disease Activity Index (CDAI) and Harvey-Bradshaw Index (HBI), were found to poorly correlate with mucosal inflammation as assessed by endoscopy , , , and . As a consequence of this, the International Organization for the Study of Inflammatory Bowel Disease (IOIBD) does no longer consider the resolution of symptoms alone as a therapeutic target in Crohn's disease , and the US Food and Drug Administration is moving from CDAI as a clinical trial end-point in CD towards more objective measures of disease, such as the findings from endoscopy .
On the other hand, over the last few years, good levels of diagnostic performance have been reported for cross-sectional imaging techniques in the assessment of CD activity, as compared with surgical and/or endoscopic reference standards . Importantly, several imaging parameters have been identified, which correlate with the presence of active intestinal inflammation: they have been employed for the calculation of imaging-based disease activity scores .
As repeated assessments of disease activity are required during the course of Crohn's disease, radiation-free techniques (i.e. bowel US and MRI) have rapidly overtaken CT scanning for this clinical purpose, because of the emerging concern of cancer risk owed to diagnostic radiation exposure . Still, it is worth mentioning that good diagnostic accuracy has been reported for CT scanning in the detection of active CD, as demonstrated by an overall sensitivity of 81% (95% CI, 77–86%), a specificity of 88% (95% CI, 82–91%), a likelihood ratio for positive results (LR+) of 6.75 and a likelihood ratio for negative results (LR−) of 0.22, as compared with endoscopy .
In a systematic review a pooled overall diagnostic accuracy of 91% (95% CI, 84–96%) has been reported for MRI in the identification of frankly active CD . The corresponding figures for mild activity and remission were respectively 62% (95% CI, 44–79%) and 62% (95% CI, 38–84%). However, caution should be exercised in interpreting these results, as the analyzed studies were highly heterogeneous with regard to: patient selection criteria (known vs. suspected CD, consecutive vs. selected cohorts), MR protocols (bowel preparation, intravenous contrast, magnetic field strength) and reference standards for disease activity (colonoscopy, histopathology and intra-operative findings). Moreover, variable criteria for disease assessment (i.e. to define the positivity of the index test) have been considered, including: bowel wall enhancement, thickness, T2 hyperintensity, presence of ulceration and stenoses, cobble-stoning, lymph node enlargement and extra-intestinal findings  (Fig. 1). In a prospective study wall thickness, relative contrast enhancement, presence of edema and ulcers at MR were identified as independent predictors of Crohn's disease endoscopic index of severity (CDEIS) in patients with ileocolonic CD . Such parameters were subsequently confirmed in a validation cohort from the same Authors  and used to derive a quantitative magnetic resonance index of activity (MaRIA), by the formula:
By using endoscopy as a reference standard, degrees of sensitivity of 81% and specificity of 89% (LR+ 7.36, LR− 0.21) have been reported for MaRIA in the grading of Crohn's disease activity . In contrast, this index was found not to correlate with CDAI in a recent multicenter observational study , this further supporting the relative inadequacy of clinical indexes in the assessment of disease activity in patients with Crohn's disease.
Over the last few years several innovations have been introduced to MR imaging, with the intent of improving its diagnostic accuracy and tissue characterization capabilities. In this context, promising results have been recently shown by diffusion-weighted imaging (DWI)-MR. DWI is a novel form of MR imaging based upon the measurement of the random Brownian motion of water molecules within a voxel of tissue. Even if the relationship between histology and diffusion is complex, in general, densely cellular tissues or tissues with cellular swelling exhibit lower diffusion coefficients . Therefore, this technique has been initially applied to the characterization of tumor masses and in cerebral ischaemia . More recently, a potential application of DWI in grading tissue inflammation and evaluating inflammatory conditions, including CD, has been postulated . The potential advantages of DWI-MR over standard MR in the study of the bowel include high contrast resolution and avoidance of gadolinium administration . In a preliminary series, an excellent level of diagnostic accuracy of DWI-MR in the detection of active CD inflammation has been reported, with a sensitivity of 94.7% and a specificity of 82.4% (LR+ 5.38, LR− 0.06) with regard to endoscopic or surgical findings . This was associated with very good levels of intra- and inter-rater reliability of the technique. Notably, DWI-MR without intravenous contrast did not prove inferior to standard contrast-enhanced MR in evaluating CD-related small-bowel inflammation in a very recent prospective non-inferiority study , thus confirming the data deriving from a retrospective series (Table 1) . The recently reported excellent agreement between DWI-MR results and the MaRIA index further supports the usefulness of this technique in the study of CD inflammatory status . However, it should be pointed out that a reduced ability of DWI-MR in detecting penetrating complications against standard MR has been described; if confirmed through larger prospective series, this issue can represent a potential limitation of this imaging technique in the diagnostic work-up of CD patients.
|Study||Study type||Technique||No. of pts.||Criteria for disease activity||Reference standard||Results|
|Rimola et al. ||Prospective||MRI (1.5 T)||50||Wall thickness, relative contrast enhancement, ulcers||Ileocolonoscopy||Accuracy 89%
|Oto et al. ||Retrospective||MRI (1.5 T) DWI||11||Wall thickening (>3 mm), wall signal on DWI, ADC map||Ileocolonoscopy, histopathology||Sensitivity 94.7%
|Seo et al. ||Non-inferiority prospective||MRI (1.5 T) DWI||44||Ileocolonoscopy||Agreement with CT 91.8%|
|Foti et al. ||Retrospective||MRI (1.5 T) DWI||20||Wall hyper-enhancement, wall thickening (>3 mm), increased T2 signal, mural stratification, enlarged lymph nodes (>5 mm)||Ileocolonoscopy||Accuracy 100%
|Neye et al. ||Prospective||B-mode power Doppler US||22||Bowel wall thickness, vascularization pattern||Ileocolonoscopy||Good concordance between US and endoscopy: k = 0.75–0.91|
|Migaleddu et al. ||Prospective||US, CEUS||47||Mucosal enhancement||Ileocolonoscopy, histopathology||Sensitivity 93.5%
|Malagò et al. ||Prospective||CEUS||30||Lesion length, wall thickness, comb sign, enlarged lymph nodes, fat proliferation, stenosis||Ileocolonoscopy||Good correlation between MRI and CEUS: rho = 0.791|
|Ripollès et al. ||Prospective||CEUS||25||Wall thickness, transmural complications, color Doppler grade, enhancement, stenosis||Histopathology||Sensitivity 93%
|Sasaki et al. ||Prospective||Doppler US||108||Bowel wall thickness, Limberg score||Ileocolonoscopy, histopathology||Limberg score 3–4
MRI: magnetic resonance imaging; DWI: diffusion weighted imaging; CEUS: contrast-enhanced ultrasound; ADC: apparent coefficient diffusion.
Thanks to a number of practical advantages, including reduced costs, high reproducibility and minimal invasiveness, bowel US has been considered as a valid alternative to both MRI and CT for the evaluation of disease activity in patients with CD , , and . Nonetheless, the widespread application of this technique has been initially hampered by concerns over levels of reduced accuracy in evaluating proximal small-bowel segments and significant inter-observer variability in reporting US parameters . Additionally, some early studies failed to document a significant correlation between ultrasonographic findings and biochemical or clinical parameters of CD-related inflammation , , and . Such negative results can be explained by the adoption of increased bowel wall thickness (BWT) as the only US parameter of disease activity, while other factors, including mucosal and sub-mucosal fibrosis, can be responsible for intestinal thickening . These considerations have led several teams to search for and validate additional US parameters towards the grading of Crohn's disease activity . In this regard, the degree of mucosal vascularization at color power Doppler has recently emerged as a relevant item to distinguish active from inactive CD . Indeed, a good level of concordance between the results of power Doppler sonography and ileocolonoscopy has been reported in both retrospective  and prospective series  and . To partially reduce the subjectivity of vascularization assessment, Limberg et al. have proposed a four-point semiquantitative scale, encompassing both bowel wall thickening and degree of vascularization . More recently, a number of ultrasound technical innovations and the introduction of novel sonographic contrast media have allowed the gathering of quantitative data on bowel wall perfusion by real-time contrast-enhanced ultrasound (CEUS)  and . In a comparative study, the superior diagnostic accuracy of CEUS over both baseline and color Doppler US for active CD has been reported . This study reported a sensitivity of 93.5%, a specificity of 93.7%, a LR+ of 14.84 and a LR− of 0.07, and an overall diagnostic accuracy of 93.6% for CEUS in the detection of active CD . Importantly, similar levels of diagnostic accuracy of CEUS and MR have been reported in another recent study , even if the former technique was associated with a high proportion of false positive cases, thereby limiting its potential applicability in the daily clinical practice.
In conclusion, both MRI and US can accurately quantify intestinal inflammation in CD, their performance continuously improving as a result of technological advances and contrast media evolution (Table 1), thus leading to hypothesize that in the future imaging techniques may replace endoscopy for this clinical indication. Importantly, the recent Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE) initiative by IOIBD has recognized the resolution of inflammation as assessed by cross-sectional imaging as a valid target in patients with Crohn's disease, when endoscopy cannot adequately evaluate inflammation . The decision to implement one technique over the other should take into account several variables, including costs, local availability and patient preference.
3. Distinction between inflammatory and fibrotic tissue
In the last few years it has become increasingly evident that Crohn's disease-related fibrogenesis is a progressive and dynamic process, which results from the concerted action of multiple mediators released during the inflammatory process, as an attempt to heal CD-related ulcers and fistulas . This is a rational way to explain several clinical observations, including the co-existence of inflammatory and fibrotic lesions in CD-affected segments  and , and the evolution of the CD phenotype over time towards stricturing or penetrating patterns . Still, estimating the relative proportion of inflammatory over fibrotic tissue in patients with CD would be of great help for therapeutic purposes, in order to reserve the prescription of anti-inflammatory drugs to patients with predominant inflammation  and .
The work by several teams has convincingly demonstrated that cross-sectional imaging may be useful in distinguishing inflammatory from fibrotic lesions in CD-affected areas , , , and , although the results of these studies are sometimes difficult to interpret because of the reported co-existence of fibrosis and inflammation in the same bowel segment at pathological analysis. Notwithstanding these difficulties, by using transmural histopathological analysis of surgically resected specimens as the reference standard, Punwani et al.  reported a significant association between bowel wall thickness and T2 signal intensity at MR and a degree of acute inflammation, as measured by the Acute Inflammatory Score (AIS). In contrast, even if fibrostenotic segments were characterized by a greater mean wall thickness with respect to non-fibrostenotic sites, the difference did not reach statistical significance (p = 0.14). The correlation between MR findings, including bowel wall thickness and T2 signal intensity, and inflammation were subsequently confirmed by other studies , , and . Conversely, the role of MR contrast enhancement in the characterization of CD-related lesions is still a matter of debate. Some studies have failed to document any significant correlation between the intensity of bowel contrast enhancement at MR and the degree of inflammation;  and  however, later studies have reported that the intensity of T1 signal contrast enhancement may provide a valuable aid in differentiating between areas with predominant inflammation vs. fibrosis , , , and . Interestingly, some authors have suggested that the qualitative rather than quantitative evaluation of the contrast enhancement patterns (layered vs. homogeneous) may be useful for CD tissue characterization  and . Indeed, according to a recent prospective study , the homogeneous MR contrast enhancement at 7 min and the progression of enhancement over time were found to strongly correlate with fibrotic changes in the affected bowel. The delayed diffusion of gadolinium in the fibrotic tissue, which is characterized by an increased density and a reduced vascularization as compared to an inflamed tissue, is likely to be responsible for the observed contrast behavior. Importantly, the same authors reported that the curve of enhancement gain percentage may be used to diagnose severe bowel fibrosis, regardless of the amount of co-existing inflammation. By using receiver-operator characteristic curves, the authors have calculated that a cut-off point at 23.5% of percentage contrast enhancement gain at 70 s to 7 min was able to distinguish severe from mild-moderate intestinal fibrosis with a sensitivity of 94% and a specificity of 89%. The calculated likelihood ratios for positive and negative results (LR+ and LR−) of 8.75 and 0.07, respectively, confirmed that this item can be particularly useful to exclude significant fibrosis in CD patients, rather than confirming it. Following these results, the authors proposed a novel classification of CD lesions, considering both the degree of inflammation and fibrosis, based upon signal intensity on T2 and percentage of enhancement gain at 70 s to 7 min. However, when the MR-based classification was tested against pathological examination, only a moderate agreement was observed (Cohen's kappa; p ≤ 0.01, κ = 0.59, 95% CI, 0.40–0.77), probably due to a reported low predictive value of T2 signal intensity for the degree of inflammation.
It is currently an area of intense research to establish whether novel MR imaging techniques, including diffusion-weighted imaging (DWI) and magnetization transfer (MT)-MR, provide any diagnostic advantage over standard MR sequences for Crohn's disease tissue characterization. A recent study has reported a significant association between the histological degree of fibrosis and the DWI apparent diffusion coefficient (ADC), the latter not being influenced by inflammatory changes . Magnetization transfer (MT) is a novel magnetic resonance technique to assess the interaction between the low and high-mobility proton pools in a given tissue, thus allowing the indirect measurement of the concentrations of selected macro-molecules (e.g. collagen) in an aqueous physiological environment . In some experimental models of Crohn's disease, MT-MRI and standard MR T2 signal intensity showed similar levels of accuracy in the detection of bowel wall fibrosis in the setting of superimposed inflammation:  and  however, the data available on patients with CD is limited .
Whilst the routine execution of CTE for disease monitoring in CD is no longer advisable due to radiation risks, this technique has previously shown to be suitable for tissue characterization of CD-affected segments. By using surgical histopathology as a reference standard, a diagnostic accuracy ranging between 70% and 80% was reported for CTE in differentiating between inflammatory and fibrostenotic lesions . Several CTE parameters, including mucosal enhancement, wall thickness, comb sign and the presence of lymphadenopathy were significantly associated with bowel inflammation, while the presence of a stenosis at CTE was associated with fibrosis at pathological examination . This finding, however, was not confirmed in subsequent studies , thus suggesting that the absence of CTE findings of inflammation in a stenotic lesion does not necessarily predict significant intestinal fibrosis. Noteworthy, a superior sensitivity of MR over CTE in the detection of fibrotic segments has been recently reported in a pediatric series (80.9% vs. 55.6% for MR and CTE, respectively)  while no differences between the two techniques were reported with regard to active inflammation.
As previously mentioned, bowel US offers doubtless advantages over standard cross-sectional imaging techniques, and it is currently considered as an established tool to monitor patients with CD. Several bowel US parameters, including stratification patterns and vascularization, have been found to be of value towards CD tissue characterization. By using pathological examination as the gold standard, a stratified US pattern was found to be predictive of predominant fibrosis in CD-related ileal stenoses, as compared to segments with predominant inflammation, which appear more uniformly hypoechoic  and . According to those authors, the observed stratified US pattern is related to collagen deposition in the submucosal layer of the bowel wall, which appears hyperechoic at US. Conversely, the reduced echogenicity observed in the inflamed bowel is probably due to hyperaemia, neovascularization and inflammatory edema. Consistently, several studies have reported a positive correlation between the degree of bowel vascularization, as evaluated by color Doppler ultrasound, and the histological degree of inflammation , , , and , a negative association between fibrosis and hypervascularization having been reported as well .
In the last few years, intense research has been carried out about the feasibility of implementing innovative US techniques for tissue characterization. In this context, ultrasound elasticity imaging (UEI) has been emerging as a promising non-invasive method to assess fibrotic changes in a selected organ by measuring its deformability after the application of a force (strain) (Fig. 2) . This, in turn, is based on the preliminary notion that tissue stiffness and its relative collagen content are directly correlated. In two preliminary reports UEI proved capable to detect fibrotic changes in experimental models of colitis with reasonably high sensitivity and reproducibility  and . Such promising results prompted several independent teams to assess the diagnostic performance of UEI in the detection of fibrosis in patients with CD. Indeed, a significant direct correlation was reported between the degree of bowel fibrosis at histological examination and the quantitative measurement of intestinal stiffness at UEI , , and . Importantly, the authors were able to demonstrate that UEI retains an excellent discriminatory ability to detect severe bowel fibrosis, and that the degree of fibrosis is the only independent determinant of UEI results at multivariate analysis, the latter not being influenced by the degrees of acute and chronic inflammation. A good inter-rater agreement for UEI results was additionally reported .
Through a parallel line of research, the usefulness of shear-wave elastography in the detection of CD-related bowel fibrosis is currently being assessed  and . Shear waves are generated by means of an ultrasound transducer, which generates an acoustic radiation force impulse (ARFI). ARFI displaces the targeted tissue at a specified depth, and then the same transducer is used to track orthogonal shear waves as they propagate through the tissue of interest . In a recent ex vivo study on surgically resected CD specimens, Dillman et al.  demonstrated that ARFI elastography-derived shear-wave velocity (SWV) measurements can accurately discriminate between a fibrotic and an acutely inflamed bowel, as high-fibrosis score bowel segments had a significantly greater mean shear-wave speed than an inflamed intestine. An in vivo confirmation of ARFI results in patients with CD is still awaited.
In conclusion, the continuing evolution of the MRI and bowel US technology, including the implementation of ultrasound elasticity imaging, will allow a more and more precise characterization of CD-affected areas (Table 2) in the near future. However, how these differences may translate into different therapeutic responses or the clinical behavior of patients with CD is presently unknown, and should be explored in future prospective studies.
|Pazahr et al. ||Magnetization transfer||31||MT ratio||The MT ratio is significantly increased in fibrotic strictures|
|Tielbeek et al. ||Diffusion-weighted magnetic resonance||20||ADC||ADC significantly correlates with the fibrostenosis score|
|Stidham et al. ||Ultrasound elasticity imaging||7||UEI strain||The UEI strain is able to differentiate stenotic vs. normal small bowel and correlates well with ex vivo elastometry|
|Baumgart et al. ||Real-time elastography||10||RTE strain||The value of the RTE strain is significantly associated with fibrosis|
|Fraquelli et al. ||Ultrasound elasticity imaging||20||UEI strain ratio||The strain ratio is significantly correlated with fibrosis and able to discriminate severe ileal fibrosis (AUC 0.917, 95% CI, 0.78–1.00)|
|Dillman et al.a||Shear-wave elastography||12||Shear-wave speed measured with VTQ and VT-IQ||High-fibrosis-score bowel segments show significantly higher mean shear-wave speed measurements than those with low fibrosis scores; AUC for distinguishing low from high-fibrosis-score bowel segments is 0.91 for VTQ (95% CI, 0.67–0.99) and 0.77 for VT-IQ (95% CI, 0.51–0.94)|
a Study of ex vivo resected bowel segments of Crohn's disease patients.
MR: magnetic resonance; MT: magnetic transfer; ADC: apparent coefficient diffusion; UEI: ultrasound elasticity imaging; RTE: real time elastography; VTQ: virtual touch quantification; VT-IQ: virtual touch-IQ.
4. Prediction of the need for surgery and response to medical therapy
Retrospective studies on the natural history of Crohn's disease have contributed to demonstrate that a variable proportion of patients experience a disabling disease course, characterized by stricturing or penetrating abdominal complications, leading to an increased need for surgical intervention . Even if an early identification of these patients is of great relevance for clinical decision-making, so far only a handful of elements have demonstrated to be associated with the subsequent course of Crohn's disease, including both clinical variables (active smoking, steroid need, age at disease onset and disease duration), and endoscopic disease severity . Importantly, the assessment of these parameters at CD diagnosis is now recommended by the IBD guidelines for risk stratification, and to guide the initial therapeutic strategy . Several research teams are currently investigating whether cross-sectional imaging results play a role in predicting relevant outcomes, including the response to medical therapy and need for surgery. In a large prospective study, a bowel wall >7-mm thickness at bowel ultrasonography (US) was found to be independently associated with an increased 1-year risk of intestinal resection (OR 19.5; 95% CI, 5.4–71.1) . These results were consistent with a previous report, which documented the positive correlation between the pre-operative bowel wall thickness and the risk of recurrence following conservative surgery for CD . As expected, the detection of stricturing and/or penetrating complications at both US and MRI has been linked to a reduced surgery-free survival over a 12–24 month follow-up  and . More surprisingly, the previously documented association between severe endoscopic lesions and the risk of surgical resection has no longer been confirmed in more recent reports , so as to suggest that abdominal imaging may be more useful than colonoscopy in the risk stratification of CD patients in the biologic era.
Conversely, whether the imaging techniques help in predicting the response to medical treatments is still largely unexplored. In a single report, luminal narrowing and prestenotic dilatation at MRI were negatively associated with any response to medical therapy (OR 7.85, 95% CI, 1.73–35.6, p = 0.008) . Further data will be required to demonstrate whether abdominal imaging can be used to direct medical therapy for patients with CD. The reported efficacy of biological therapies in inducing mucosal healing, defined as the absence of any luminal alterations at colonoscopy, prompted several groups to explore the relevance of this therapeutic end-point in predicting selected outcomes. Indeed, the achievement of mucosal healing in patients affected by CD has been associated with a reduction of the relapse rate, the number of hospitalization stays and the need for surgery , , , and . Moreover, mucosal healing has independently been linked to the reduced risk of clinical relapse upon anti-TNF interruption . Importantly, abdominal imaging has been proposed as a less invasive alternative to colonoscopy for assessing mucosal healing following anti-TNF therapy in patients with CD. By using a validated score (MaRIA score)  and , Ordás et al.  could demonstrate that MRI accurately predicts mucosal healing (Sn 85%, Sp 78%, accuracy 83%) as compared to ileocolonoscopy, and can therefore replace the latter technique in re-evaluating patients following medical treatment. Similarly, ultrasonography has been demonstrated to adequately predict mucosal healing in patients with CD . The correlation between the findings of two techniques was good (K = 0.73, p < 0.001) and the accuracy of US was high in predicting endoscopic remission (Sn 83%, Sp 92%, accuracy 86%, 95% CI, 75.5–93.0).
The well-known efficacy of immunosuppressants and anti-TNF antibodies in determining the healing of CD mucosal lesions prompted several authors to explore the effects of these agents on the resolution of transmural disease and on the normalization of bowel wall thickness, defined as “transmural healing” (TH), in close analogy with the concept of mucosal healing. In a small preliminary series, Van Assche et al.  reported that the complete resolution of transmural lesions after anti-TNF therapy is rarely observed, even the authors observed a progressive improvement of MR parameters of activity, thus confirming previous results . More recently, Ordás et al.  were able to observe the normalization of the transmural MR alterations, including wall thickness, edema, mural hypervascularization and extra-mural lesions, in patients achieving endoscopic mucosal healing 12 weeks after the start of anti-TNF. By using bowel ultrasound, Castiglione et al.  reported that TH, as defined by the normalization of bowel wall thickness (≤3 mm), could be achieved by 25% of patients with CD treated with anti-TNF, and significantly correlated with mucosal healing.
At present, the clinical relevance of TH in the management of patients with CD is unknown, and further prospective studies will be needed to evaluate whether the achievement of this therapeutic goal may lead to additional clinical benefits as compared with endoscopic mucosal healing.
5. Assessment of CD post-surgical recurrence
Despite the increasing use of thiopurines and anti-TNF drugs, some population-based studies have indicated that nearly half of the patients with Crohn's disease would require surgery within 10 years from diagnosis . As known, the surgical resection of the inflamed bowel in CD is not curative, thus the operated patients are at risk for post-surgical relapse. This is characterized by the recurrence of CD-related lesions in the pre-anastomotic area (endoscopic recurrence), eventually followed by symptoms (clinical recurrence), and potentially repeated surgical interventions (surgical recurrence), which pose as a source of disability and decreased quality of life for patients with CD  and . Some studies report that the risk of endoscopic recurrence in CD may be as high as 62% and 75% six and twelve months after resection respectively , while clinical and surgical recurrences occur in up to 80% and 50% of cases, respectively, after a 20-year follow-up . Noteworthy, the severity of endoscopic recurrence at the anastomosis site six and twelve months after surgery, as assessed by Rutgeerts’ score , has been found to significantly predict the risk of clinical recurrence  and , and ileocolonoscopy findings are currently used to guide the therapeutic management of CD in the post-surgical setting. In this clinical context, promising results have been reported for the cross-sectional imaging techniques, which may therefore represent valuable alternatives to frequent colonoscopies. Two studies  and  have assessed the diagnostic accuracy of MR enteroclysis in detecting and grading recurrent CD following ileocolonic resection, as compared with ileocolonoscopy. Even if the MR parameters had not been previously validated, mild bowel wall thickening and contrast enhancement without strictures were arbitrarily adopted as signs of low-grade recurrence at MR, while radiological strictures and increased bowel wall thickness with contrast enhancement were considered as parameters defining severe recurrence. Overall, MR showed an excellent diagnostic accuracy in the detection of moderate to severe anastomotic recurrence, as the reported values of sensitivity and specificity were 100% and 89%, respectively. Accordingly, an excellent correlation between MR parameters and endoscopic Rutgeerts’ scores was reported (kappa 0.673, r = 0.90). Importantly, anastomotic stenosis prevented the endoscopic exploration of the neoterminal ileum in about 30% of patients, underlining the additional benefits of MR in this clinical setting. MR was less accurate in the detection of low-grade anastomotic recurrences, as it proved unable to distinguish between i1 and i2 Rutgeerts’ scores.
The diagnostic value of CT enterography in the evaluation and grading of CD post-surgical recurrences has been assessed by several papers , , , and . Most of these studies have showed CT scan to have an excellent diagnostic performance, with sensitivity, specificity and accuracy values of 90% of more, as compared with either colonoscopy  and  or a combination of endoscopic, clinical and histopathologic features  and . Among the examined CT parameters (i.e. anastomotic wall thickening, evidence of stenosis with prestenotic dilatation, degree of mucosal hyper-enhancement, presence of comb sign and creeping fat), severe anastomotic stenosis and anastomotic wall thickening >3 mm were confirmed as the most sensitive findings for the detection of anastomotic recurrence, with sensitivity of 97% and 93%, respectively, while stratification had a specificity of 100% .
Technological advances, and the deployment of high-frequency probes in the study of the bowel, have made it possible to apply US to the detection of post-surgical CD recurrence. The diagnostic performance of bowel US in this clinical setting has been specifically assessed by several cross-sectional studies, and compared to endoscopic results. In most studies, increased bowel wall thickness (BWT) at the anastomotic site was uniformly recognized as one of the most relevant parameters to define post-surgical recurrence, as BWT > 3 mm was shown to identify endoscopic recurrence with excellent sensibility and specificity , , , , , , , and . In some studies, the ultrasound pattern of the bowel at the anastomotic site has shown to ameliorate the diagnostic accuracy of simple BWT measurements  and . Interestingly, early alterations of BWT at bowel US following surgery have shown to predict both endoscopic and surgical recurrence of CD in prospective studies  and , thus suggesting that this technique may be useful for the early risk stratification of patients in the post-surgical setting, and possibly for identifying patients requiring early colonoscopy. The reported limits of US in this clinical setting include non-optimal reproducibility (concordance K = 0.72 for BWT), which may be partly due to some heterogeneity in the technical equipment used (Power Doppler, enteral or intravenous contrast).
In conclusion, although colonoscopy still stands as the gold standard for the assessment of post-surgical CD recurrence, abdominal imaging may represent a valid alternative to repeat endoscopic examinations. CT scan and MR have similar performance in assessing post-surgical relapse, but where available, MR is superior in following up these patients because of no radiation exposure, high inter-observer agreement and high accuracy also in patients with anastomotic strictures and new proximal locations of CD. Due to radiation exposure combined with the need of periodic follow-up, CT techniques nowadays take a marginal role in the follow-up of post-surgical recurrences in patients with CD, even though their level of accuracy is high. US may be a valid choice to avail in many IBD care centers and is more easily accessible compared to MR. However, more studies are needed to evaluate the cost-effectiveness of cross-sectional imaging compared with ileocolonoscopy in evaluating post-surgical recurrence in patients with CD.
6. Abdominal imaging as a tool to assess CD-related bowel damage
In the last decade the results from several long-term cohort studies have placed greater and greater emphasis on the progressive nature of CD, as they having showed that most patients are characterized, early in the course of their disease, by a non-stricturing/non-penetrating phenotype, which possibly evolves over time into a complicated phenotype, mostly as a result of progressive bowel wall fibrosis  and . Additionally, the growing use of cross-sectional imaging to evaluate CD patients has made it possible to obtain the transmural view of CD-affected intestinal tracts, thus enabling clinicians to realize that clinical symptoms and inflammatory activity at the mucosal level do not necessarily parallel any severity of bowel wall involvement and any presence of complications . More importantly, the serial observations of bowel wall changes over time and following pharmacological therapy have led to the understanding that most CD complications, once developed, are irreversible and can be usually resolved only by surgical intervention .
These considerations have led clinicians to focus on the concept of bowel damage, i.e. the cumulative amount of structural gut changes occurring over time in the course of CD , as opposed to inflammatory activity. The concept of tissue damage itself is not novel, as it has been already extensively used in other clinical settings, such as rheumatoid arthritis . The potential application of a bowel damage score in CD would include the measurement of the long-term impact of CD, the comparison of different therapeutic strategies in terms of long-term outcome, and the identification of parameters at disease onset associated with a high risk of rapid progression. Given the transmural nature of most CD-related complications, the cross-sectional imaging techniques conceivably play a leading role in the building of bowel damage scores . Indeed, the magnetic resonance imaging and computed tomography results provide the backbone for the calculation of the recently developed Lèmann Index , which is the first attempt of a global CD bowel damage index. For the calculation of the Lèmann Index, the digestive tract is arbitrarily divided into four organs: upper digestive tract, small bowel, colon/rectum, and anus. These organs are further divided into segments: three segments for the upper digestive tract, six for the colon/rectum, and one for the anus. For the small bowel, each lesion within a 20-cm length is considered to represent one small-bowel segment, the number of segments being capped at 20. For each segment, an ordinal score is given to stricturing and penetrating lesions on the basis of their severity (ranging from wall thickening <3 mm to definite stricture with prestenotic dilatation for stricturing lesions and from superficial ulceration to phlegmon or fistula for penetrating lesions). Such ordinal scores are then included in a final score after their transformation into numerical coefficients to fit with the investigator's damage evaluations. Noteworthy, any previous bowel resections are included in the score as severe lesions. The result is a numerical index (ranging from 0, no damage, to 140, maximal damage) which is internally validated and shows a fair level of reliability (intraclass correlation coefficient estimate 0.60). As expected, the median Lèmann Index positively correlates with Crohn's disease duration, while the clinical disease activity using CDAI exerts no significant influence.
Recently, a bowel ultrasound-based numerical index (Sonographic Lesion Index for CD, SLIC) has been developed as an alternative mean to quantify small bowel damage in patients with Crohn's disease . SLIC is calculated by taking into account both continuous variables, such as the amount of bowel wall thickening, the lumen diameter and length of the lesion(s), and discrete variables, such as the number of lesion sites, the presence of abscesses, fistulas, enlarged lymph nodes and mesentery adipose tissue alterations. SLIC can range between 0 (no damage) and 200 (maximal damage), and is further subdivided according to a severity scale of 5 classes, from the lowest to highest score (from A to E). In contrast with the Lèmann Index, in its validation study SLIC was significantly correlated with disease activity, as measured by CDAI and C-reactive protein (CRP) levels. Importantly, the investigators found that the patients classified in high-severity classes by SLIC (D and E) underwent surgery within one year more frequently than those in class C, B and A .
In summary, novel cross-sectional imaging based scores have been recently introduced for the quantification of CD-related structural bowel damage, to complement disease activity scores. Long-term prospective data from external cohorts will be required to assess the impact and relevance of damage scores in the clinical management of CD patients.
Along with the established role in the diagnosis of Crohn's disease and the detection of extra-intestinal complications, the usefulness of cross-sectional imaging techniques in monitoring disease activity, quantifying fibrotic evolution and predicting response to medical therapy and post-surgical recurrence in patients with Crohn's disease is currently being validated. Phase III and IV diagnostic studies that demonstrate a significant effectiveness of these diagnostic tools in defining treatment strategies and modifying disease outcome, are still missing. Such studies should be strongly encouraged in the future, in order to develop diagnostic algorithms with tested efficacy .
Conflict of interest
This work was supported by the Italian Ministry of Health (GR-2011-02352001).
-  K.T. Thia, W.J. Sandborn, W.S. Harmsen, et al. Risk factors associated with progression to intestinal complications of Crohn's disease in a population-based cohort. Gastroenterology. 2010;139:1147-1155 Crossref
-  D.J. Grand, A. Harris, E.V. Loftus Jr. Imaging for luminal disease and complications: CT enterography, MR enterography, small-bowel follow-through, and ultrasound. Gastroenterology Clinics of North America. 2012;41:497-512 Crossref
-  J. Panés, R. Bouzas, M. Chaparro, et al. Systematic review: the use of ultrasonography, computed tomography and magnetic resonance imaging for the diagnosis, assessment of activity and abdominal complications of Crohn's disease. Alimentary Pharmacology and Therapeutics. 2011;34:125-145
-  E. Quaia, B. Cabibbo, M. Sozzi, et al. Biochemical markers and MR imaging findings as predictors of Crohn disease activity in patients scanned by contrast-enhanced MR enterography. Academic Radiology. 2014;21:1225-1232 Crossref
-  M.A. Denis, C. Reenaers, F. Fontaine, et al. Assessment of endoscopic activity index and biological inflammatory markers in clinically active Crohn's disease with normal C-reactive protein serum level. Inflammatory Bowel Diseases. 2007;13:1100-1105 Crossref
-  J.F. Colombel, W.J. Sandborn, W. Reinisch, et al. Infliximab, azathioprine, or combination therapy for Crohn's disease. New England Journal of Medicine. 2010;362:1383-1395 Crossref
-  L. Peyrin-Biroulet, W. Reinisch, J.F. Colombel, et al. Clinical disease activity, C-reactive protein normalisation and mucosal healing in Crohn's disease in the SONIC trial. Gut. 2014;63:88-95 Crossref
-  L. Peyrin-Biroulet, W. Sandborn, B.E. Sands, et al. Selecting therapeutic targets in inflammatory bowel disease (STRIDE): determining therapeutic goals for treat-to-target. American Journal of Gastroenterology. 2015;110:1324-1338
-  N. Williet, W.J. Sandborn, L. Peyrin-Biroulet. Patient-reported outcomes as primary end points in clinical trials of inflammatory bowel disease. Clinical Gastroenterology and Hepatology. 2014;12:1246-1256
-  K. Horsthuis, S. Bipat, P.C. Stokkers, et al. Magnetic resonance imaging for evaluation of disease activity in Crohn's disease: a systematic review. European Radiology. 2009;19:1450-1460 Crossref
-  J. Rimola, S. Rodriguez, O. García-Bosch, et al. Magnetic resonance for assessment of disease activity and severity in ileocolonic Crohn's disease. Gut. 2009;58:1113-1120 Crossref
-  J. Rimola, I. Ordás, S. Rodriguez, et al. Magnetic resonance imaging for evaluation of Crohn's disease: validation of parameters of severity and quantitative index of activity. Inflammatory Bowel Diseases. 2011;17:1759-1768 Crossref
-  I. Ordás, J. Rimola, S. Rodríguez, et al. Accuracy of magnetic resonance enterography in assessing response to therapy and mucosal healing in patients with Crohn's disease. Gastroenterology. 2014;146:374-382
-  A.J. Coimbra, J. Rimola, S. O’Byrne, et al. Magnetic resonance enterography is feasible and reliable in multicenter clinical trials in patients with Crohn's disease, and may help select subjects with active inflammation. Alimentary Pharmacology and Therapeutics. 2016;43:61-72
-  M.E. Moseley, Y. Cohen, J. Mintorovitch, et al. Early detection of regional cerebral ischemia in cats: comparison of diffusion- and T2-weighted MRI and spectroscopy. Magnetic Resonance in Medicine. 1990;14:330-346 Crossref
-  S. Kiryu, K. Dodanuki, H. Takao, et al. Free-breathing diffusion-weighted imaging for the assessment of inflammatory activity in Crohn's disease. Journal of Magnetic Resonance Imaging. 2009;29:880-886
-  A. Oto, F. Zhu, F. Kulkarni, et al. Evaluation of diffusion-weighted MR imaging for detection of bowel inflammation in patients with Crohn's disease. Academic Radiology. 2009;16:597-603 Crossref
-  N. Seo, S.H. Park, K.J. Kim, et al. MR enterography for the evaluation of small-bowel inflammation in Crohn disease by using diffusion-weighted imaging without intravenous contrast material: a prospective noninferiority study. Radiology. 2015; [Epub ahead of print]
-  P.V. Foti, R. Farina, M. Coronella, et al. Crohn's disease of the small bowel: evaluation of ileal inflammation by diffusion-weighted MR imaging and correlation with the Harvey-Bradshaw index. La Radiologia Medica. 2015;120:585-594 Crossref
-  C. Hordonneau, A. Buisson, J. Scanzi, et al. Diffusion-weighted magnetic resonance imaging in ileocolonic Crohn's disease: validation of quantitative index of activity. American Journal of Gastroenterology. 2014;109:89-98 Crossref
-  F. Parente, G. Maconi, S. Bollani, et al. Bowel ultrasound in assessment of Crohn's disease and detection of related small bowel strictures: a prospective comparative study versus X ray and intraoperative findings. Gut. 2002;50:490-495 Crossref
-  G. Maconi, F. Parente, S. Bollani, et al. Abdominal ultrasound in the assessment of extent and activity of Crohn's disease: clinical significance and implication of bowel wall thickening. American Journal of Gastroenterology. 1996;91:1604-1609
-  F. Parente, S. Greco, M. Molteni, et al. Role of early ultrasound in detecting inflammatory intestinal disorders and identifying their anatomical location within the bowel. Alimentary Pharmacology and Therapeutics. 2003;18:1009-1016 Crossref
-  C. Bru, M. Sans, M.M. Defelitto, et al. Hydrocolonic sonography for evaluating inflammatory bowel disease. American Journal of Roentgenology. 2001;177:99-105 Crossref
-  H. Neye, W. Voderholzer, S. Rickes, et al. Evaluation of criteria for the activity of Crohn's disease by power Doppler sonography. Digestive Diseases. 2004;22:67-72 Crossref
-  T. Sasaki, R. Kunisaki, H. Kinoshita, et al. Doppler ultrasound findings correlate with tissue vascularity and inflammation in surgical pathology specimens from patients with small intestinal Crohn's disease. BMC Research Notes. 2014;7:363 Crossref
-  V. Migaleddu, A.M. Scanu, E. Quaia, et al. Contrast-enhanced ultrasonographic evaluation of inflammatory activity in Crohn's disease. Gastroenterology. 2009;137:43-52 Crossref
-  B. Limberg. Diagnosis of chronic inflammatory bowel disease by ultrasonography. Zeitschrift fur Gastroenterologie. 1999;37:495-508
-  R. Malagò, M. D’Onofrio, W. Mantovani, et al. Contrast-enhanced ultrasonography (CEUS) vs. MRI of the small bowel in the evaluation of Crohn's disease activity. La Radiologia Medica. 2012;117:268-281
-  F. Rieder, E.M. Zimmermann, F.H. Remzi, et al. Crohn's disease complicated by strictures: a systematic review. Gut. 2013;62:1072-1084 Crossref
-  M.V. Chiorean, K. Sandrasegaran, R. Saxena, et al. Correlation of CT enteroclysis with surgical pathology in Crohn's disease. American Journal of Gastroenterology. 2007;102:2541-2550 Crossref
-  M. Zappa, C. Stefanescu, D. Cazals-Hatem, et al. Which magnetic resonance imaging findings accurately evaluate inflammation in small bowel Crohn's disease? A retrospective comparison with surgical pathologic analysis. Inflammatory Bowel Diseases. 2011;17:984-993 Crossref
-  L. Peyrin-Biroulet, E.V. Loftus, J.F. Colombel, et al. The natural history of adult Crohn's disease in population-based cohorts. American Journal of Gastroenterology. 2010;105:289-297 Crossref
-  G.R. Lichtenstein, A. Olson, S. Travers, et al. Factors associated with the development of intestinal strictures or obstructions in patients with Crohn's disease. American Journal of Gastroenterology. 2006;101:1030-1038
-  S. Punwani, M. Rodriguez-Justo, A. Bainbridge, et al. Mural inflammation in Crohn disease: location-matched histologic validation of MR imaging features. Radiology. 2009;252:712-720 Crossref
-  J. Rimola, N. Planell, S. Rodríguez, et al. Characterization of inflammation and fibrosis in Crohn's disease lesions by magnetic resonance imaging. American Journal of Gastroenterology. 2015;110:432-440 Crossref
-  F. Rieder, J.R. de Bruyn, B.T. Pham, et al. Results of the 4th scientific workshop of the ECCO (Group II): markers of intestinal fibrosis in inflammatory bowel disease. Journal of Crohn's and Colitis. 2014;8:1166-1178 Crossref
-  J.A. Tielbeek, M.L. Ziech, Z. Li, et al. Evaluation of conventional, dynamic contrast enhanced and diffusion weighted MRI for quantitative Crohn's disease assessment with histopathology of surgical specimens. European Radiology. 2014;24:619-629 Crossref
-  M.L. Ziech, S. Bipat, J.J. Roelofs, et al. Retrospective comparison of magnetic resonance imaging features and histopathology in Crohn's disease patients. European Journal of Radiology. 2011;80:e299-e305
-  F. Fornasa, C. Benassuti, L. Benazzato. Role of magnetic resonance enterography in differentiating between fibrotic and active inflammatory small bowel stenosis in patients with Crohn's disease. Journal of Clinical Imaging Science. 2011;1:35 Crossref
-  I.C. Lawrance, J.C. Welman, P. Shipman, et al. Correlation of MRI-determined small bowel Crohn's disease categories with medical response and surgical pathology. World Journal of Gastroenterology. 2009;15:3367-3375 Crossref
-  J. Adler, S.D. Swanson, P. Schmiedlin-Ren, et al. Magnetization transfer helps detect intestinal fibrosis in an animal model of Crohn disease. Radiology. 2011;259:127-135 Crossref
-  J.R. Dillman, S.D. Swanson, L.A. Johnson, et al. Comparison of noncontrast MRI magnetization transfer and T2-weighted signal intensity ratios for detection of bowel wall fibrosis in a Crohn's disease animal model. Journal of Magnetic Resonance Imaging. 2015;42:801-810 Crossref
-  S. Pazahr, I. Blume, P. Frei, et al. Magnetization transfer for the assessment of bowel fibrosis in patients with Crohn's disease: initial experience. Magma. 2013;26:291-301 Crossref
-  J. Adler, D.R. Punglia, J.R. Dillman, et al. Computed tomography enterography findings correlate with tissue inflammation, not fibrosis in resected small bowel Crohn's disease. Inflammatory Bowel Diseases. 2012;18:849-856 Crossref
-  K.B. Quencer, K. Nimkin, M. Mino-Kenudson, et al. Detecting active inflammation and fibrosis in pediatric Crohn's disease: prospective evaluation of MR-E and CT-E. Abdominal Imaging. 2013;38:705-713 Crossref
-  G. Maconi, L. Carsana, P. Fociani, et al. Small bowel stenosis in Crohn's disease: clinical, biochemical and ultrasonographic evaluation of histological features. Alimentary Pharmacology and Therapeutics. 2003;18:749-756 Crossref
-  K. Nylund, R. Jirik, M. Mezl, et al. Quantitative contrast-enhanced ultrasound comparison between inflammatory and fibrotic lesions in patients with Crohn's disease. Ultrasound in Medicine and Biology. 2013;39:1197-1206 Crossref
-  T. Ripollès, N. Rausell, J.M. Paredes, et al. Effectiveness of contrast-enhanced ultrasound for characterisation of intestinal inflammation in Crohn's disease: a comparison with surgical histopathology analysis. Journal of Crohn's and Colitis. 2013;7:120-128
-  E. Quaia. Contrast-enhanced ultrasound of the small bowel in Crohn's disease. Abdominal Imaging. 2013;38:1005-1013 Crossref
-  W. Kratzer, C. Von Tirpitz, R. Mason, et al. Contrast-enhanced power Doppler sonography of the intestinal wall in the differentiation of hypervascularized and hypovascularized intestinal obstructions in patients with Crohn's disease. Journal of Ultrasound in Medicine. 2002;21:149-157
-  J. Ophir, I. Céspedes, H. Ponnekanti, et al. Elastography: a quantitative method for imaging the elasticity of biological tissues. Ultrasonic Imaging. 1991;13:111-134
-  K. Kim, L.A. Johnson, C. Jia, et al. Noninvasive ultrasound elasticity imaging (UEI) of Crohn's disease: animal model. Ultrasound in Medicine and Biology. 2008;34:902-912 Crossref
-  R.W. Stidham, J. Xu, L.A. Johnson, et al. Ultrasound elasticity imaging for detecting intestinal fibrosis and inflammation in rats and humans with Crohn's disease. Gastroenterology. 2011;141:819-826
-  D.C. Baumgart, H.P. Müller, U. Grittner, et al. US-based real-time elastography for the detection of fibrotic gut tissue in patients with stricturing Crohn disease. Radiology. 2015;275:889-899 Crossref
-  M. Fraquelli, F. Branchi, F.M. Cribiù, et al. The role of ultrasound elasticity imaging in predicting ileal fibrosis in Crohn's disease patients. Inflammatory Bowel Diseases. 2015;21:2605-2612
-  J.R. Dillman, R.W. Stidham, P.D. Higgins, et al. Ultrasound shear wave elastography helps discriminate low-grade from high-grade bowel wall fibrosis in ex vivo human intestinal specimens. Journal of Ultrasound in Medicine. 2014;33:2115-2123 Crossref
-  J.R. Dillman, R.W. Stidham, P.D. Higgins, et al. US elastography-derived shear wave velocity helps distinguish acutely inflamed from fibrotic bowel in a Crohn disease animal model. Radiology. 2013;267:757-766 Crossref
-  M.L. Palmeri, K.R. Nightingale. Acoustic radiation force-based elasticity imaging methods. Interface Focus. 2011;1:553-564 Crossref
-  T. Jess, L. Riis, I. Vind, et al. Changes in clinical characteristics, course, and prognosis of inflammatory bowel disease during the last 5 decades: a population-based study from Copenhagen, Denmark. Inflammatory Bowel Diseases. 2007;13:481-489 Crossref
-  M. Allez, M. Lemann, J. Bonnet, et al. Long term outcome of patients with active Crohn's disease exhibiting extensive and deep ulcerations at colonoscopy. American Journal of Gastroenterology. 2002;97:947-953
-  G. Van Assche, A. Dignass, J. Panes, et al. The second European evidence-based Consensus on the diagnosis and management of Crohn's disease: definitions and diagnosis. Journal of Crohn's and Colitis. 2010;4:7-27 Crossref
-  F. Castiglione, I. De Sio, A. Cozzolino, et al. Bowel wall thickness at abdominal ultrasound and the one-year-risk of surgery in patients with Crohn's disease. American Journal of Gastroenterology. 2004;99:1977-1983 Crossref
-  G. Maconi, G.M. Sampietro, M. Cristaldi, et al. Preoperative characteristics and postoperative behavior of bowel wall on risk of recurrence after conservative surgery in Crohn's disease: a prospective study. Annals of Surgery. 2001;233:345-352 Crossref
-  A. Jauregui-Amezaga, J. Rimola, I. Ordás, et al. Value of endoscopy and MRI for predicting intestinal surgery in patients with Crohn's disease in the era of biologics. Gut. 2015;64:1397-1402 Crossref
-  K.F. Frøslie, J. Jahnsen, B.A. Moum, et al. Mucosal healing in inflammatory bowel disease: results from a Norwegian population-based cohort. Gastroenterology. 2007;133:412-422
-  I.C. Solberg, M.H. Vatn, O. Høie, et al. Clinical course in Crohn's disease: results of a Norwegian population-based ten-year follow-up study. Clinical Gastroenterology and Hepatology. 2007;5:1430-1438 Crossref
-  F. Baert, L. Moortgat, G. Van Assche, et al. Mucosal healing predicts sustained clinical remission in patients with early-stage Crohn's disease. Gastroenterology. 2010;138:463-468 Crossref
-  P. Rutgeerts, G. Van Assche, W.J. Sandborn, et al. Adalimumab induces and maintains mucosal healing in patients with Crohn's disease: data from the EXTEND trial. Gastroenterology. 2012;142:1102-1111
-  E. Louis, J.Y. Mary, G. Vernier-Massouille, et al. Maintenance of remission among patients with Crohn's disease on antimetabolite therapy after infliximab therapy is stopped. Gastroenterology. 2012;142:63-70
-  N. Moreno, T. Ripollés, J.M. Paredes, et al. Usefulness of abdominal ultrasonography in the analysis of endoscopic activity in patients with Crohn's disease: changes following treatment with immunomodulators and/or anti-TNF antibodies. Journal of Crohn's and Colitis. 2014;8:1079-1087 Crossref
-  G. Van Assche, K.A. Herrmann, E. Louis, et al. Effects of infliximab therapy on transmural lesions as assessed by magnetic resonance enteroclysis in patients with ileal Crohn's disease. Journal of Crohn's and Colitis. 2013;7:950-957 Crossref
-  J.A. Tielbeek, M. Löwenberg, S. Bipat, et al. Serial magnetic resonance imaging for monitoring medical therapy effects in Crohn's disease. Inflammatory Bowel Diseases. 2013;19:1943-1950
-  F. Castiglione, A. Testa, M. Rea, et al. Transmural healing evaluated by bowel sonography in patients with Crohn's disease on maintenance treatment with biologics. Inflammatory Bowel Diseases. 2013;19:1928-1934
-  E.C. Lee, N. Papaioannou. Recurrences following surgery for Crohn's disease. Clinics in Gastroenterology. 1980;9:419-438
-  P. Rutgeerts, K. Geboes, G. Vantrappen, et al. Predictability of the postoperative course of Crohn's disease. Gastroenterology. 1990;99:956-963
-  A. Orlando, F. Mocciaro, S. Renna, et al. Early post-operative endoscopic recurrence in Crohn's disease patients: data from an Italian Group for the study of inflammatory bowel disease (IG-IBD) study on a large prospective multicenter cohort. Journal of Crohn's and Colitis. 2014;8:1217-1221 Crossref
-  A. Buisson, J.B. Chevaux, P.B. Allen, et al. Review article: the natural history of postoperative Crohn's disease recurrence. Alimentary Pharmacology and Therapeutics. 2012;35:625-633 Crossref
-  G. Olaison, K. Smedh, R. Sjödahl. Natural course of Crohn's disease after ileocolic resection: endoscopically visualised ileal ulcers preceding symptoms. Gut. 1992;33:331-335 Crossref
-  S. Onali, E. Calabrese, C. Petruzziello, et al. Post-operative recurrence of Crohn's disease: a prospective study at 5 years. Digestive and Liver Disease. 2016;48:489-494
-  J. Sailer, P. Peloschek, W. Reinisch, et al. Anastomotic recurrence of Crohn's disease after ileocolic resection: comparison of MR enteroclysis with endoscopy. European Radiology. 2008;18:2512-2521 Crossref
-  S. Koilakou, J. Sailer, P. Peloschek, et al. Endoscopy and MR enteroclysis: equivalent tools in predicting clinical recurrence in patients with Crohn's disease after ileocolic resection. Inflammatory Bowel Diseases. 2010;16:198-203 Crossref
-  P. Soyer, M. Boudiaf, M. Sirol, et al. Suspected anastomotic recurrence of Crohn disease after ileocolic resection: evaluation with CT enteroclysis. Radiology. 2010;254:755-764 Crossref
-  R. Mao, X. Gao, Z.H. Zhu, et al. CT enterography in evaluating postoperative recurrence of Crohn's disease after ileocolic resection: complementary role to endoscopy. Inflammatory Bowel Diseases. 2013;19:977-982 Crossref
-  F. Paparo, M. Revelli, C. Puppo, et al. Crohn's disease recurrence in patients with ileocolic anastomosis: value of computed tomography enterography with water enema. European Journal of Radiology. 2013;82:e434-e440 Crossref
-  L.M. Minordi, A. Vecchioli, P. Mirk, et al. CT enterography with polyethylene glycol solution vs CT enteroclysis in small bowel disease. British Journal of Radiology. 2011;84:112-119 Crossref
-  A. Orlando, I. Modesto, F. Castiglione, et al. The role of calprotectin in predicting endoscopic post-surgical recurrence in asymptomatic Crohn's disease: a comparison with ultrasound. European Review for Medical and Pharmacological Sciences. 2006;10:17-22
-  A. Andreoli, P. Cerro, G. Falasco, et al. Role of ultrasonography in the diagnosis of postsurgical recurrence of Crohn's disease. American Journal of Gastroenterology. 1998;93:1117-1121 Crossref
-  N. Pallotta, M. Giovannone, P. Pezzotti, et al. Ultrasonographic detection and assessment of the severity of Crohn's disease recurrence after ileal resection. BMC Gastroenterology. 2010;10:69 Crossref
-  S. Onali, E. Calabrese, C. Petruzziello, et al. Endoscopic vs ultrasonographic findings related to Crohn's disease recurrence: a prospective longitudinal study at 3 years. Journal of Crohn's and Colitis. 2010;4:319-328 Crossref
-  A. Rispo, L. Bucci, G. Pesce, et al. Bowel sonography for the diagnosis and grading of postsurgical recurrence of Crohn's disease. Inflammatory Bowel Diseases. 2006;12:486-490 Crossref
-  F. Castiglione, L. Bucci, G. Pesce, et al. Oral contrast-enhanced sonography for the diagnosis and grading of postsurgical recurrence of Crohn's disease. Inflammatory Bowel Diseases. 2008;14:1240-1245 Crossref
-  E. Calabrese, C. Petruzziello, S. Onali, et al. Severity of postoperative recurrence in Crohn's disease: correlation between endoscopic and sonographic findings. Inflammatory Bowel Diseases. 2009;15:1635-1642 Crossref
-  J.M. Paredes, T. Ripollés, X. Cortés, et al. Non-invasive diagnosis and grading of postsurgical endoscopic recurrence in Crohn's disease: usefulness of abdominal ultrasonography and 99mTc-hexamethylpropylene amineoxime-labelled leucocyte scintigraphy. Journal of Crohn's and Colitis. 2010;4:537-545 Crossref
-  F. Parente, G.M. Sampietro, M. Molteni, et al. Behaviour of the bowel wall during the first year after surgery is a strong predictor of symptomatic recurrence of Crohn's disease: a prospective study. Alimentary Pharmacology and Therapeutics. 2004;20:959-968 Crossref
-  T. Cammarota, D.G. Ribaldone, A. Resegotti, et al. Role of bowel ultrasound as a predictor of surgical recurrence of Crohn's disease. Scandinavian Journal of Gastroenterology. 2013;48:552-555 Crossref
-  J. Cosnes, S. Cattan, A. Blain, et al. Long-term evolution of disease behavior of Crohn's disease. Inflammatory Bowel Diseases. 2002;8:244-250 Crossref
-  M.L. Ziech, C. Lavini, M.W. Caan, et al. Dynamic contrast-enhanced MRI in patients with luminal Crohn's disease. European Journal of Radiology. 2012;81:3019-3027 Crossref
-  B. Pariente, J. Cosnes, S. Danese, et al. Development of the Crohn's disease digestive damage score, the Lémann score. Inflammatory Bowel Diseases. 2011;17:1415-1422 Crossref
-  J.T. Sharp, F. Wolfe, D.M. Mitchell, et al. The progression of erosion and joint space narrowing scores in rheumatoid arthritis during the first twenty-five years of disease. Arthritis and Rheumatism. 1991;34:660-668 Crossref
-  B. Pariente, L. Peyrin-Biroulet, L. Cohen, et al. Gastroenterology review and perspective: the role of cross-sectional imaging in evaluating bowel damage in Crohn disease. American Journal of Roentgenology. 2011;197:42-49 Crossref
-  B. Pariente, J.Y. Mary, S. Danese, et al. Development of the Lémann index to assess digestive tract damage in patients with Crohn's disease. Gastroenterology. 2015;148:52-63
-  E. Calabrese, F. Zorzi, S. Zuzzi, et al. Development of a numerical index quantitating small bowel damage as detected by ultrasonography in Crohn's disease. Journal of Crohn's and Colitis. 2012;6:852-860 Crossref
-  A. Colli, M. Fraquelli, G. Casazza, et al. The architecture of diagnostic research: from bench to bedside – research guidelines using liver stiffness as an example. Hepatology. 2014;60:408-418 Crossref
a Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Italy
b Gastroenterology and Endoscopy Unit, Fondazione IRCCS Ca’ Granda, Ospedale Policlinico di Milano, Italy
⁎ Corresponding author at: Department of Pathophysiology and Transplantation, University of Milan, Via Francesco Sforza, 35, 20122 Milan, Italy. Tel.: +39 0255033368; fax: +39 0255033644.
© 2016 Editrice Gastroenterologica Italiana S.r.l., Published by Elsevier B.V.