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Diffusion-weighted magnetic resonance enterocolonography in predicting remission after anti-TNF induction therapy in Crohn's disease

Digestive and Liver Disease

Abstract

Background

Diffusion-weighted magnetic resonance entero-colonography (DW-MREC) with no rectal distension and with no bowel cleansing is accurate to assess inflammatory activity in ileocolonic Crohn's disease (CD).

Aim

To study DW-MREC parameters as predictors of remission (CDAI < 150 and CRP < 5 mg/L) after anti-TNF induction therapy.

Methods

Forty consecutive CD patients were prospectively and consecutively included. All the patients underwent DW-MREC with apparent diffusion coefficient (ADC) and MaRIA calculation before starting anti-TNF. Mean ADC was defined as the mean of the segmental ADC.

Results

Twenty patients (50.0%) experienced remission at W12. Low mean ADC (2.05 ± 0.22 vs 1.89 ± 0.25, p = 0.03) and high total MaRIA (39.2 ± 16.6 vs 51.7 ± 18.2, p = 0.03) were predictive of remission at W12. Using a ROC curve, we determined a mean ADC of 1.96 as predictive cut-off of remission at W12 (AUC = 0.703 [0.535–0.872]) with sensitivity, specificity, positive predictive value and negative predictive value of 70.0%, 65.0%, 66.7% and 68.4%, respectively. In multivariate analysis, mean ADC < 1.96 (OR = 4.87, 95% CI [1.04–22.64]) and total MaRIA > 42.5 (OR = 5.11, 95% CI [1.03–25.37]), reflecting high inflammatory activity, were predictive of remission at week 12.

Conclusions

DW-MREC using quantitative parameters i.e. ADC, is useful in detecting and assessing inflammatory activity but also to predict efficacy of anti-TNF induction therapy in CD.

Keywords: Anti-TNF, Crohn's disease, Diffusion-weighted MRI, Predictive factor.

1. Introduction

Crohn's disease (CD) is a chronic relapsing and remitting disorder that can involve the entire length of the digestive tract [1]. Although anti-TNF therapy is, to date, the most effective treatment in CD, almost one third of patients experienced primary failure [2], [3], [4], and [5]. Regarding the potential side effects and the costs of biologics, determining predictors of anti-TNF efficacy remains a key point in clinical practice. Several studies trials reported potential clinical [6], [7], [8], and [9], biological [10] and [11] or genetic [10], [12], [13], and [14] predictive factors for efficacy of anti-TNF induction therapy.

New therapeutic goals such as achieving mucosal healing [15], [16], and [17] or preventing digestive damage [18] and [19] have emerged in the era of biologics and require objective tools to evaluate disease activity. Although colonoscopy is to date the gold standard for assessing ileal and colonic disease activity, the need to repeat this procedure during the CD monitoring in daily practice, have led physicians to look for alternative non-invasive approaches. Thus, magnetic resonance imaging (MRI) has been increasingly used for the diagnosis and the monitoring of CD patients and is very effective to assess inflammation and therapeutic response [20], [21], and [22]. Recently, Diffusion-Weighted Magnetic Resonance Entero-Colonography (DW-MREC) has shown high efficacy to assess inflammatory activity in the ileum using the Clermont score (=1.646 × bowel thickness − 1.321 × ADC + 5.613 × oedema + 8.306 × ulceration + 5.039) and in the colon/rectum using the apparent diffusion coefficient (ADC) which is the quantitative parameter of DW-MRI [23], [24], [25], and [26].

We aimed to study DW-MREC parameters as predictors of remission defined as CDAI < 150 and CRP < 5 mg/L at week 12. Predictors of clinical response at week 12 (ΔCDAI ≥ 100) were investigated as secondary endpoint.

2. Materials and methods

2.1. Ethical considerations

The study was performed in accordance with the Declaration of Helsinki, Good Clinical Practice and applicable regulatory requirements. The study was approved by local Ethics Committee (IRB number 00008526).

2.2. Patients and examinations

We performed an observational pilot study of a single-centre cohort in which standardized evaluation was used by experienced clinicians for all patients. A total of 40 patients from the Clermont-Ferrand IBD Unit with an established diagnosis of CD according to Lennard–Jones [27] criteria were prospectively and consecutively included between October 2012 and October 2013. Inclusion criteria were: CD patients requiring anti-TNF therapy based on experienced physician judgement (A.B. and G.B.) AND Crohn's disease activity index (CDAI) > 150. CD patients treated with anti-TNF in prevention of endoscopic postoperative recurrence were excluded. CD patients experiencing anoperineal lesions were included only if anti-TNF treatment was prescribed because of luminal CD. Exclusion criteria were: patients with common contraindications to anti-TNF therapy [28], patients with claustrophobia or other common MRI contraindications such as implanted cardiac device, metallic intraocular foreign body, allergy to gadolinium, or severe renal failure (Modification of Diet in Renal Disease (MDRD) < 30 ml/min). Patients with intra-abdominal abscess should have been effectively be treated by antibiotics or drainage to be included. Population characteristics are given in Table 1.

Table 1 Baseline population characteristics.

Total
Disease duration (months), median [IQR] 34 [4–193]
Early Crohn, n (%) 10 (25.0)
Age at inclusion (years), mean ± SD 36.8 ± 15.0
Family IBD history, n (%) 5 (12.5)
Active smokers, n (%) 17 (42.5)
Previous intestinal resection, n (%) 9 (22.5)
Anoperineal lesion, n (%) 14 (35.0)
Age at diagnosis (years), mean ± SD 27.8 ± 13.4
Montreal classification
 Age, n (%)
  A1 9 (22.5)
  A2 26 (65.0)
  A3 5 (12.5)
 Location, n (%)
  L1 18 (45.0)
  L2 5 (12.5)
  L3 17 (42.5)
  L4 5 (12.5)
 Behaviour, n (%)
  B1 12 (30.0)
  B2 17 (42.5)
  B3 11 (27.5)
Anti-TNF, n (%)
 Infliximab 18 (45.0)
 Adalimumab 22 (55.0)
Steroids naïve, n (%) 8 (20.0)
Immunosuppressants naïve, n (%) 16 (40.0)
Anti-TNF naïve, n (%) 30 (75.0)
Concomittant therapies
 5-ASA, n (%) 2 (5.0)
 Budesonide, n (%) 5 (12.5)
 Corticosteroids, n (%) 4 (10.0)
 Thiopurines, n (%) 16 (40.0)
 Methotrexate, n (%) 3 (7.5)
CDAI, median [IQR] 240 [192–264]
CRP, median [IQR] 20.1 [11.5–48.5]
CRP > 5 mg/L, n (%) 37 (92.5)

n, number; IQR, interquartile range; SD, standard deviation; CDAI, Crohn's Disease Activity Index.

2.3. Magnetic resonance imaging examinations

MR enterocolonography (MREC) with diffusion-weighted and injected sequences were performed in all patients. Each examination was interpreted independently by an experienced radiologist (C.H.) [23], [25], and [26] who were unaware of clinical or biological data. On the day of MRI-DWI, patients had to have been fasting for at least 4 h before the examination. The MRI imaging examinations with no bowel cleansing and with no rectal enema were performed with a 1.5 Tesla GE Optima MR 450w (General Electric HealthCare, Fairfield, CT) as previously described [23], [25], and [26]. To achieve an adequate distension of the distal ileum, 1000 ml of polyethylene glycol solution (Fortrans, Ipsen Pharma, Paris, France) was given to all patients, 25 min before MRI in those with previous small bowel resection or 40 min before in non-operated patients. To reduce bowel peristalsis, 1 mg of glucagon was administrated intravenously before contrast sequences. Injected sequences were performed after intravenous administration of 0.2 ml/kg body weight of gadobemate dimeglumine (Multi-Hance, Bracco Imaging, Evry, France). MR protocol was given in Table 2[23], [25], and [26]. The diffusion-weighted sequence used a diffusion factor b fixed at 800 s/mm2[23], [25], [26], and [29] in the axial plane because this value represents the best compromise between signal-to-noise ratio and lesion detection sensitivity. Two values of factor b are commonly used to define ADC. Using two sequences with 2 different factors b, the degree of mobility of water molecules can be measured quantitatively by calculating the ADC. To obtain a parametric image of ADC, 2 similar sequences S0 and S have to be performed, one without (b = 0) and the other with the addition of gradient of diffusion (b = 800 in our protocol). Image analysis was performed using a dedicated post-processing workstation (Advantage Window Work Station, General Electric HealthCare). For segmental analysis we used a division into five segments (distal ileum, caecum/right colon, transverse colon, left/sigmoid colon, and rectum) as for endoscopic scores. The collected MRI parameters were given in Table 3. ADC was calculated in the area of highest signal intensity in the bowel wall, based on the judgement of the radiologist. We previously reported that, using this method, the inter-observer agreement was very high (Lin's concordance coefficient = 0.96) [25] ADC < 1.9 mm2/s defined an active colonic segment while Clermont score > 8.4 defined an ileal active segment [23] and [25]. Ileal activity was considered as severe when Clermont score ≥ 12.5 [23], [25], and [26].

Table 2 Characteristics description of MRI sequences used in this study protocol.

Sequences Plane FOV (cm) TE (ms) TR (ms) Flip angle (degree) Slice thickness (mm) Acquisition duration (s)
T2 SSFSE Axial 34 120 820 90 7 30
T2 SSFSE Coronal 41 120 710 90 5 20
2D FIESTA FS Axial 34 2 4.8 85 6.5 40
DWI b0-b800 Axial 34 70 3200 90 6 120
T1 FS LAVA Coronal 42 1.9 4 12 3.2 240
T1 FS LAVA Axial 40 1.9 4 12 3.8 45

FOV, field of view; FS, fat sat; MRI, magnetic resonance imaging; SSFSE, single-shot fast spin echo; TE, echo time; TR, repetition time; 2D, two dimensional.

Table 3 Univariate analysis of clinical predictors for remission (CDAI < 150 AND CRP < 5 g/L) for CD patients treated with anti-TNF therapy at week 12.

No remission
n = 20
Remission
n = 20
p value
Disease duration (months), median [IQR] 58 [6–219] 21 [3–193] 0.40
Early Crohn, n (%) 4 (20.0) 6 (30.0) 0.47
Age at inclusion (years), mean ± SD 36.1 ± 14.5 37.6 ± 15.7 0.89
Family IBD history, n (%) 4 (20.0) 1 (5.0) 0.34
Active smokers, n (%) 7 (35.0) 10 (50.0) 0.34
Previous intestinal resection, n (%) 7 (35.0) 2 (10.0) 0.13
Anoperineal lesion, n (%) 8 (40.0) 6 (30.0) 0.51
Age at diagnosis (years), mean ± SD 25.5 ± 11.6 30.2 ± 14.9 0.21
Montreal classification
 Age, n (%)
  A1 6 (30.0) 3 (15.0) 0.63
  A2 12 (60.0) 14 (70.0)
  A3 2 (10.0) 3 (15.0)
 Location, n (%) 1.00
  L1 9 (45.0) 9 (45.0)
  L2 2 (10.0) 3 (15.0)
  L3 9 (45.0) 8 (40.0)
  L4 0 (0.0) 5 (25.0) 0.047
 Behaviour, n (%) 0.62
  B1 5 (25.0) 7 (35.0)
  B2 10 (50.0) 7 (35.0)
  B3 5 (25.0) 6 (30.0)
Anti-TNF, n (%) 0.20
 Infliximab 7 (35.0) 11 (55.0)
 Adalimumab 13 (65.0) 9 (45.0)
Steroids naïve, n (%) 3 (15.0) 5 (25.0) 0.70
Immunosuppressants naïve, n (%) 8 (40.0) 8 (40.0) 1.00
Anti-TNF naïve, n (%) 15.0 (75.0) 15.0 (75.0) 1.00
Concomittant therapies
 5-ASA, n (%) 1 (5.0) 1 (5.0) 1.00
 Budesonide, n (%) 4 (20.0) 1 (5.0) 0.34
 Corticosteroids, n (%) 1 (5.0) 3 (15.0) 0.61
 Thiopurines, n (%) 7 (35.0) 9 (45.0) 0.52
 Methotrexate, n (%) 2 (10.0) 1 (5.0) 1.00
CDAI, median [IQR] 225 [191–262] 232 [192–265] 0.24
CRP, median [IQR] 20.1 [11.4–49.0] 20.0 [11.5–48.8] 0.57
CRP >5 mg/L, n (%) 18 (90.0) 19 (95.0) 0.60

n, number; IQR, interquartile range; SD, standard deviation; IBD, inflammatory bowel disease; TNF, tumor necrosis factor; CDAI, Crohn's disease activity index; CRP, C-reactive protein. Statistically significant differences are presented as bold type.

2.4. Study design

All patients underwent DW-MREC within 28 days before starting treatment. The MaRIA was calculated globally and per segment to quantify disease activity as published by Rimola et al. [20] and [21] The Clermont score [23], [25], and [26] was calculated for each terminal ileum while the ADC value was calculated for each segment. The mean ADC was the sum of each segmental ADC divided by the number of segments (5 or less in cases of surgical resection). Minimal ADC was defined as the lowest ADC value retrieved from each patient. In addition, a clinical assessment determining disease activity (CDAI) and C-reactive protein (CRP) was done at baseline and week 12. After baseline evaluations, patients were treated with infliximab (IFX) or adalimumab (ADA) for induction of remission at the discretion of the attending physician. ADA was started at 160 mg subcutaneously, followed by 80 mg at week 2 and 40 mg every other week thereafter. IFX was administered intravenously as 5 mg/kg at week 0, week 2 and week 6.

Clinical response was defined as ΔCDAI ≥ 100 or CDAI decrease below 150 while remission was defined as CDAI < 150 and CRP level < 5 mg/L [30] and [31]. All the endpoints were evaluated at week 12.

2.5. Data managing and statistical analysis

Study data were collected and managed using REDCap electronic data capture tools hosted at Clermont-Ferrand University Hospital [32]. REDCap (Research Electronic Data Capture) is a secure, web-based application designed to support data capture for research studies, providing (1) an intuitive interface for validated data entry; (2) audit trails for tracking data manipulation and export procedures; (3) automated export procedures for seamless data downloads to common statistical packages; and (4) procedures for importing data from external sources.

Considering this work as a pilot study, it seemed difficult to propose a priori sample size estimation. An a posteriori estimation of statistical was proposed. The power was 80%, to highlight a difference concerning the mean ADC according to remission at week 12 (2.05 ± 0.22 vs 1.89 ± 0.25) for a two-tailed type I error of 5%. Therefore, as discussed by Feise [34], it must be careful to focus not only upon statistical significance, but also upon the quality of the research within the study and the magnitude of difference. Statistical analysis was performed using Stata software (version 13, StataCorp, College Station, US). The tests were two-sided, with a Type I error set at α = 0.05. Baseline characteristics were presented as mean (±standard-deviation) or median [interquartile range] according to statistical distribution (assumption of normality assessed using the Shapiro–Wilk test) for continuous data and as the number of patients and associated percentages for categorical parameters. Comparisons of patient's characteristics between the independent groups were made using the chi-squared or Fisher's exact tests for categorical variables, and using Student's t-test or the Mann–Whitney test for quantitative parameters (homoscedasticity verified using Fisher-Snedecor test). As proposed by some statisticians, we chose to report all the individual p-values without doing any mathematical correction for distinct tests comparing groups [33]. A particular focus was given to the magnitude of improvement and to the clinical relevance [34]. In multivariate context, regression models (logistic for dichotomous dependant variable) were performed to take into account adjustment on covariables fixed according to univariate results and clinically relevance: smoking status, age, disease duration, concomitant thiopurines, CRP at inclusion, stenosis and fistula.

3. Results

3.1. Baseline population characteristics and MRI results

Population characteristics are shown in Table 1. Among the 40 CD patients, 24 (60.0%) were female, 17 (42.5%) were active smokers, 10 (25.0%) were considered as early Crohn [35] and 9 (22.5%) previously underwent intestinal resection. Median disease duration and mean age at inclusion were 34 [4–193] months and 36.8 ± 15.0 years, respectively. Overall 30 CD patients were anti-TNF naïve. Twenty two patients (55.0%) and 18 patients (45.0%) were treated with ADA or IFX, respectively. Among them, 16 patients (40.0%) received concomitant therapy with thiopurines (11/18 for IFX and 6/22 for ADA). Median CDAI and median CRP at inclusion were 225 [192–264], and 20.0 mg/L [11.5–48.5], respectively. Only 3 patients had CRP < 5 mg/L at baseline. Detailed MRI results are given in Table 4.

Table 4 Univariate analysis of MRI predictors for remission (CDAI < 150 AND CRP < 5 g/L) for CD patients treated with anti-TNF therapy at week 12.

Quantitative parameters No remission
n = 20
Remission
n = 20
p value
Segmental ileal MaRIA 21.9 ± 9.9 22.7 ± 9.0 0.79
Total MaRIA 39.2 ± 16.6 51.7 ± 18.2 0.03
Mean MaRIA 8.01 ± 3.32 10.36 ± 3.66 0.13
Clermont score 23.6 ± 10.2 23.7 ± 8.8 0.76
Mean ADC 2.05 ± 0.22 1.89 ± 0.25 0.03
Minimal ADC 1.34 ± 0.32 1.25 ± 0.22 0.58
Qualitative parameters Patients in remission p value
MRI activity according to MaRIA, n (%)
 Non active 1/3 (33.3) 0.31
 Active 0/3 (0.0)
 Severe 19/34 (55.9)
 
MRI activity according to Clermont score, n (%)
 Non active 2/6 (33.3) 0.66
 Active 1/1 (100.0)
 Severe 17/33 (51.5)
 
Colonic MRI activity according to ADC, n (%) 0.11
 Non active 9/23 (39.1)
 Active 11/17 (64.7)
 
Ileal stenosis, n (%) 1.00
 No 16/31 (51.6)
 Yes 4/9 (44.4)
 
Prestenotic dilation, n (%) 1.00
 No 16/32 (50.0)
 Yes 4/8 (50.0)
 
Intestinal fistula, n (%) 0.45
 No 17/31 (54.8)
 Yes 3/9 (33.3)
 
Intra-abdominal abscess, n (%) 1.00
 No 19/38 (50.0)
 Yes 1/2 (50.0)
 
Sclerolipomatosis, n (%) 0.49
 No 13/28 (46.4)
 Yes 7/12 (58.3)
 
Mesenteric lymph nodes enlargement, n (%) 0.11
 No 6/17 (35.3)
 Yes 14/23 (60.9)

n, number; SD, standard deviation; NA, not applicable; MRI, magnetic resonance imaging; ADC, apparent diffusion coefficient; MaRIA, Magnetic Resonance imaging Index of Activity. For quantitative parameters, results are expressed in mean ± SD. Statistically significant differences are presented as bold type.

3.2. Remission

Overall, 20 patients (50.0%) experienced remission at week 12. An upper gastrointestinal tract involvement was associated with remission (0/20 vs 5/20, p = 0.047) in univariate analysis. No other clinical parameters including CRP value at baseline (p = 0.57) were predictive of remission at week 12 (Table 3). Low mean ADC (2.05 ± 0.22 vs 1.89 ± 0.25, p = 0.03) and high total MaRIA (39.2 ± 16.6 vs 51.7 ± 18.2, p = 0.03) were predictive of remission at week 12 (Table 4). Using a ROC curve (Fig. 1), we determined a mean ADC of 1.96 as predictive cut-off of remission at week 12 (AUC = 0.703 [0.535–0.872]) with sensitivity, specificity, positive predictive value and negative predictive value of 70.0%, 65.0%, 66.7% and 68.4%, respectively. A ROC curve was also performed for total MaRIA 42.5 (AUC = 0.663 [0.492–0.835]) (Fig. 1). We found a total MaRIA of 42.5 (AUC = 0.663 [0.492–0.835]) as the best as predictive cut-off of remission at week 12. Sensitivity, specificity, positive predictive value and negative predictive value were 75.0%, 55.0%, 62.5% and 68.8%, respectively.

gr1

Fig. 1 Receiver operating characteristic (ROC) curves illustrating the performances of the apparent diffusion coefficient (ADC), the quantitative parameter of Diffusion-Weighted Magnetic Resonance Entero-Colonography, and the Magnetic Resonance Index of Activity (MaRIA) to predict remission after anti-TNF induction therapy.

In multivariate analysis, mean ADC < 1.96 (OR = 4.87, 95% CI [1.04–22.64]) and total MaRIA > 42.5 (OR = 5.11, 95% CI [1.03–25.37]) were predictive of remission at week 12.

3.3. Clinical response

Overall, 25 patients (67.5%) achieved clinical response at week 12. No clinical factor was associated with clinical response including CRP value at baseline (p = 0.96). High Clermont score (27.2 ± 8.4 vs 21.4 ± 9.4, p = 0.05) and high ileal MaRIA (25.4 ± 8.4 vs 20.6 ± 9.5, p = 0.05), reflecting ileal inflammatory activity, were predictive of clinical response at week 12 (Table 3). Active colonic segment defined as ADC<1.9, calculated using diffusion-weighted sequences, was also predictive of clinical response at week 12 (47.8% vs 82.4%, p = 0.03). In multivariate analysis, no MRI factors were significantly predictive of clinical response at week 12.

4. Discussion

To our knowledge, this work is the first study assessing parameters retrieved from cross sectional imaging, especially DW-MREC, as predictor of remission after anti-TNF induction therapy.

Diffusion-weighted Imaging is a method deriving its image contrast from differences in the motion of water molecules between tissues used in different topics especially neurovascular diseases and oncology. Recently, our team and others confirmed that DW-MREC was a well-tolerated, non-time-consuming, accurate, and reproducible tool for detecting and assessing inflammation in ileal and colonic CD [23], [24], [25], [29], [36], [37], [38], [39], and [40]. The Clermont score (=1.646 × bowel thickness − 1.321 × ADC + 5.613 × oedema + 8.306 × ulceration + 5.039) dedicated to the ileum is an accurate tool to assess inflammatory activity in the terminal ileum, highly correlated to the MaRIA [23] and [25] and the Simplified Endoscopic Score for Crohn's Disease (SES-CD) [24] and [41]. We reported also a high accuracy of the ADC, the quantitative parameter of DW-MREC, to detect and assess inflammatory activity in colonic CD [25]. Recently, we reported, that the ADC accuracy to detect endoscopic ulceration was high in a non distended colon (accuracy = 0.79) [26]. We obtained similar results with the Clermont score in the ileum (accuracy = 0.75) [26]. It was the first time that a team reported that DW-MRE using quantitative parameter (ADC and Clermont score), could be effective in a non distended colon. Several authors considered the interest of DW-MRE and ADC as limited owing to several theoretical limits such as the reliability and the reproducibility of ADC calculation (especially in a non distended colon), and the low specificity of diffusion sequences. Our team and others [23], [24], [25], [26], and [29] used the same b-values and demonstrated high accuracy of ADC accordingly. In addition, we previously reported a very high inter-observer agreement in calculating ADC (Lin's concordance coefficient = 0.96) [25]. With a single measure in the most severe lesion, we showed in 2 different cohorts that ADC was highly correlated to the MaRIA in the colon and is able to detect endoscopic ulceration with high accuracy [25] and [26]. The specificity was also high in detecting endoscopic ulcerations (specificity = 82.7%) [26].

As anti-TNF therapies are associated with serious side effects (infections, lymphoma, cancer, etc.) [42], [43], [44], and [45] and are cost prohibitive, it remains a key point to select CD patients who could benefit from biologics.

Several studies interested in clinical factors able to predict response to anti-TNF therapy [6], [7], [8], and [9]. A landmark cohort from Leuven, including 240 patients, reported age (OR = 0.971, 95% CI = 0.947–0.995, p = 0.018), isolated ileitis (OR = 0.359, 95% CI = 0.177–0.728, p = 0.004), and previous surgery (OR = 0.429, 95% CI = 0.233–0.787, p = 0.006) as inversely correlated with response, whereas isolated colitis (OR = 1.905, 95% CI = 1.010–3.597, p = 0.046) was positively correlated with response to infliximab [6]. Isolated colitis was also identified as predictor for response to infliximab in a prospective study [8]. Active smoking was associated with lack of response in two studies [7] and [8]. Several studies highlighted the positive impact of concomitant immunosuppressant therapy on response to infliximab [6], [7], [8], and [9] before the publication of the results from the SONIC trial showing that combotherapy (infliximab and azathioprine) was more effective than monotherapy in CD patients anti-TNF naïve [4]. A retrospective study reported that an inflammatory disease phenotype and male gender (p = 0.03) could also predict sustained clinical benefit [9]. In the present study, we did not report any clinical predictive factor of clinical response or remission. It is explained by the fact that this pilot study was not designed to answer this question. The sample size was adapted to focus on MRI parameters.

Herein, we showed that mean ADC (2.05 ± 0.22 vs 1.89 ± 0.25, p = 0.03) and total MaRIA (39.2 ± 16.6 vs 51.7 ± 18.2, p = 0.03), reflecting high inflammatory degree, were predictive of remission at week 12. These data could be considered as conflicting with the paper from Allez and colleagues reporting that deep and extensive endoscopic ulcers were predictive of colectomy in CD [46]. It could be explained by the fact that these results (inclusion period ranging from 1990 to 1996) could be probably not reproducible in the era of biologics [47]. All these results were in line with a previous paper showing that a high CRP level at baseline, reflecting systemic high degree of systemic inflammation was predictive of anti-TNF efficacy [10]. However as MRI detected ileocolonic inflammation more specifically than CRP, we demonstrated with our sample that objective digestive inflammation visualized using DW-MREC was associated with induction of remission in CD patients treated with anti-TNF therapies. As our goal was to develop a tool usable in daily practice, we determined ADC < 1.96 as the best threshold to predict remission after anti-TNF therapy. This cut-off could be helpful for IBD physician in daily practice to take the decision of starting anti-TNF.

The main strengths of this study were the prospective design, including patients from the Clermont-Ferrand IBD centre with experienced radiologists in the DW-MREC use, the original approach and the fact that our results could be helpful for daily practice. In addition, our definition of remission included both a clinical item (i.e. CDAI < 150) and a biological item (i.e. CRP normalization). The pertinence of using CDAI as endpoint is more and more discussed. Recent data, from a post hoc analysis from the SONIC trial, showed that 47% of patients with CDAI < 150 had no mucosal healing [48]. Besides the fact that CDAI did not correlate with mucosal healing, CDAI was not associated with favourable long-term outcomes. The CRP value without kinetic is considered only as additional information in CD patients follow-up because normal CRP value was not correlated to mucosal healing. A small sample size Belgian study reported that 92.9% of CD patients with CDAI > 150 and normal CRP experienced endoscopic lesion including almost one third with severe lesions defined as CDEIS ≥ 6 [49]. Thus, we chose to add CRP normalization (a dynamic variable) in our composite definition of remission, because in a large Hungarian cohort, clinical efficacy and normalized CRP at week 12 were associated with medium-term clinical efficacy and mucosal healing during adalimumab therapy [30] while a post hoc analysis from the hallmark ACCENT 1 trial found that normalized CRP levels at week 14 increased the likelihood of maintained response or remission during 1 year of infliximab maintenance therapy [31].

The sample size could be considered as a limit. However, the power seemed satisfactory, around 80%, to highlight a difference concerning the mean ADC according to remission at week 12 (2.05 ± 0.22 vs 1.89 ± 0.25) for a two-tailed type I error equals 5%. Even if the sample size was not so high, our results do not seem underpowered. In addition, performing faecal markers dosages in our protocol would have probably provided some interesting data.

In conclusion, owing to our results, we could suggest to perform DW-MREC before starting anti-TNF induction therapy in daily practice to select patients with objective digestive inflammation and those who could benefit from anti-TNF therapy. DW-MREC with no bowel cleansing and with no rectal enema is a useful tool to detect and assess ileal and colonic inflammation in CD [23], [24], and [25] and could be helpful to predict remission after anti-TNF induction therapy. These results from our pilot study should be confirmed in an independent larger cohort.

Conflict of interest

None declared.

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Footnotes

a University Hospital Estaing, Gastroenterology Department, Clermont-Ferrand, France

b UMR 1071 Inserm/Université d’Auvergne, USC-INRA 2018, Microbes, Intestine, Inflammation et Susceptibility of the Host, Clermont-Ferrand, France

c University Hospital Estaing, Radiology Department, Clermont-Ferrand, France

d GM Clermont-Ferrand University and Medical Center, DRCI, Biostatistics Unit, Clermont-Ferrand, France

Corresponding author at: Department of Gastroenterology, University Hospital Estaing of Clermont-Ferrand, 1 place Lucie et Raymond Aubrac, 63100 Clermont-Ferrand, France. Tel.: +33 4 73 750 523; fax: +33 4 73 750 524.