Magnetic resonance enterography changes after antibody to tumor necrosis factor (anti-TNF) alpha therapy in Crohn’s disease: correlation with SES-CD and clinical-biological markers

Between April 2012 and April 2015, 27 outpatients diagnosed with CD according to the Lennard-Jones criteria (Table 1) [12], were prospectively studied at single centre. The patient cohort comprised 18 males and 9 females, with a median age of 27,4 years (age range, 19–49). The median disease duration was 6,1 years (mean SD, 2,2). Inclusion criteria were age ≥ 18, moderate-to-severe intestinal disease (Crohn’s Disease Activity Index – CDAI - score > 220 points) and elevated C-reactive protein (CRP) level (>5 mg/l). Exclusion criteria were active or latent tuberculosis, contraindications for MR, treatment with more than 15 mg of systemic corticosteroids (prednisone equivalent) within the 2 weeks prior to baseline MRI, documented abdominal abscess or internal fistula as well as medical contraindications for anti TNF therapy.

The anti-TNF treatment consisted of administering an induction regimen, either with IFX or ADA in the case of patients who had previously been treated with IFX and who had presented complications in its administration. The induction regimen for IFX consisted of administering three intravenous doses of 5 mg/Kg in weeks 0, 2 and 6, and maintenance every 8 weeks thereafter. The induction regimen for ADA consisted of an 160 mg subcutaneous injection as an initial dose, followed by 80 mg after 2 weeks and 40 mg every other week thereafter [5]. After obtaining written informed consent, endoscopy (reference standard), clinical-biological assessment and MRI were performed in all patients prior to the first anti-TNF drugs infusion and at week 26. Ileocolonoscopy and MRI were performed within a maximum interval of 7 days and the time gap between these tests and the start-end of anti-TNF therapy was to a maximum of 3 days.

Ileocolonoscopy was considered the reference standard for the evaluation of IBD extension and severity. In all cases endoscopy was performed under anaesthesia by experienced endoscopist in IBD (NDV) using standard equipment (CV-180; Olympus, Japan) and following the standard protocol used in clinical practice (colonic cleansing with 4 L polyethylene glycol plus low-fiber diet 3 days before). The length of terminal ileum evaluated on colonoscopy ranged from 5 to 15 cm. Quantification of endoscopic lesions was calculated globally and per segment using the Simple Endoscopic Score for Crohn’s Disease (SES-CD). For accuracy of endoscopic data collection, endoscopist completed the SES-CD on a predefined scoring sheet immediately after finishing the procedure.

For the grading of endoscopic findings with SES-CD, the bowel was divided into 5 segments: terminal ileum; right, transverse, and left colon; and rectum. Four endoscopic variables in the 5 segments were scored from 0 to 3 [13]. The variable “presence and size of ulcers” was scored 0 when no ulcers were present, 1 for small ulcers (diameter, 0.1–0.5 cm), 2 for medium-sized ulcers (diameter, 0.5–2 cm), and 3 for large ulcers (>2 cm). The variable “extent of ulcerated surface” was scored 0 when no ulcers were present, 1 when extent was <10 %, 2 when extent was 10 % to 30 %, and 3 when extent was >30 %. The variable “extent of affected surface” was scored 0 if none, 1 when <50 %, 2 when 50 % to 75 %, and 3 when >75 %. The variable “presence and type of narrowing” was scored 0 when no narrowing was present, 1 for a single passable narrowing, 2 for multiple passable narrowed areas, and 3 for a non-passable narrowing. The resulting score was (Table 2): SES-CD = sum of all variables – 1,4 × number of affected segments.

The SES score can range from 0 to 60, with a higher score indicating more severe disease. Investigator reporting the endoscopic lesions was blinded to the results of the MRI examination.

All MRI examinations were performed in the supine position with a 1.5 T magnet (Achieva, Philips Medical System, Eindhoven, The Netherlands) equipped with a phased-array-16-elements coil. 1 h prior to MRI, all patients received orally 1000–1500 ml of iso-osmotic PEG solution, which was freshly prepared by dissolving in water a granular powder containing PEG (58.32 g), sodium sulphate (5.69 g) sodium bicarbonate (1.69 g), sodium chloride (1.46 g) and potassium chloride (0.74 g) (Selg 1000, Promefarm, Milan, Italy). In order to ensure an adequate intestinal distension, a coronal T2 scan was performed after 30 min after oral contrast administration. If the minimum diameter of the small bowel loops was 15 mm o larger, the bowel distension was judged satisfactory and MRI was continued after intravenous administration of 20 mg N-butylscopolamine (Buscopan, Boringher Ingelheim, Ingelheim am Rhein, Germany) in order to suppress small bowel peristalsis and avoid motion artifacts.

Then, the acquisition protocol outlined in Table 3 was performed. 3D T1-weighted high-resolution isotropic volume excitation (THRIVE) before and 30–40s, 70–90s and 120–140 s after intravenous administration of 0.2 ml/kg body weight of gadolinium chelate (Gd-DTPA, Magnevist, Schering AG, Germany) and finally a T1-weighted water selective (WATS) fat-saturated sequence in the axial plane late after injection were acquired.

Image analysis was performed by one experienced radiologist (LPS) and one junior radiologist (SR) using a dedicated postprocessing workstation (ViewForum, Philips Medical System, Eindhoven, The Netherlands). To allow comparison with endoscopic score, the same division into segments was considered. The small and large bowel were examined to detect the segment with the most severe lesions on the basis of the following criteria: bowel wall thickness (mm), presence of mucosal ulcers (defined as deep depressions in the mucosal surface), presence of mural oedema (hyperintensity on T2-weighted sequences of the bowel wall relative to the signal of the psoas muscle), presence of enlarged regional mesenteric lymph nodes, presence of fistula or abscess, and relative contrast enhancement (RCE) of the intestinal wall. Quantitative measurements of wall signal intensity (WSI) were obtained from the areas with the greatest thickening [region of interest (ROI)] before and after intravenous injection of gadolinium (70 s). RCE was calculated according to the following formula: RCE = [(WSI postgadolinium − WSI pregadolinium)/(WSI pregadolinium)] × 100 × (SD noise pregadolinium/SD noise postgadolinium). As defined by Rimola et al. [14, 15] for measurement of therapeutic response by means of MRI and to allow comparison with the reference standard (SES-CD), the MaRIA in each segment was calculated according to the following formula: 1.5 × wall thickening (mm) + 0.02 × RCE (relative contrast enhancement) + 5 × oedema + 10 × ulcers.

The global MaRIA score was calculated as the sum of the MaRIA in ileum, right colon, transverse colon, left colon-sigmoid and rectum.

In order to quantify disease activity the SES-CD and the MaRIA were calculated at baseline and 26 weeks after treatment initiation. MH was defined as the absence of mucosal ulcerations at week 26 in patients who had mucosal lesions endoscopically confirmed at baseline [16]. The endoscopic response was defined as a decrease from baseline in SES-CD score of at least 5 points and at least 50 % [17] with a complete endoscopic remission (MH) when SES-CD score ≤ 2 [18]. In MRI examinations the MH was defined as the complete disappearance of intestinal lesions at week 26, while the radiologic response was defined as an overall MaRIA score reduction of at least 9.7 points.

In addition, the response to treatment was assessed both clinically as well as biologically by calculating the CDAI and the nephelometric determination of the serum concentration of CRP. The CDAI is a numerical calculation derived from the sum of products from a list of 8 items (Table 4), and multiplied by weighting factors for each item to define the severity of “disease activity” in patients with CD [19]. Three categories were identified to define the clinical-biological response: (a) Lack of response when the CDAI and CRP levels increased or did not change; (b) Partial response when the CDAI decreased by more than 70 points and CRP levels decreased but did not restore to normal and (c) Remission when the CDAI was lower than 150 points and CRP levels were normal.

Quantitative variables are given as means and standard deviation (SD) and proportions are expressed as percentages and 95 % confident intervals (CIs). Differences in quantitative measures were tested by Student’s test. The associations between continuous variables were evaluated with Pearson’s bivariate correlation analysis. To determine the best cut-off value both of the overall MaRIA and of the Δ MaRIA scores for predicting endoscopic remission (SES-CD score ≤ 2) receiver operating characteristic (ROC) curves were calculated. Inter-observer agreement between paired evaluations of MR by two radiologists (LPS and SR) was performed with Pearson correlation coefficient.

The protocols were reviewed and approved by the Ethics Committee of our University Hospital and was conducted in accordance with the Declaration of Helsinki. All patients gave written informed consent to participate in this study.

Due to statutory provisions regarding data- and privacy protection, the dataset supporting the conclusions of this article is available upon individual request directed to the corresponding author.