METRIC-EF: magnetic resonance enterography to predict disabling disease in newly diagnosed Crohn's disease-protocol for a multicentre, non-randomised, single-arm, prospective study

INTRODUCTION: Crohn's disease (CD) is characterised by discontinuous, relapsing enteric inflammation. Instituting advanced therapies at an early stage to suppress inflammation aims to prevent future complications such as stricturing or penetrating disease, and subsequent surgical resection. Therapeutics are effective but associated with certain side-effects and relatively expensive. There is therefore an urgent need for robust methods to predict which newly diagnosed patients will develop disabling disease, to identify patients who are most likely to benefit from early, advanced therapies. We aim to determine if magnetic resonance enterography (MRE) features at diagnosis improve prediction of disabling CD within 5 years of diagnosis. METHODS AND ANALYSIS: We describe the protocol for a multicentre, non-randomised, single-arm, prospective study of adult patients with newly diagnosed CD. We will use patients already recruited to the METRIC study and extend their clinical follow-up, as well as a separate group of newly diagnosed patients who were not part of the METRIC trial (MRE within 3 months of diagnosis), to ensure an adequate sample size. Follow-up will extend for at least 4 years. The primary outcome is to evaluate the comparative predictive ability of prognostic models incorporating MRE severity scores (Magnetic resonance Enterography Global Score (MEGS), simplified MAgnetic Resonance Index of Activity (sMaRIA) and Lémann Index) versus models using standard characteristics alone to predict disabling CD (modified Beaugerie definition) within 5 years of new diagnosis. ETHICS AND DISSEMINATION: This study protocol achieved National Health Service Research Ethics Committee (NHS REC), London-Hampstead Research Ethics Committee approval (IRAS 217422). Our findings will be disseminated via conference presentations and peer-reviewed publications. TRIAL REGISTRATION NUMBER: ISRCTN76899103

Influence of oral contrast type and volume on patient experience and quality of luminal distension at MR Enterography in Crohn's disease:an observational study of patients recruited to the METRIC trial

OBJECTIVES: To compare the distention quality and patient experience of oral mannitol and polyethylene glycol (PEG) for MRE. METHODS: This study is a retrospective, observational study of a subset of patients enrolled in a multicentre, prospective trial evaluating the diagnostic accuracy of MRE for small bowel Crohn’s. Overall and segmental MRE small bowel distention, from 105 patients (64 F, mean age 37) was scored from 0 = poor to 4 = excellent by two experienced observers (68 [65%] mannitol and 37 [35%] PEG). Additionally, 130 patients (77 F, mean age 34) completed a questionnaire rating tolerability of various symptoms immediately and 2 days after MRE (85 [65%] receiving mannitol 45 [35%] receiving PEG). Distension was compared between agents and between those ingesting ≤ 1 L or > 1 L of mannitol using the test of proportions. Tolerability grades were collapsed into “very tolerable,” “moderately tolerable,” and “not tolerable.” RESULTS: Per patient distension quality was similar between agents (“excellent” or “good” in 54% [37/68] versus 46% [17/37]) with mannitol and PEG respectively. Jejunal distension was significantly better with mannitol compared to PEG (40% [27/68] versus 14% [5/37] rated as excellent or good respectively). There was no significant difference according to the volume of mannitol ingested. Symptom tolerability was comparable between agents, although fullness following MRE was graded as “very tolerable” in 27% (12/45) of patients ingesting PEG, verses 44% (37/84) ingesting mannitol, difference 17% (95% CI 0.6 to 34%). CONCLUSION: Mannitol-based solutions and PEG generally achieve comparable distension quality and side effect profiles, although jejunal distension is better quality with mannitol. Neither distension quality nor side-effect profile is altered by ingestion of more than 1 L of mannitol. KEY POINTS: • Mannitol-based and PEG-based oral preparation agents generally achieve comparable distension quality for MRE with the exception of the jejunum which is better distended with mannitol. • Mannitol-based and PEG-based oral preparation agents used for MRE have similar side effect profiles. • Neither distension quality nor side-effect profile is altered by ingestion of more than 1 L of mannitol. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00330-022-08614-9

Diagnostic performance of sonographic activity scores for adult terminal ileal Crohn's disease compared to magnetic resonance and histological reference standards: experience from the METRIC trial

OBJECTIVES: The simple ultrasound activity score for Crohn's disease (SUS-CD) and bowel ultrasound score (BUSS) are promising intestinal ultrasound (IUS) indices of CD, but studied mainly in small settings with few sonographers. We compared SUS-CD and BUSS against histological and magnetic resonance enterography (MRE) reference standards in a post hoc analysis of a prospective multicentre, multireader trial. METHODS: Participants recruited to the METRIC trial (ISRCTN03982913) were studied, including those with available terminal ileal (TI) biopsies. Sensitivity and specificity of SUS-CD and BUSS for TI CD activity were calculated with 95% confidence intervals (CI), from the prospective observations of the original METRIC trial sonographers against the histological activity index (HAI) and the simplified magnetic resonance index of activity (sMARIA). RESULTS: We included 284 patients (median 31.5 years, IQR 23-46) from 8 centres, who underwent IUS and MRE. Of these, 111 patients had available terminal ileal biopsies with HAI scoring. Against histology, sensitivity and specificity for active disease were 79% (95% CI 69-86%) and 50% (31-69%) for SUS-CD, and 66% (56-75%) and 68% (47-84%) for BUSS, respectively. Compared to sMARIA, the sensitivity and specificity for active CD were 81% (74-86%) and 75% (66-83%) for SUS-CD, and 68% (61-74%) and 85% (76-91%) for BUSS, respectively. The sensitivity of SUS-CD was significantly greater than that of BUSS against HAI and sMARIA (p < 0.001), but its specificity was significantly lower than of BUSS against the MRE reference standard (p = 0.003). CONCLUSIONS: Particularly when compared to MRE activity scoring, SUS-CD and BUSS are promising tools in a real-world clinical setting. CLINICAL RELEVANCE STATEMENT: When tested using data from a multicentre, multireader diagnostic accuracy trial, the simple ultrasound activity score for Crohn's disease (SUS-CD) and bowel ultrasound score (BUSS) were clinically viable intestinal ultrasound indices that were reasonably sensitive and specific for terminal ileal Crohn's disease, especially when compared to a magnetic resonance reference standard. KEY POINTS: The simple ultrasound activity score for Crohn's disease and bowel ultrasound score are promising intestinal ultrasound indices of Crohn's disease but to date studied mainly in small settings with few sonographers. Compared to histology and the magnetic resonance reference standard in a multicentre, multireader setting, the sensitivity of simple ultrasound activity score for Crohn's disease is significantly greater than that of bowel ultrasound score. The specificity of simple ultrasound activity score for Crohn's disease was significantly lower than that of bowel ultrasound score compared to the magnetic resonance enterography reference standard. The specificity of both indices was numerically higher when the magnetic resonance enterography reference standard was adopted

Diagnostic performance of sonographic activity scores for adult terminal ileal Crohn’s disease compared to magnetic resonance and histological reference standards:experience from the METRIC trial

Objectives: The simple ultrasound activity score for Crohn’s disease (SUS-CD) and bowel ultrasound score (BUSS) are promising intestinal ultrasound (IUS) indices of CD, but studied mainly in small settings with few sonographers. We compared SUS-CD and BUSS against histological and magnetic resonance enterography (MRE) reference standards in a post hoc analysis of a prospective multicentre, multireader trial. Methods: Participants recruited to the METRIC trial (ISRCTN03982913) were studied, including those with available terminal ileal (TI) biopsies. Sensitivity and specificity of SUS-CD and BUSS for TI CD activity were calculated with 95% confidence intervals (CI), from the prospective observations of the original METRIC trial sonographers against the histological activity index (HAI) and the simplified magnetic resonance index of activity (sMARIA). Results: We included 284 patients (median 31.5 years, IQR 23–46) from 8 centres, who underwent IUS and MRE. Of these, 111 patients had available terminal ileal biopsies with HAI scoring. Against histology, sensitivity and specificity for active disease were 79% (95% CI 69–86%) and 50% (31–69%) for SUS-CD, and 66% (56–75%) and 68% (47–84%) for BUSS, respectively. Compared to sMARIA, the sensitivity and specificity for active CD were 81% (74–86%) and 75% (66–83%) for SUS-CD, and 68% (61–74%) and 85% (76–91%) for BUSS, respectively. The sensitivity of SUS-CD was significantly greater than that of BUSS against HAI and sMARIA (p &lt; 0.001), but its specificity was significantly lower than of BUSS against the MRE reference standard (p = 0.003). Conclusions: Particularly when compared to MRE activity scoring, SUS-CD and BUSS are promising tools in a real-world clinical setting.Clinical relevance statement: When tested using data from a multicentre, multireader diagnostic accuracy trial, the simple ultrasound activity score for Crohn’s disease (SUS-CD) and bowel ultrasound score (BUSS) were clinically viable intestinal ultrasound indices that were reasonably sensitive and specific for terminal ileal Crohn’s disease, especially when compared to a magnetic resonance reference standard.</p

Modelo para redução do risco à segurança do consumidor no desenvolvimento de produtos de consumo /

Dissertação (Mestrado) - Universidade Federal de Santa Catarina, Centro Tecnológico

Magnetic resonance enterography, small bowel ultrasound and colonoscopy to diagnose and stage Crohn’s disease; patient acceptability, and perceived burden

Objectives: To compare patient acceptability and burden of magnetic resonance enterography (MRE) and ultrasound (US) to each other, and to other enteric investigations, particularly colonoscopy. Methods: 159 patients (mean age 38, 94 female) with newly diagnosed or relapsing Crohn’s disease, prospectively recruited to a multicentre diagnostic accuracy study comparing MRE and US, completed an experience questionnaire on the burden and acceptability of small bowel investigations between December 2013 and September 2016. Acceptability, recovery time, scan burden and willingness to repeat the test were analysed using the Wilcoxon signed rank and McNemar tests; and group differences in scan burden with Mann-Whitney U and Kruskal-Wallis tests. Results: Overall, 128 (88%) patients rated MRE as very or fairly acceptable, lower than US (144, 99%; p<0.001), but greater than colonoscopy (60, 60%; p<0.001). MRE recovery time was longer than US (p<0.001), but shorter than colonoscopy (p<0.001). Patients were less willing to undergo MRE again than US (127 vs 133, 91% vs. 99%; p=0.012), but more willing than for colonoscopy (68, 75%; p=0.017). MRE generated greater burden than US (p<0.001), although burden scores were low. Younger age and emotional distress were associated with greater MRE and US burden. Higher MRE discomfort was associated with patient preference for US (p=0.053). Patients rated test accuracy as more important than scan discomfort. Conclusions.: MRE and US are well tolerated. Although MRE generates greater burden, longer recovery, and is less preferred than US, it is more acceptable than colonoscopy. Patients however place greater emphasis on diagnostic accuracy than burden

The role of Magnetic Resonance Enterography and Small Bowel Ultrasound in Crohn’s Disease

Crohn’s disease (CD), a life-long condition resulting in recurrent gastrointestinal inflammation, is estimated to affect one in every 650 people in the UK. Accurate assessment of the disease is crucial to optimise medical and surgical management. Small bowel assessment is heavily reliant on radiological imaging. As the condition predominantly affects young patients, who are more sensitive to the harmful effects of ionizing radiation, ultrasound, and Magnetic Resonance Imaging (MRI) assessment are the preferred radiological investigations. The thesis explores the utility of MR enterography (MRE) and small bowel ultrasound (SBUS) in Crohn’s disease. The thesis is structured as follows: Section A provides an overview on the utility of MRE and SBUS in Crohn’s disease including review and evaluation of the pre-existing literature. It outlines methodological details of the METRIC (MREnterography or ulTRasound in Crohn’s disease) trial: a multicentre, non-randomised, single-arm, prospective comparison study of magnetic resonance enterography and small bowel ultrasound compared to a reference standard in patients aged over 16 years and briefly outlines its main results. Section B details specific substudies of the METRIC trial, investigating the inter-observer variability of the two techniques, influence of oral contrast type and volume on patient experience and quality of luminal distension at MRE and the influence of Diffusion Weighted Imaging and Contrast Enhanced T1 sequences on the diagnostic accuracy of MRE. Section C presents further complementary studies which undertake more in depth analysis of the two imaging techniques: (1) evaluating the relationship between contrast enhanced MRE texture analysis parameters and the presence or absence of histological markers of hypoxia and angiogenesis and (2) evaluating changes in the Dynamic Contrast Enhanced pharmacokinetic and Diffusion Weighted Imaging parameters at MRE relative to clinical response to anti-TNF medication and (3) providing histological validation of SBUS features of inflammation and fibrosis. Section D concludes and summarises the thesis and makes recommendations for future research

Monitoring Crohn's disease during anti-TNF-α therapy: validation of the magnetic resonance enterography global score (MEGS) against a combined clinical reference standard.

OBJECTIVES: To assess the ability of magnetic resonance enterography global score (MEGS) to characterise Crohn's disease (CD) response to anti-TNF-α therapy. METHODS: Thirty-six CD patients (median age 26 years, 20 males) commencing anti-TNF-α therapy with concomitant baseline MRI enterography (MRE) were identified retrospectively. Patients' clinical course was followed and correlated with subsequent MREs. Scan order was randomised and MEGS (a global activity score) was applied by two blinded radiologists. A physician's global assessment of the disease activity (remission, mild, moderate or severe) at the time of MRE was assigned. The cohort was divided into clinical responders and non-responders and MEGS compared according to activity status and treatment response. Interobserver agreement was assessed. RESULTS: Median MEGS decreased significantly between baseline and first follow-up in responders (28 versus 6, P < 0.001) but was unchanged in non-responders (26 versus 18, P = 0.28). The median MEGS was significantly lower in clinical remission (9) than in moderate (14) or severe (29) activity (P < 0.001). MEGS correlated significantly with clinical activity (r = 0.53; P < 0.001). Interobserver Bland-Altman limits of agreement (BA LoA) were -19.7 to 18.5. CONCLUSIONS: MEGS decreases significantly in clinical responders to anti-TNF-α therapy but not in non-responders, demonstrates good interobserver agreement and moderate correlation with clinical disease activity. KEY POINTS: • MRI scores of Crohn's activity are used increasingly in clinical practice and therapeutic trials. • Such scores have been advocated as biomarkers of therapeutic response. • MEGS reflects clinical response to anti-TNF-α therapy and the clinical classification of disease activity. • MEGS demonstrates good interobserver agreement