Primary biliary cirrhosis (PBC) is a classical autoimmune liver disease for which effective immunomodulatory therapy is lacking. Here we perform meta-analyses of discovery datasets from genome-wide association studies of European subjects (n=2,764 cases and 10,475 controls) followed by validation genotyping in an independent cohort (n=3,716 cases and 4261 controls). We discover and validate six previously unknown risk loci for PBC (Pcombined<5×10−8) and used pathway analysis to identify JAK-STAT/IL12/IL27 signaling and cytokine-cytokine pathways, for which relevant therapies exist.

SummaryBackgroundMagnetic resonance enterography (MRE) and ultrasound are used to image Crohn's disease, but their comparative accuracy for assessing disease extent and activity is not known with certainty. Therefore, we did a multicentre trial to address this issue.MethodsWe recruited patients from eight UK hospitals. Eligible patients were 16 years or older, with newly diagnosed Crohn's disease or with established disease and suspected relapse. Consecutive patients had MRE and ultrasound in addition to standard investigations. Discrepancy between MRE and ultrasound for the presence of small bowel disease triggered an additional investigation, if not already available. The primary outcome was difference in per-patient sensitivity for small bowel disease extent (correct identification and segmental localisation) against a construct reference standard (panel diagnosis). This trial is registered with the International Standard Randomised Controlled Trial, number ISRCTN03982913, and has been completed.Findings284 patients completed the trial (133 in the newly diagnosed group, 151 in the relapse group). Based on the reference standard, 233 (82%) patients had small bowel Crohn's disease. The sensitivity of MRE for small bowel disease extent (80% [95% CI 72–86]) and presence (97% [91–99]) were significantly greater than that of ultrasound (70% [62–78] for disease extent, 92% [84–96] for disease presence); a 10% (95% CI 1–18; p=0·027) difference for extent, and 5% (1–9; p=0·025) difference for presence. The specificity of MRE for small bowel disease extent (95% [85–98]) was significantly greater than that of ultrasound (81% [64–91]); a difference of 14% (1–27; p=0·039). The specificity for small bowel disease presence was 96% (95% CI 86–99) with MRE and 84% (65–94) with ultrasound (difference 12% [0–25]; p=0·054). There were no serious adverse events.InterpretationBoth MRE and ultrasound have high sensitivity for detecting small bowel disease presence and both are valid first-line investigations, and viable alternatives to ileocolonoscopy. However, in a national health service setting, MRE is generally the preferred radiological investigation when available because its sensitivity and specificity exceed ultrasound significantly.FundingNational Institute of Health and Research Health Technology Assessment.

Faecal Hb concentration measurements have considerable potential to contribute to reducing unnecessary endoscopy for the majority of symptomatic patients.

Background and Aims The simplified magnetic resonance enterography (MRE) index (sMARIA), London and “extended” London scoring systems are widely used in Crohn’s disease (CD) to assess disease activity, although validation studies have usually been single centre, retrospective and/or used few readers. Here, we evaluated these MRE indices within a prospective multicentre, multireader diagnostic accuracy trial. Methods A subset of participants (newly diagnosed or suspected of relapse) recruited to the METRIC trial with available terminal ileal (TI) biopsies was included. Using pre-specified thresholds, the sensitivity and specificity of sMARIA, London and “extended” London scores for active and severe (sMARIA) TI CD were calculated using different thresholds for the histological activity index (HAI). Results We studied 111 patients (median 29 years, interquartile range 21-41, 75 newly diagnosed, 36 suspected relapse) from 7 centres, of whom 22 had no active TI CD (HAI=0), 39 mild (HAI=1), 13 moderate (HAI=2), and 37 severe CD activity (HAI=3). In total, 26 radiologists prospectively scored MRE datasets as per their usual clinical practice. Sensitivity and specificity for active disease (HAI&gt;0) were 83% (95% confidence interval 74-90%) and 41% (23-61%) for sMARIA, 76% (67-84%) and 64% (43-80%) for the London score, and 81% (72-88%) and 41% (23-61%) for the “extended” London score, respectively. The sMARIA had 84% (69-92%) sensitivity and 53% (41-64%) specificity for severe CD. Conclusions When tested at their proposed cut-offs in a real-world setting, sMARIA, London and “extended” London indices achieve high sensitivity for active TI disease against a histological reference standard, but specificity is low.

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