Background: ABX464 (obefazimod) is a small molecule that selectively upregulates miR-124 in immune cells. The aim of this study was to assess ABX464 as a treatment for patients with moderate-to-severe, active ulcerative colitis (UC).
Methods: In this phase 2b, double-blind, randomized, placebo-controlled induction trial, patients were recruited from 95 centers (hospitals and health-care centers) in 16 countries. Eligible patients were aged 18–75 years, with a diagnosis of moderate-to-severe, active UC and a modified Mayo score (MMS) of 5 points or higher, and a documented non-response or intolerance to previous treatment. Enrolled patients were randomly assigned (1:1:1:1) via an interactive voice and web response system to receive once daily oral ABX464 100 mg, ABX464 50 mg, ABX464 25 mg, or matched placebo. Randomization was stratified according to study site (US vs. non-US) and to whether the patient had previous exposure to second-line treatment with biologics or Janus kinase inhibitors. The primary end point was the change from baseline in MMS at week 8. The primary efficacy analysis was done in the full analysis set (FAS), defined as all randomly assigned patients who received at least 1 dose of study treatment and had baseline data for at least 1 efficacy variable, and was analyzed according to the principles of intention-to-treat. Safety analyses included patients who had been randomly assigned and who received at least 1 dose of study treatment. The 96-week open-label extension is ongoing.
Findings: Between August 13, 2019, and April 16, 2021, 254 patients were randomly allocated to ABX464 100 mg (n = 64), ABX464 50 mg (n = 63), ABX464 25 mg (n = 63), or placebo (n = 64). Two patients, both in the ABX464 25-mg group, were excluded from the FAS. In the FAS at week 8, the least squares mean (LSM) change from baseline in MMS was -2.9 (95% confidence interval [CI]: -3.4 to -2.5) for the ABX464 100-mg group, -3.2 (95% CI: -3.7 to -2.7) for the ABX464 50-mg group, -3.1 (95% CI: -3.6 to -2.6) for the ABX464 25-mg group, and -1.9 (95% CI: -2.4 to -1.5) for placebo group; the magnitude of the difference in MMS from baseline was significantly greater in all 3 ABX464 groups compared with placebo (p = 0.0039 for ABX464 100 mg vs. placebo, p = 0.0003 for ABX464 50 mg vs. placebo, and p = 0.0010 for ABX464 25 mg vs. placebo). The most frequently reported adverse event was headache, which was reported for 27 of 64 patients (42%) in the ABX464 100-mg group, 19 of 63 (30%) in the 50-mg group, 13 of 62 (21%) in the 25-mg group, and 5 of 64 (8%) in the placebo group. Severe (grade 3) headache was reported for 3 patients (5%) in the ABX464 100-mg group, 2 (3%) in the ABX464 50-mg group, 1 (2%) in the ABX464 25-mg group, and none in the placebo group. The only serious adverse event reported for 2 or more patients in any group was UC (1 in each of the ABX464 100-mg and 50-mg groups, and 3 [5%] in the placebo group).

Interpretation: All doses of ABX464 significantly improved moderate-to-severe, active ulcerative colitis compared with placebo, as measured by changes in modified Mayo score from baseline to week 8. A phase 3 clinical program is ongoing.

Prof. Dr. S. Vermeire, Department of Gastroenterology and Hepatology, University Hospitals Leuven, Leuven, Belgium,

E-Mail: severine.vermeire@uzleuven.be

DOI: 10.1016/s2468-1253(22)00233-3

Background: Bile acid diarrhea is an underdiagnosed disease estimated to affect 1–2% of the general population. Case reports indicate that the glucagon-like peptide 1 receptor agonist liraglutide might be an effective treatment for bile acid diarrhea. The aim of this study was to investigate the safety and efficacy of liraglutide for the treatment of bile acid diarrhea.
Methods: The authors conducted a randomized, double-blind, active-comparator, double-dummy, non-inferiority clinical trial at the Center for Clinical Metabolic Research at Copenhagen University Hospital, Herlev and Gentofte, Hellerup, Denmark. Patients aged 18–75 years with 75selenium-homotaurocholic acid test (SeHCAT)-verified moderate-to-severe primary bile acid diarrhea were randomly assigned (1:1) to receive liraglutide (1 daily subcutaneous injection uptitrated from 0.6–1.8 mg per day over 3 weeks) or colesevelam (3 capsules of 625 mg twice daily), the standard of care, for 6 weeks following 1 run-in week with no treatment. The primary end point was the proportion of participants experiencing a reduction in daily stool frequency of 25% or greater after 6 weeks. Data from all participants were included in the analysis of the primary outcome. The non-inferiority limit was set to 15% in favor of colesevelam.
Findings: Between April 1, 2019, and January 31, 2021, 52 patients were enrolled; 26 were assigned to liraglutide and 26 to colesevelam. 20 of 26 participants (77%) on liraglutide and 13 of 26 (50%) on colesevelam experienced a 25% or greater reduction in stool frequency, corresponding to a significant risk difference of -27% in favor of liraglutide (1-sided 95% confidence interval: -100 to -6). Liraglutide was therefore superior to colesevelam in reducing daily stool frequency. Mild nausea with a duration of 10–21 days was reported by 6 participants in the liraglutide group and by 1 participant in the colesevelam group. No other adverse events were reported.

Interpretation: The superiority of liraglutide compared with colesevelam in reducing stool frequency suggests consideration of liraglutide as a potential new treatment modality for bile acid diarrhea, although larger confirmatory trials powered for superiority are warranted.

Prof. Dr. F.K. Knop, Center for Clinical Metabolic Research, Copenhagen University Hospital, Herlev and Gentofte, Hellerup, Denmark,

E-Mail: filip.krag.knop.01@regionh.dk

DOI: 10.1016/s2468-1253(22)00198-4

Background and aims: The long-term efficacy and possible adverse events of fecal microbiota transplantation (FMT) for irritable bowel syndrome (IBS) are unknown. This study performed a 3-year follow-up of the patients in a previous clinical trial to clarify these aspects.
Methods: This study included 125 patients (104 females, and 21 males): 38 in a placebo group, 42 who received 30 g of donor feces, and 45 who received 60 g of donor feces. Feces was administered to the duodenum. The patients provided a fecal sample and completed 5 questionnaires at baseline and at 2 and 3 years after FMT. Fecal bacteria and dysbiosis index were analyzed using 16S ribosomal RNA gene polymerase chain reaction DNA amplification/probe hybridization covering the V3 to V9 regions.
Results: Response rates were 26.3%, 69.1%, and 77.8% in the placebo, 30-g, and 60-g groups, respectively, at 2 years after FMT, and 27.0%, 64.9%, and 71.8%, respectively, at 3 years after FMT. The response rates were significantly higher in the 30-g and 60-g groups than in the placebo group. Patients in the 30-g and 60-g groups had significantly fewer IBS symptoms and fatigue, and a greater quality of life both at 2 and 3 years after FMT. The dysbiosis index decreased only in the active treatment groups at 2 and 3 years after FMT. Fluorescent signals of 10 bacteria had significant correlations with IBS symptoms and fatigue after FMT in the 30-g and 60-g groups. No long-term adverse events were recorded.

Conclusions: Fecal microbiota transplantation performed according to the protocol resulted in high response rates and long-standing effects with only few mild self-limited adverse events.

Dr. Dr. M. El-Salhy, Section for Gastroenterology, Department of Medicine, Stord Helse Fonna Hospital, Stord, Norway,

E-Mail: magdy.elsalhy@sklbb.no

DOI: 10.1053/j.gastro.2022.06.020

Objective: Recent studies reported an association between non-alcoholic fatty liver disease (NAFLD) and increased risk of new-onset heart failure (HF). However, the magnitude of the risk and whether this risk changes with severity of liver disease remains uncertain. A meta-analysis of observational studies was performed to quantify the magnitude of the association between NAFLD and risk of new-onset HF.
Design: The authors systematically searched Scopus, Web of Science and PubMed from database inception to March 2022 to identify eligible observational studies, in which NAFLD was diagnosed by serum biomarkers/scores, International Classification of Diseases (ICD) codes, imaging techniques or liver histology. The primary outcome was new-onset HF, as assessed mainly by ICD codes. Data from selected studies were extracted, and meta-analysis was performed using random-effects models to obtain summary hazard ratios (HRs) with 95%-confidence intervals (CIs).
Results: They identified 11 longitudinal cohort studies with aggregate data on 11,242,231 middle-aged individuals from different countries and 97,716 cases of incident HF over a median of 10 years. NAFLD was associated with a moderately higher risk of new-onset HF (pooled random-effects HR = 1.50, 95% CI: 1.34–1.67, p < 0.0001; I2 = 94.8%). This risk was independent of age, sex, ethnicity, adiposity measures, diabetes, hypertension and other common cardiovascular risk factors. Sensitivity analyses did not change these results. The funnel plot did not show any significant publication bias.

Conclusion: Non-alcoholic fatty liver disease is associated with a 1.5-fold higher long-term risk of new-onset heart failure, regardless of the presence of diabetes, hypertension and other common cardiovascular risk factors. However, the observational design of the studies does not allow for proving causality.

Prof. Dr. G. Targher, Endocrinology and Metabolism, Department of Medicine, University of Verona, Verona, Italy,

E-Mail: giovanni.targher@univr.it

DOI: 10.1136/gutjnl-2022-327672

Background and aims: Clinical guidelines do not recommend long-term anticoagulation in non-cirrhotic splanchnic vein thrombosis (NC-SVT) without underlying thrombophilia because it is assumed that there is a very low risk of recurrent thrombosis (RT). The first aim was to describe the incidence of RT in people with NC-SVT without an indication for long-term anticoagulation. The second aim was to identify RT risk factors and afterwards verify them in a validation cohort.
Methods: This is a multicenter, retrospective observational study evaluating risk factors for RT in 64 people with NC-SVT of idiopathic/local factor etiology. In a subgroup of 48 individuals, the potential value of additional thrombophilic parameters to predict RT was analyzed. Findings were validated in 70 individuals with idiopathic/local factor NC-SVT.
Results: Of the 64 participants in the training cohort, 17 (26%) presented splanchnic and/or extrasplanchnic RT (overall-RT) during follow-up (cumulative incidence: 2%, 10%, 19%, and 34% at 1, 2, 5, and 10 years, respectively). In addition, 53% of people with splanchnic RT were asymptomatic. No clinical or biochemical parameters predicted overall-RT. However, in the 48 people with an additional comprehensive thrombophilic study, factor VIII ≥ 150% was the only independent factor predicting overall-RT (hazard ratio [HR] = 7.10, 95% confidence interval [CI]: 2.17–23.17, p < 0.01). In the validation cohort, 19 individuals (27%) presented overall-RT, and it was also independently predicted by factor VIII > 150% (HR = 3.71, 95% CI: 1.31–10.5, p < 0.01). The predictive value of factor VIII was confirmed in both people with idiopathic/local factor etiology associated NC-SVT.

Conclusions: People with idiopathic/local factor non-cirrhotic splanchnic vein thrombosis (NC-SVT) are at risk of overall-recurrent thrombosis (RT). Splanchnic RT can be asymptomatic and requires screening for its detection. Values of factor VIII ≥ 150% may help identify individuals at high risk of overall-RT who could benefit from long-term anticoagulation.

Dr. A. Baiges or Prof. Dr. J.C. Garcia-Pagán, Barcelona Hepatic Hemodynamic Laboratory, Liver Unit, Hospital Clínic, Institut de Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain,

E-Mail: abaigesa@clinic.cat

E-Mail: jcgarcia@clinic.cat

DOI: 10.1016/j.jhep.2022.08.023

Background: Metabolic dysfunction-associated fatty liver disease (MAFLD) represents a new inclusive definition of the whole spectrum of liver diseases associated to metabolic disorders. The main objective of this study was to compare patients with MAFLD and non-MAFLD with hepatocellular carcinoma (HCC) included in a nationally representative cohort.
Methods: The authors analyzed 6882 consecutive patients with HCC enrolled from 2002 to 2019 by 23 Italian Liver Cancer centers to compare epidemiological and future trends in 3 subgroups: pure, single etiology MAFLD (S-MAFLD); mixed etiology MAFLD (metabolic and others, M-MAFLD); and non-MAFLD HCC.
Results: MAFLD was diagnosed in the majority of patients with HCC (68.4%). The proportion of both total MAFLD and S-MAFLD HCC significantly increased over time (from 50.4% and 3.6% in 2002–2003, to 77.3% and 28.9% in 2018–2019, respectively; p < 0.001). In Italy S-MAFLD HCC is expected to overcome M-MAFLD HCC in about 6 years. Patients with S-MAFLD HCC were older, more frequently men and less frequently cirrhotic with clinically relevant portal hypertension and a surveillance-related diagnosis. They had more frequently large tumors and extrahepatic metastases. After weighting, and compared with patients with non-MAFLD, S-MAFLD and M-MAFLD HCC showed a significantly lower overall (p = 0.026, p = 0.004) and HCC-related (p < 0.001, for both) risk of death. Patients with S-MAFLD HCC showed a significantly higher risk of non-HCC-related death (p = 0.006).

Conclusions: The prevalence of metabolic dysfunction-associated fatty liver disease (MAFLD) with hepatocellular carcinoma (HCC) in Italy is rapidly increasing to cover the majority of patients with HCC. Despite a less favorable cancer stage at diagnosis, patients with MAFLD HCC have a lower risk of HCC-related death, suggesting reduced cancer aggressiveness.

Prof. Dr. G. Svegliati-Baroni, Liver Disease and Transplant Unit, Polytechnic University of Marche, Ancona, Marche, Italy,

E-Mail: gsvegliati@gmail.com

DOI: 10.1136/gutjnl-2021-324915

Background: Endoscopic duodenal stenting is the current standard treatment for malignant gastric outlet obstruction (GOO) in patients with limited life expectancy. However, duodenal stenting is prone to stent dysfunction. Endoscopic ultrasound-guided gastroenterostomy (EUS-GE) is a novel technique with potentially superior stent patency. The authors compared clinical success, safety, and stent dysfunction of EUS-GE and duodenal stenting in patients with malignant GOO using propensity score matching.
Methods: This international, multicenter, retrospective study analyzed consecutive patients undergoing EUS-GE or duodenal stenting for GOO between 2015 and 2021 in 3 European centers. Primary outcomes were clinical success (GOO scoring system [GOOSS] ≥ 2) and stent dysfunction (GOOSS ≤ 1 after initial clinical success). A propensity score matching (1:1) analysis was performed using age, sex, underlying disease, disease stage, ascites, and peritoneal carcinomatosis as variables.
Results: 214 patients underwent EUS-GE (n = 107) or duodenal stenting (n = 107). After propensity score matching, 176 patients were matched and compared. Technical success rates for EUS-GE and duodenal stenting were 94% (95% confidence interval [CI]: 89–99%) versus 98% (95% CI: 95–100%), respectively (p = 0.44). Clinical success rates were 91% (95% CI: 85–97%) versus 75% (95% CI: 66–84%; p = 0.008). Stent dysfunction occurred in 1% (95% CI: 0–4%) versus 26% (95% CI: 15–37%) of patients (p < 0.001). Adverse event rate was 10% (95% CI: 4–17%) versus 21% (95% CI: 12–29%; p = 0.09).

Conclusion: Endoscopic ultrasound-guided gastroenterostomy (EUS-GE) had higher clinical success and lower stent dysfunction, with similar safety, compared with duodenal stenting, suggesting that EUS-GE may be preferred over duodenal stenting in patients with malignant gastric outlet obstruction.

Dr. Dr. R.L.J. van Wanrooij, Department of Gastroenterology and Hepatology, Amsterdam UMC, Amsterdam, The Netherlands,

E-Mail: rl.vanwanrooij@amsterdamumc.nl

DOI: 10.1055/a-1782-7568

Background: Two-year follow-up data from this randomized controlled trial showed that peroral endoscopic myotomy (POEM) is associated with a significantly higher efficacy than pneumatic dilation as initial treatment of therapy-naive patients with achalasia. Here, the authors report therapeutic success rates in patients treated with POEM compared with pneumatic dilation at the 5-year follow-up.
Methods: They did a multicenter, randomized controlled trial in 6 hospitals in the Netherlands, Germany, Italy, Hong Kong, and the USA. Adults aged 18–80 years with newly diagnosed symptomatic achalasia (based on an Eckardt score > 3) were eligible for inclusion. Patients were randomly assigned (1:1) to POEM or pneumatic dilation using web-based randomization with a random block size of 8 and stratification according to site. Randomization concealment for treatment type was double-blind until official study enrolment. Treatment was unmasked because of the different technical approach of each procedure. Patients in the pneumatic dilation group were dilated with a single series of 30–35-mm balloons. The need for subsequent dilations in the pneumatic dilation group, and the need for dilation after initial treatment in the POEM group, was considered treatment failure. The primary outcome was therapeutic success (Eckardt score ≤ 3 in the absence of severe treatment-related complications and no need for retreatment). Analysis of the primary outcome was by modified intention-to-treat, including all patients randomly assigned to a group, excluding those patients who did not receive treatment or were lost to follow-up. Safety was assessed in all included patients.
Findings: Between September 21, 2012, and July 20, 2015, 182 patients were assessed for eligibility, 133 of whom were included in the study and randomly assigned to POEM (n = 67) or pneumatic dilation (n = 66). Five-year follow-up data were available for 62 patients in the POEM group and 63 patients in the pneumatic dilation group. 50 (81%) patients in the POEM group had treatment success at 5 years, compared with 25 (40%) in the pneumatic dilation group, an adjusted absolute difference of 41% (95% confidence interval [CI]: 25–57; p < 0.0001). Reasons for failure were no initial effect of treatment (1 patient in the POEM group vs. 12 patients in the pneumatic dilation group) and recurrent symptoms causing treatment failure (11 patients in the POEM group [7 patients between 2 and 5 years] vs. 25 patients in the pneumatic dilation group [9 patients between 2 and 5 years]); 1 patient in the pneumatic dilation group had treatment failure due to an adverse event. Proton-pump inhibitor use (mostly daily) was significantly higher after POEM than after pneumatic dilation among patients still in clinical remission (23/50 patients [46%] vs. 3/24 patients [13%]; p = 0.008). Five-year follow-up endoscopy of patients still in clinical remission showed reflux esophagitis in 14 of 42 patients (33%) in the POEM group (12 [29%] grade A or B, 2 [5%] grade C or D) and 2 of 16 patients (13%) in the pneumatic dilation group (2 [13%] grade A or B, none grade C or D; p = 0.19). No intervention-related serious adverse events occurred between 2 and 5 years after treatment. The following non-intervention-related serious adverse events occurred between 2 and 5 years: a stroke (1 [2%]) in the POEM group; and death due to a melanoma (1 [2%]) and dementia (1 [2%]) in the pneumatic dilation group.

Interpretation: Based on this study, peroral endoscopic myotomy (POEM) should be proposed as an initial treatment option for patients with achalasia. Although this study has shown that POEM has greater long-term efficacy with a low risk of major treatment-related complications, this should not lead to abandonment of pneumatic dilation from clinical practice. Ideally, all treatment options should be discussed with treatment-naive patients with achalasia and a shared decision should be made.

Prof. Dr. A.J. Bredenoord, Department of Gastroenterology and Hepatology, Amsterdam UMC, Amsterdam, The Netherlands,

E-Mail: a.j.bredenoord@amsterdamumc.nl

DOI: 10.1016/s2468-1253(22)00300-4

Background and aims: The purpose of this study was to detect pancreatic ductal adenocarcinoma (PDAC) at the prediagnostic stage (3–36 months before clinical diagnosis) using radiomics-based machine-learning (ML) models, and to compare performance against radiologists in a case-control study.
Methods: Volumetric pancreas segmentation was performed on prediagnostic computed tomography scans (CTs) (median interval between CT and PDAC diagnosis: 398 days) of 155 patients and an age-matched cohort of 265 subjects with normal pancreas. A total of 88 first-order and gray-level radiomic features were extracted and 34 features were selected through the least absolute shrinkage and selection operator-based feature selection method. The dataset was randomly divided into training (292 CTs: 110 prediagnostic and 182 controls) and test subsets (128 CTs: 45 prediagnostic and 83 controls). Four ML classifiers, k-nearest neighbor (KNN), support vector machine (SVM), random forest (RM), and extreme gradient boosting (XGBoost), were evaluated. Specificity of model with highest accuracy was further validated on an independent internal dataset (n = 176) and the public National Institutes of Health (NIH) dataset (n = 80). Two radiologists (R4 and R5) independently evaluated the pancreas on a 5-point diagnostic scale.
Results: Median (range) time between prediagnostic CTs of the test subset and PDAC diagnosis was 386 (97–1092) days. SVM had the highest sensitivity (mean; 95% confidence interval) (95.5; 85.5–100.0), specificity (90.3; 84.3–91.5), F1-score (89.5; 82.3–91.7), area under the curve (AUC) (0.98; 0.94–0.98), and accuracy (92.2%; 86.7–93.7) for classification of CTs into prediagnostic versus normal. All 3 other ML models, KNN, RF, and XGBoost, had comparable AUCs (0.95, 0.95, and 0.96, respectively). The high specificity of SVM was generalizable to both the independent internal (92.6%) and the NIH dataset (96.2%). In contrast, interreader radiologist agreement was only fair (Cohen's kappa 0.3) and their mean AUC (0.66; 0.46–0.86) was lower than each of the 4 ML models (AUCs: 0.95–0.98) (p < 0.001). Radiologists also recorded false-positive indirect findings of PDAC in control subjects (n = 83) (7% R4, 18% R5).

Conclusions: Radiomics-based machine-learning models can detect pancreatic ductal adenocarcinoma (PDAC) from normal pancreas when it is beyond human interrogation capability at a substantial lead time before clinical diagnosis. Prospective validation and integration of such models with complementary fluid-based biomarkers has the potential for PDAC detection at a stage when surgical cure is a possibility.

A.H. Goenka, M.D., Department of Radiology, Mayo Clinic, Rochester, MN, USA, ">A.H. Goenka, M.D., Department of Radiology, Mayo Clinic, Rochester, MN, USA,

E-Mail: goenka.ajit@mayo.edu

DOI: 10.1053/j.gastro.2022.06.066