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Alimentary Pharmacology & Therapeutics

Published by Wiley
Online ISSN: 1365-2036
Discipline: Gastroeterology & Hepatology
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Aims and scope

Alimentary Pharmacology & Therapeutics is an international journal of gastroenterology and hepatology. The journal accepts systematic reviews, meta-analyses, randomised controlled trials and original papers concerned with Gastroenterology and Hepatology. AP&T is particularly interested in therapies and diagnostics, including all aspects of translation from bench to bedside: identification of novel therapeutic targets, epidemiology, clinical trials, drug safety and meta-analyses.

 

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Recent publications
Article
LINKED CONTENT This article is linked to Friedman et al papers. To view these articles, visit https://doi.org/10.1111/apt.17113
 
Disease activity and time on IV vedolizumab treatment at the time of the switch to SC vedolizumab in relation to outcome. (A) Faecal calprotectin levels at follow‐up after 6 months, stratified for patients with inactive (n = 56) and active (n = 13) disease at baseline as defined by a Faecal calprotectin <150 and ≥150 μg/g, respectively. Paired samples t‐test or Wilcoxon matched‐pairs signed‐rank test performed as appropriate. (B) Correlation analysis for time on IV vedolizumab treatment before the switch and faecal calprotectin levels at 6 months after the switch. Spearman's rank‐order test was performed (n = 77). Abbreviations: IV, intravenous; M, months; ns, not significant; SC, subcutaneous. p < 0.05 denotes statistical significance.
Article
LINKED CONTENT This article is linked to Bergqvist et al papers. To view these articles, visit https://doi.org/10.1111/apt.16927 and https://doi.org/10.1111/apt.17112
 
Reframing the definition of EGJOO to reduce false alarms. The updates in CCv4.0, including increased data points to assess for LES obstruction on HRM, requirement of obstructive symptoms and corroboration of LES obstructive physiology on a non‐HRM test, have led to less ‘false alarms’ of EGJOO diagnosis. EGJ, oesophagogastric junction; EGJOO, EGJ outflow obstruction; LES, lower oesophageal sphincter; HRM, high‐resolution manometry.
Article
LINKED CONTENT This article is linked to Visaggi et al papers. To view these articles, visit https://doi.org/10.1111/apt.17101
 
Article
LINKED CONTENT This article is linked to Goodoory et al papers. To view these articles, visit https://doi.org/10.1111/apt.17132 and https://doi.org/10.1111/apt.17143
 
Fourteen‐day AKI incidence (A) and 30‐day AKI incidence (B). The attached p‐value was calculated using log‐rank testing. AKI, acute kidney injury.
Article
LINKED CONTENT This article is linked to Tergast et al papers. To view these articles, visit https://doi.org/10.1111/apt.17066 and https://doi.org/10.1111/apt.17156
 
Article
LINKED CONTENT This article is linked to Papatheodoridis et al papers. To view these articles, visit https://doi.org/10.1111/apt.17093 and https://doi.org/10.1111/apt.17117
 
Article
LINKED CONTENT This article is linked to Lin et al papers. To view these articles, visit https://doi.org/10.1111/apt.17089
 
Article
LINKED CONTENT This article is linked to Bergqvist et al papers. To view these articles, visit https://doi.org/10.1111/apt.16927 and https://doi.org/10.1111/apt.17147
 
Article
LINKED CONTENT This article is linked to Papatheodoridis et al papers. To view these articles, visit https://doi.org/10.1111/apt.17093 and https://doi.org/10.1111/apt.17146
 
Article
LINKED CONTENT This article is linked to Jachs et al papers. To view these articles, visit https://doi.org/10.1111/apt.16945 and https://doi.org/10.1111/apt.16138
 
Article
LINKED CONTENT This article is linked to Choudhary et al papers. To view these articles, visit https://doi.org/10.1111/apt.17104 and https://doi.org/10.1111/apt.17134
 
Article
LINKED CONTENT This article is linked to Tergast et al papers. To view these articles, visit https://doi.org/10.1111/apt.17066 and https://doi.org/10.1111/apt.17099
 
Changes in HBsAg and HDV‐RNA in a 38‐year‐old woman with chronic hepatitis D treated with PEGIFN alfa‐2a monotherapy. Pretreatment liver biopsy: fibrosis grade 2, lobular activity: 3. HDV, hepatitis D virus; PEGIFN, pegylated interferon alfa.
Article
LINKED CONTENT This article is linked to Jachs et al papers. To view these articles, visit https://doi.org/10.1111/apt.16945 and https://doi.org/10.1111/apt.16115
 
Article
LINKED CONTENT This article is linked to Sohouli et al papers. To view these articles, visit https://doi.org/10.1111/apt.17109
 
Article
LINKED CONTENT This article is linked to Choudhary et al papers. To view these articles, visit https://doi.org/10.1111/apt.17104 and https://doi.org/10.1111/apt.17163
 
Article
LINKED CONTENT This article is linked to Tergast et al papers. To view these articles, visit https://doi.org/10.1111/apt.16831 and https://doi.org/10.1111/apt.17157
 
Article
LINKED CONTENT This article is linked to Tergast et al papers. To view these articles, visit https://doi.org/10.1111/apt.17066 and https://doi.org/10.1111/apt.17168
 
Article
LINKED CONTENT This article is linked to Goodoory et al papers. To view these articles, visit https://doi.org/10.1111/apt.17132 and https://doi.org/10.1111/apt.17160
 
Article
LINKED CONTENT This article is linked to Rosiou et al papers. To view these articles, visit https://doi.org/10.1111/apt.17039 and https://doi.org/10.1111/apt.17137
 
Article
LINKED CONTENT This article is linked to Rosiou et al papers. To view these articles, visit https://doi.org/10.1111/apt.17039 and https://doi.org/10.1111/apt.17140
 
Article
Background Hepatitis B virus (HBV) infection is a serious global health burden. TRIM26 has been reported to affect hepatitis C virus replication. Aims To manifest the role of TRIM26 on HBV replication and explore if there are single‐nucleotide polymorphisms (SNPs) in TRIM26 associated with response to pegylated interferon‐alpha (PegIFNα) treatment in patients with chronic hepatitis B (CHB). Methods We investigated the effect and mechanism of TRIM26 on HBV replication in vitro. The association between SNPs in TRIM26 and PegIFNα treatment response was evaluated in two independent cohorts including 238 and 707 patients with HBeAg‐positive CHB. Results Knockdown of TRIM26 increased, while overexpression of TRIM26 inhibited, HBV replication. Co‐immunoprecipitation assays and immunofluorescence showed that TRIM26 interacted and co‐localised with HBx. Co‐transfection of HBx‐HIS and TRIM26‐FLAG plasmids in Huh7 cells showed that TRIM26 inhibited the expression of HBx. Furthermore, TRIM26 inhibited HBV replication by mediating HBx ubiquitination degradation, and TRIM26 SPRY domain was responsible for the interaction and degradation of HBx. Besides, IFN increased TRIM26 expression. TRIM26 rs116806878 was associated with response to PegIFNα in two CHB cohorts. Moreover, a polygenic score integrating TRIM26 rs116806878, STAT4 rs7574865 and CFB rs12614 (previously reported to be associated with response to PegIFNα) was related to response to PegIFNα in CHB. Conclusions TRIM26 inhibits HBV replication; IFN promotes TRIM26 expression. TRIM26 exerts an inhibitory effect on HBx by promoting ubiquitin‐mediated degradation of HBx. Furthermore, TRIM26 rs116806878 is a potential predictive biomarker of response to PegIFNα in patients with CHB.
 
Patient flow chart.
Prevalence of chronic hepatitis B virus (HBV) infection of 695,925 subjects born in 1970–2002.
Incidence rates of (A) hepatocellular carcinoma and (B) hepatic events in adults born in 1983–1987 (unvaccinated cohort) and born in 1988–1997 (vaccinated cohort), adjustment of competing death, age, gender and antiviral treatment.
Article
Background Universal vaccination of newborns with hepatitis B virus (HBV) vaccine is the most important strategy to prevent chronic HBV infection and its complications of which hepatocellular carcinoma (HCC) as the deadliest. Aims To evaluate the impact of universal HBV vaccination on the prevalence of chronic HBV infection, and the incidences of HCC and hepatic events in young adults born before and after the introduction of the universal HBV vaccination programme in 1988 in Hong Kong Methods This was a territory‐wide retrospective observational cohort study of consecutive adult subjects born in 1970–2002 with hepatitis B surface antigen (HBsAg) checked. Subjects born during the vaccination era (1988–2002) were included in the vaccinated cohort; subjects born between 1970 and 1987 were included in the unvaccinated cohort. Results We included 695,925 subjects for HBV prevalence analysis. Chronic HBV infection dropped from 14.3% in subjects born in 1970, to 6.7% in subjects born in 1988. In total, 53,960 vaccinated and 318,290 unvaccinated subjects who had available clinical data were included for event analysis. HCC and hepatic events occurred in 44 (0.1%) and 75 (0.1%) of the vaccinated subjects and in 1305 (0.4%) and 1806 (0.6%) of the unvaccinated subjects, respectively. All incidence rates remained numerically lower in vaccinated subjects after adjustment for age, gender and antiviral treatment, but failed to reach statistical significance due to very low incidence rates. Conclusions Universal HBV vaccination markedly reduces the prevalence of chronic HBV infection and may contribute to the decreased incidences of HCC and hepatic events.
 
Impairment at work and in activities of daily living because of IBS.
Impairment in home management, social leisure activities, private leisure activities and maintaining close relationships because of IBS.
Article
Background Few studies have demonstrated the impact of irritable bowel syndrome (IBS) on work and activities of daily living. Methods We collected demographic, gastrointestinal symptom, psychological health and quality of life data from 752 adults with Rome IV‐defined IBS. We used the work productivity and activity impairment questionnaire for irritable bowel syndrome and the work and social adjustment scale to examine the degree of both impairment at work and in activities of daily living, as well as factors associated with these. Results Of 467 individuals who were employed, 133 (28.5%) reported absenteeism, 373 (85.6%) presenteeism and 382 (81.8%) overall work impairment. A mean of 1.97 hours of work per week was lost due to IBS. Extrapolating this across the entire UK, we estimate that between 72 and 188 million hours of work are lost per year due to IBS in individuals of working age. Among all 752 participants, 684 (91.0%) reported any activity impairment with 220 (29.3%) reporting impairment in home management, 423 (56.3%) in social leisure activities, 207 (27.5%) in private leisure activities, and 203 (27.0%) in maintaining close relationships. Severe IBS, higher levels of anxiety, depression, somatization and gastrointestinal symptom‐specific anxiety, and lower levels of IBS‐related quality of life were associated with impairment in both work and activities of daily living. Conclusion Patients with IBS experience a substantial impact on their work and activities of daily living because of their IBS. Future studies should assess the impact of medical interventions on the ability to work and participate in social activities.
 
Flow chart of the study population with inflammatory bowel disease (IBD) and primary sclerosing cholangitis (PSC) taken from the French National Système National des Données de Santé (SNDS).
Cumulative incidence of biliary tract cancers and/or liver transplantation as first censoring event during follow‐up. One patient had simultaneous occurrence of diagnosis of biliary tract cancer and liver transplantation. In all patients, the first 6 months of follow‐up refer to the exclusion period in which cases and person‐years were not taken into account in the analyses.
Multivariable adjusted hazard ratios (HR) for biliary tract cancer and/or liver transplantation according to treatment exposure between patients exposed to thiopurines and/or anti‐TNF and patients unexposed to thiopurines and anti‐TNF. anti‐TNF, tumour necrosis factor antagonists.
Article
Background Patients with primary sclerosing cholangitis (PSC) and inflammatory bowel disease (IBD) are at risk of biliary tract cancer and liver damage (possibly leading to liver transplantation), and are often treated for IBD with thiopurines and/or tumour necrosis factor antagonists (anti‐TNF) on a long‐term basis. Aims To assess the risk of biliary tract cancer and liver transplantation in patients exposed to thiopurines and/or anti‐TNF in a French nationwide cohort. Methods We performed a population‐based study of patients aged 18 years or older with PSC and IBD in the French national health insurance database. Patients were followed from 1 January 2009 to 31 December 2018. The risks of biliary tract cancer and liver transplantation associated with thiopurines and anti‐TNF exposure were assessed with marginal structural Cox proportional hazard models, adjusting for baseline demographics and comorbidities, and time‐varying medications and PSC activity. Results Among the 1929 patients with PSC and IBD included, 37 biliary tract cancers and 83 liver transplantations occurred. Compared with patients not exposed to thiopurines or anti‐TNF agents, patients exposed to thiopurines (hazard ratio [HR], 1.05; 95% confidence interval [CI], 0.39–2.82) or anti‐TNF agents (HR, 0.59; 95% CI, 0.13–2.80) had no excess risk of biliary tract cancer. Similarly, patients exposed to thiopurines (HR, 0.67; 95% CI, 0.30–1.48) or anti‐TNF agents (HR, 0.68; CI, 0.22–2.09) had no excess risk of liver transplantation. Conclusions Patients with PSC and IBD who are exposed to thiopurines or anti‐TNF agents are not at excess risk of biliary tract cancer or liver transplantation.
 
Flowchart. Abbreviations: IBD, inflammatory bowel disease; UC, ulcerative colitis; CD, Crohn's disease. †The index date was defined as the first‐time admission date of an IBD diagnosis between 1 January 1977 and 31 December 2018 for IBD patients, which also served as the index date for the matched comparisons. ‡Type errors include death or emigration prior to the first‐time IBD diagnosis.
Cumulative incidence functions of all‐cause dementia in patients with inflammatory bowel disease and matched general population comparators. Abbreviations: UC, ulcerative colitis; CD, Crohn's disease; CI, confidence interval.
Unadjusted and adjusted hazard ratios of dementia subtypes in patients with inflammatory bowel disease compared to matched general population comparators. Abbreviations: IBD, inflammatory bowel disease; UC, ulcerative colitis; CD, Crohn's disease; HR, hazard ratio; CI, confidence interval; PDD/DLB, Parkinson's disease dementia and dementia with Lewy bodies. †Controlled for sex, birthyear (±1 year) and region of residence. ‡Adjusted for modified Charlson Comorbidity Index score, diabetes (type 1 or 2), atrial fibrillation or flutter, hypertension, obesity, chronic obstructive pulmonary disease, depression, hearing impairment and head trauma. §Other dementia represented any other dementia than the subtypes shown in the table.
Article
Background Inflammatory bowel disease (IBD) may be associated with increased dementia risk, but the literature is conflicting. Aim To investigate dementia risk in patients with IBD Methods We conducted a nationwide population‐based cohort study in Denmark (1977–2018) including all patients with incident IBD matched with up to 10 general population comparators without IBD by sex, year of birth and region of residence. We calculated cumulative incidence proportions (CIPs) of dementia treating death as a competing risk, and adjusted hazard ratios (HRs) comparing IBD patients with matched comparisons. In a nested case–control analysis, we investigated the impact of IBD severity, steroid use, colorectal and small bowel surgery, and healthcare system contacts on dementia risk. Results Of 88,985 patients with IBD (69.6% with ulcerative colitis [UC], 30.4% with Crohn's disease [CD]) and 884,108 comparisons, 2076 patients (78.1% with UC) and 23,011 comparisons (76.6% UC comparisons) developed dementia. The 40‐year CIP of all‐cause dementia was 7.2% for UC patients and 5.8% for CD patients. UC patients had a slightly increased HR of all‐cause dementia (HR = 1.07 [95% confidence interval (CI): 1.01;1.12]) and Alzheimer's disease (HR = 1.10 [95% CI: 1.01–1.19]). CD patients had an increased HR of all‐cause dementia (HR = 1.15 [95% CI: 1.05–1.27]) and frontotemporal dementia (HR = 2.70 [95% CI: 1.44–5.05]). Dementia in IBD patients was associated with frequent healthcare system contacts. Conclusions UC and CD are associated with slightly increased all‐cause dementia risk, particularly frontotemporal dementia in CD patients. Frequent healthcare system contacts by patients with IBD and detection bias may play a role in the association.
 
Study flow chart
Article
Background Patients with active inflammatory bowel disease (IBD) and mental illnesses experience worse IBD outcomes. Aim To describe the incidence of mental illnesses, including deliberate self‐harm, in IBD patients. Methods A population‐based retrospective cohort study using IQVIA medical research data of a primary care database covering the whole UK, between January 1995 and January 2021. IBD patients of all ages were matched 4:1 by demographics and primary care practice to unexposed controls. Following exclusion of patients with mental ill health at study entry, adjusted hazard ratios (HR) of developing depression, anxiety, deliberate self‐harm, severe mental illness and insomnia were calculated using a Cox proportional hazards model. Results We included 48,799 incident IBD patients: 28,352 with ulcerative colitis and 20,447 with Crohn's disease. Incidence rate ratios of mental illness were higher in IBD patients than controls (all p < 0.001): deliberate self‐harm 1.31 (95% CI 1.16–1.47), anxiety 1.17 (1.11–1.24), depression 1.36 (1.31–1.42) and insomnia 1.62 (1.54–1.69). Patients with Crohn's disease were more likely to develop deliberate self‐harm HR 1.51 (95% CI 1.28–1.78), anxiety 1.38 (1.16–1.65), depression 1.36 (1.26–1.47) and insomnia 1.74 (1.62–1.86). Patients with IBD are at increased risk of deliberate self‐harm (HR 1.20 [1.07–1.35]). The incidence rate ratios of mental illnesses were particularly high during the first year following IBD diagnosis: anxiety 1.28 (1.13–1.46), depression 1.62 (1.48–1.77) and insomnia 1.99 (1.78–2.21). Conclusion Deliberate self‐harm, depression, anxiety and insomnia were more frequent among patients with IBD. IBD is independently associated with an increased risk of deliberate self‐harm.
 
Post‐translational processing of precore protein and antigens detected by HBcrAg assays (adapted from Hong et al.³³). Multiple species of HBeAg and p22cr are generated by alternative processing of C‐terminus.
Key steps in hepatitis B life cycle: (a) virus particles bind to NTCP receptor, triggering clathrin‐mediated endocytosis (b) conversion of rcDNA to cccDNA by host enzymes (c) transcription of cccDNA into subgenomic and pregenomic mRNAs (d) encapsidation of pgRNA by capsid proteins (e) reverse transcription of pgRNA to rcDNA (f) transport of rcDNA containing nucleocapsids to multivesicular bodies (MVB) (g) exocytosis of mature virions and subviral particles (h) in a minor pathway, failure of primer translocation results in the formation of dslDNA and this can integrate into host DNA. cccDNA, covalently closed circular DNA; NTCP, sodium taurocholate co‐transporting peptide; pgRNA, pregenomic mRNA; rcDNA, relaxed circular DNA.
Article
Background Chronic hepatitis B remains a global health problem with an estimated 296 million people affected worldwide. Individuals are at risk of serious complications such as cirrhosis and hepatocellular carcinoma and accurately predicting these clinical endpoints has proven difficult. However, several viral biomarkers have recently been developed, including quantitative HBV surface antigen (qHBsAg), hepatitis B RNA (HBV RNA) and core‐related antigen (HBcrAg), and shown promise in a range of clinical settings. Aims To critically appraise these novel biomarkers, exploring their potential uses, availability of assays and areas for future development. Methods We performed a literature search of PubMed, identifying articles published in the field of hepatitis B biomarkers between 2010 and 2022. Results Novel biomarkers such as HBcrAg, HBV RNA and qHBsAg may be useful in predicting treatment outcomes, stratifying the risk of future complications and estimating off‐treatment viral reactivation. Furthermore, HBV RNA and HBcrAg titres may accurately reflect cccDNA transcriptional activity, and this is particularly informative in the context of nucleoside analogue therapy. On a cautionary note, most studies have been performed in Caucasian or Asian populations, and methods for detecting HBV RNA lack standardisation. Conclusion Novel viral biomarkers have the potential to provide additional insights into the natural history of infection and allow a more bespoke, cost‐effective framework of care. However, access remains limited, and further efforts are needed to validate their use in ethnically diverse populations, confirm predictive cut‐off values, and establish their role in the era of novel antiviral therapies.
 
The cumulative proportion of infections from time of birth to 3 years of age according to the time of the first infection of any kind, in children exposed to paternal IBD medications.
Article
Background Information regarding the impact of paternal inflammatory bowel disease (IBD) medications on child outcomes is scarce. Aim To examine the risk of childhood infections associated with fathers' use of anti‐inflammatory/immunosuppressive medications taken before conception. Methods This is a nationwide cohort study based on Danish health registries, comprising all live‐born singleton children born between January 1997 and February 2019 who were fathered by men with IBD. Exposed cohorts included children fathered by men treated with 5‐aminosalicylates (5‐ASAs), thiopurines, corticosteroids or anti‐tumour necrosis factor‐α (anti‐TNF‐α) agents within 3 months before conception. The unexposed cohort included children not exposed to paternal IBD medications. Outcomes were the first infection, diagnosed in the hospital setting in the first year of life, and from the age of 1 to 3 years. Results In all, 2178 children were fathered by men exposed to 5‐ASAs, 843 to thiopurines, 417 to systemic corticosteroids and 436 to anti‐TNF‐α agents; 6799 children were unexposed. The adjusted hazard ratio (aHR) for infections within the first year of life for 5‐ASAs was 0.78 (95% CI, 0.66–0.91), thiopurines 0.89 (95% CI, 0.73–1.09), systemic corticosteroids 0.95 (95% CI, 0.70–1.29), and anti‐TNF‐α agents 1.17 (95% CI, 0.94–1.46). The aHR for infections from 1 to 3 years for 5‐ASAs was 0.97 (95% CI, 0.83–1.13), thiopurines 0.87 (95% CI, 0.71–1.07), systemic corticosteroids 1.25 (95% CI, 0.94–1.65), and anti‐TNF‐α agents 0.79 (95% CI, 0.60–1.03). Conclusion Fathers' use of anti‐inflammatory/immunosuppressive medications before conception was not significantly associated with childhood infections. These results fill an important research gap regarding paternal medication safety.
 
Study profile. Patients were not assessable when one of more key data items were missing. Abbreviations: TSH: thyroid‐stimulating hormone, fT3: free triiodothyronine, fT4: free thyroxine.
Forest plot showing the coefficients from a multivariable linear regression model of associations with fT3/fT4 ratio. The resultant values represent the change of fT3/fT4 ratio associated with each variable. Abbreviations: CRP = C‐reactive protein.
Beeswarm plot of fT3/fT4 ratio at baseline and primary non‐response at week 14, (A) combined cohort (B) infliximab‐treated patients, (C) adalimumab‐treated patients. The number of individuals tested for each group are shown in black at the top of each panel.
Beeswarm plot of fT3/fT4 ratio at baseline, stratified by outcome at week 14. The number of individuals tested for each group are shown in black at the top of each panel.
Forest plot showing the coefficients from a multivariable logistic regression model of associations with primary non‐response.
Article
Background During illness, adaptations of the hypothalamic–pituitary‐thyroid axis reduce energy expenditure, protein catabolism and modulate immune responses to promote survival. Lower serum free triiodothyronine‐to‐thyroxine (fT3/fT4) ratio has been linked to non‐response to treatment in a range of diseases, including in biologic‐treated patients with inflammatory bowel disease. Aim To assess whether baseline serum fT3/fT4 ratio predicted primary non‐response (PNR) and non‐remission to infliximab and adalimumab in patients with Crohn's disease Methods Thyroid function tests were undertaken in stored serum from biologic‐naïve adult patients with active luminal Crohn's disease immediately prior to treatment with infliximab (427 originator; 122 biosimilar) or adalimumab (448) in the Personalised Anti‐TNF Therapy in Crohn's Disease study (PANTS). Results Baseline median [IQR] fT3/fT4 ratios were lower in women than men (0.30 [0.27–0.34] vs 0.32 [0.28–0.36], p < 0.001), in patients with more severe inflammatory disease, and in patients receiving corticosteroids (0.28 [0.25–0.33] vs. 0.32 [0.29–0.36], p < 0.001). Multivariable logistic regression analysis demonstrated that fT3/fT4 ratio was independently associated with PNR at week 14 (odds ratio [OR] 0.51, 95% confidence interval [CI] 0.31–0.85, p = 0.009), but not non‐remission or changes in faecal calprotectin concentrations at week 54. The optimal threshold to determine PNR was 0.31 (area under the curve 0.57 [95% CI 0.54–0.61], sensitivity 0.62 [95% CI 0.41–0.74], and specificity 0.53 [95% CI 0.42–0.73]). Conclusions Lower baseline serum fT3/fT4 ratio was associated with female sex, corticosteroid use and disease activity. It predicted PNR to anti‐TNF treatment at week 14, but not non‐remission at week 54.
 
Flowchart showing the selection of hEDS/HSD patients (cases) and control population. (A) cases; (B) controls.
Article
Background and Aims To evaluate symptom presentation and underlying pathophysiology of colonic/anorectal dysfunction in females with functional constipation (FC) and hypermobile Ehlers–Danlos syndrome (hEDS)/hypermobility spectrum disorder (HSD) Methods Case–control study of 67 consecutive female patients with an established diagnosis of hEDS/HSD referred to a specialist centre for investigation of FC (Rome III criteria), age‐matched (1:2 ratio) to 134 female controls with FC scoring 0 on the validated 5‐point joint hypermobility questionnaire. Symptoms and results of colonic/anorectal physiology testing were compared. An independent series of 72 consecutive females with hEDS/HSD, referred to a separate hospital for investigation of FC, was used to validate physiological findings. Results Females with hEDS/HSD were more likely to report constipation for ≥ 5 years (76.1% vs. 61.2%, p = 0.035), and a greater proportion had a high Cleveland Clinic constipation score (≥12: 97.0% vs. 87.3%; p = 0.027). The proportions with delayed whole‐gut transit were similar between groups (35.3% vs. 41.7%; p = 0.462), as were the proportions with functional or structural abnormalities on defaecography (functional: 47.8% vs. 36.6%; p = 0.127; structural: 65.7% vs. 66.4%; p = 0.916). However, rectal hyposensitivity was more common in those with hEDS/HSD (43.3% vs. 20.1%; p = 0.0006); this was confirmed in the validation cohort (rectal hyposensitivity: 45.8%). Conclusions Rectal hyposensitivity is a common pathophysiological factor in females with FC and hEDS/HSD as confirmed in two separate cohorts. The rectal hyposensitivity may be due to altered rectal biomechanics/neuronal pathway dysfunction. Management may be better focused on enhancement of sensory perception (e.g., sensory biofeedback).
 
Disease outcomes at 12 months in children with moderate–severe disease who were eligible and ineligible for inclusion in the original randomised controlled trials. Normal ESR <25 mm/h; normal CRP <0.5 mg/dl. SFR, steroid free remission.
Time from initiation of biologics to switching treatment in children with moderate–severe disease who were eligible vs ineligible for inclusion in the original randomised controlled trials.
Rate of clinical remission in the original RCTs and in the real‐world cohort stratified by disease and drug type. Remission rates were evaluated at 12 months for infliximab and adalimumab, and at 4 months for vedolizumab and ustekinumab, as done in the original RCTs.
Article
Background Patients enrolled in randomised controlled trials (RCTs) may differ from the target population due to restricted eligibility criteria. Aim To compare treatment response to biologics in routine practice for children with inflammatory bowel diseases (IBD) who would and would not have been eligible for enrolment in the regulatory RCT of the same drug. Methods We enrolled children with IBD who initiated adalimumab, infliximab, vedolizumab or ustekinumab. The eligibility criteria as defined in the RCT of the corresponding biologic were applied to each patient. The primary outcome was 12‐month steroid‐free remission (SFR) without switching biologics or undergoing surgery. Results We screened 289 children (198 [68%] with Crohn's disease [CD], 91 [32%] with ulcerative colitis [UC]) with 326 initiations of biologics. Only 62 of 164 (38%) children with moderate–to‐severe disease would have been eligible for inclusion in the original RCTs. The SFR rate was higher in the eligible children (51%) than in the ineligible children (31%; OR 2.3 [95%CI 1.2–4.5]; p = 0.01). The main exclusion criterion was prohibited previous therapies (47%). Ineligible CD patients were older, more often had a family history of IBD and had higher levels of CRP than eligible children; in UC there were no differences between the groups. Conclusion Most children with IBD who initiate biologics would not have been eligible to be included in the corresponding regulatory RCTs. The outcomes of ineligible patients were worse than for eligible patients. Results from RCTs should be interpreted with caution when applied to clinical practice.
 
Time trends of various types of hyperplastic and neoplastic colon lesions. The left y‐axis pertains to hyperplastic polyp (HP), sessile serrated adenoma (SSA), and tubular adenoma (TA), whereas the right y‐axis pertains to colorectal cancer (CRC) and traditional serrated adenoma (TSA).
Article
Background The general probabilities of finding different types of hyperplastic or neoplastic colon lesions clustering in the same patient are unknown. We hypothesised that a systematic analysis of polyp clustering would reveal a high frequency of different concurrent types and that such clustering would be influenced by the underlying histopathology of the individual polyps. Methods Using an electronic database of histopathologic records, a cross‐sectional study of 2,910,174 colonoscopies evaluated the concordant occurrence of hyperplastic and neoplastic mucosal lesions. Results Amongst patients harbouring any colon polyp, one can expect to find another histopathologic type in about 22%. Being the most prevalent type of polyp, tubular adenoma was the most common type of colonic polyp to be associated with other lesions. For instance, 31% of all colonoscopies with sessile serrated adenomas or hyperplastic polyps also revealed tubular adenomas. Hyperplastic polyp, the second most prevalent type of colonic polyp, was also the second most common type of polyp to be found associated with other types of neoplasia. For instance, 25% of all colonoscopies with sessile serrated adenomas and 31% of those with tubular adenomas also revealed hyperplastic polyps. Conclusions Different types of colon polyps commonly coincide in individual patients. The present set of data from a large nationwide database may provide guidance for the endoscopist of what variety in colon polyps to expect during colonoscopy.
 
Article
Background Irritable bowel syndrome (IBS) is one of the most common disorders of gut‐brain interaction, with a complex pathophysiology. Antispasmodics are prescribed as the first‐line therapy because of their action on gut dysmotility. In this regard, peppermint oil also has antispasmodic properties. Aim To update our previous meta‐analysis to assess efficacy and safety of peppermint oil, particularly as recent studies have cast doubt on its role in the treatment of IBS. Methods We searched the medical literature up to 2nd April 2022 to identify randomised controlled trials (RCTs) of peppermint oil in IBS. Efficacy and safety were judged using dichotomous assessments of effect on global IBS symptoms or abdominal pain, and occurrence of any adverse event or of gastro‐oesophageal reflux. Data were pooled using a random effects model, with efficacy and safety reported as pooled relative risks (RRs) with 95% confidence intervals (CIs). Results We identified 10 eligible RCTs (1030 patients). Peppermint oil was more efficacious than placebo for global IBS symptoms (RR of not improving = 0.65; 95% CI 0.43–0.98, number needed to treat [NNT] = 4; 95% CI 2.5–71), and abdominal pain (RR of abdominal pain not improving = 0.76; 95% CI 0.62–0.93, NNT = 7; 95% CI 4–24). Adverse event rates were significantly higher with peppermint oil (RR of any adverse event = 1.57; 95% CI 1.04–2.37). Conclusions Peppermint oil was superior to placebo for the treatment of IBS, but adverse events were more frequent, and quality of evidence was very low. Adequately powered RCTs of peppermint oil as the first‐line treatment for IBS are needed.
 
Study outline. After randomisation, subjects received a daily dose of 2400 mg mesalazine or placebo during the intervention period (day 0–day 56). IBS‐SSS, Irritable bowel syndrome severity scoring system; HAD, Hospital anxiety and depression scale; MPT, Mucosal patch technology.
Study flow chart. Disposition showing the number of patients assessed for eligibility, randomised, and patients completing the intervention. The non‐gastrointestinal (GI) cancer was not diagnosed during study participation.
Results from a meta‐analysis of randomised clinical trials comparing effects on IBS symptoms from mesalazine versus placebo using random effects. Columns SMD (standardised mean difference), 95% CI (95% confidence interval) and weight are displayed graphically at the centre of the figure, with vertical lines representing SMD, horizontal lines 95% CI and size of grey boxes represent weight. The pooled SMD estimate of the random‐effects model and its confidence intervals are represented by the grey triangle.
Article
Background Low‐grade immune activation in the gut is a potential treatment target in irritable bowel syndrome (IBS). Aims To determine improvement in IBS symptoms after mesalazine treatment, and the utility of measures of immune activity in the rectal mucosa Methods This was a randomised, double‐blind, placebo‐controlled, parallel‐arm, multicentre trial in subjects with IBS (Rome III criteria), with an eight‐week treatment period of mesalazine 2400 mg or plcebo once‐daily. The primary endpoint was the global assessment of satisfactory relief of IBS symptoms in ≥50% of weeks during intervention. IBS symptoms were also measured with the IBS severity scoring system; immune activity was measured by mucosal patch technology. A post hoc meta‐analysis of randomised placebo‐controlled trials of mesalazine in IBS was added. Results Of 181 included patients, 91 received mesalazine and 90 received placebo. The primary endpoint was met by 32 (36%) patients after mesalazine and 27 (30%) after placebo (p = 0.40). There were no differences in response rates related to IBS subtype or post‐infection symptom onset. More reduction of abdominal bloating was noted in the mesalazine group (p = 0.02). The meta‐analysis showed no effect of mesalazine on IBS symptoms. No mucosal patch technology measure could predict response to mesalazine, and found no differences in the effects of intervention on levels of immune markers. Conclusions Mesalazine is ineffective in reducing IBS symptoms. Rectal measures of immune activity by the mucosal patch technology cannot predict a higher chance of response to mesalazine.
 
Article
Background Intestinal T cells are key in gut barrier function. Their role in early stages of alcohol‐associated liver disease (ALD) remain unknown. Aim To explore the links between intestinal T cells, microbial translocation and ALD. Methods Patients with alcohol use disorder (AUD) following a rehabilitation programme were compared to subjects with non‐alcoholic fatty liver disease (NAFLD) and healthy controls. Clinical and laboratory data (liver stiffness, controlled attenuation parameter, AST, ALT, K18‐M65) served to identify AUD patients with isolated steatosis (minimal liver disease) or steatohepatitis/fibrosis (ALD). Serum microbial translocation markers were measured by ELISA, duodenal and plasma levels of sphingolipids by targeted LC–MS. T lymphocytes in duodenal biopsies were characterised by immunohistochemistry, flow cytometry and RNA sequencing on FACS‐sorted cells. Mechanisms for T‐cell alterations were assessed in vitro. Results Patients with ALD, but not those with minimal liver disease, showed reduced numbers of duodenal CD8+ T resident memory (TRM) cells compared to controls or patients with NAFLD. TRM transcriptomic analysis, in vitro analyses and pharmacological inhibition of cathepsin B confirmed TRM apoptosis driven by lysosomal membrane permeabilisation and cathepsin B release into the cytosol. Altered lipid metabolism and increased duodenal and plasma sphingolipids correlated with apoptosis. Dihydroceramide dose‐dependently reduced viability of TRM. Duodenal TRM phenotypic changes, apoptosis and transcriptomic alterations correlated with increased levels of microbial translocation markers. Short‐term abstinence did not reverse TRM cell death in patients with ALD. Conclusions Duodenal CD8+ TRM apoptosis related to functional changes in lysosomes and lipid metabolism points to impaired gut adaptive immunity specifically in patients with AUD who developed early ALD.
 
The upper trajectory presents median annual taxable earnings in adult age in patients diagnosed with childhood‐onset inflammatory bowel disease (IBD) between 1990 and 2014 and general population reference individuals. The lower trajectory presents adjusted, absolute and relative, median differences in annual taxable earnings between patients diagnosed with childhood‐onset IBD between 1990 and 2014 and general population reference individuals (dots represent median differences and lines the 95 confidence interval for each estimate).
Median annual taxable earnings in adult age by sex in patients diagnosed with childhood‐onset inflammatory bowel disease (IBD) between 1990 and 2014 and general population reference individuals
The upper trajectory presents median annual taxable earnings in adult age in patients diagnosed with childhood‐onset inflammatory bowel disease (IBD) between 1990 and 2014 exposed to IBD‐related surgery or long‐term (>30 days) inpatient treatment (with IBD as the main diagnosis) during childhood and general population reference individuals. The lower trajectory presents adjusted, absolute and relative, median differences in annual taxable earnings between patients diagnosed with childhood‐onset IBD between 1990 and 2014 exposed to IBD‐related surgery or long‐term inpatient treatment during childhood and general population reference individuals (dots represent median differences and lines represent the 95 confidence interval for each estimate).
Article
Background IBD with onset during childhood seems to represent a severe disease phenotype with increased morbidity. We have previously demonstrated that children with IBD have significantly lower final grades in compulsory school compared to healthy peers. Aim To evaluate the association of childhood‐onset IBD with a later professional career and subsequent earnings. Methods We identified 5404 individuals diagnosed with childhood‐onset (<18 years) IBD between 1990 and 2014 (2818 with ulcerative colitis and 2818 with Crohn's disease) in the Swedish National Patient Register. Patients were matched with 10 general population reference individuals by sex, birth year, and place of residence (n = 51,295). Data on earnings during 1992–2017 were obtained through the longitudinal integration database for health insurance and labour market studies. Earnings were converted into Euros (inflation‐adjusted to 2019). The differences in earnings between patients and general population reference individuals were calculated through quantile regression. Results Patients with childhood‐onset IBD had significantly lower annual taxable earnings from ages 20 to 30 (adjusted median annual income difference (AMAID) at age 30: −5.4% [95% CI −9.1% to −1.8%]). In particular, annual taxable earnings through early adult age were lower in patients who, during childhood, had had surgery or long‐term inpatient treatment for IBD (AMAID at age 30: −16.3% [95% CI ‐24.7% to −7.9%]). Conclusions Overall, the negative influence of disease on earnings in early adult age was modest for patients with childhood‐onset IBD. The markedly larger negative income gap from ages 20 to 30 in patients with more severe IBD during childhood should be recognised.
 
Hazard ratios for (A) incident colorectal cancer diagnosis and (B) colorectal cancer death during all available follow‐up time (1969–2017 in Sweden and 1977–2011 in Denmark) in patients with Crohn's disease and ulcerative colitis and matched general population comparators. Numbers represent: Number of events in IBD patients/1000 person‐years of follow‐up, hazard ratio (95% confidence interval).
Cause‐specific hazard ratios for transitions from the start of follow‐up to colorectal cancer diagnosis, colorectal cancer death and other death, in patients with inflammatory bowel disease (Crohn's disease [CD] and ulcerative colitis [UC]) and the matched reference population.
Incidence rate of colorectal cancer (CRC) per month in relation to the date of inflammatory bowel disease (IBD) diagnosis in patients with elderly‐onset IBD (60–69 years, 70–79 years, 80+ years and overall, at diagnosis).
Adjusted hazard ratio (HR) for colorectal cancer (CRC) diagnosis (left panel) and death (right panel) in patients with Crohn's disease (CD) and ulcerative colitis (UC), excluding the first year of follow‐up (FU). Data are presented by calendar year in relation to a matched reference population.
Colorectal cancer in elderly‐onset inflammatory bowel disease patients eligible for cancer surveillance according to international guidelines: Hazard ratios for (A) incident colorectal cancer diagnosis and (B) colorectal cancer death during all available follow‐up time (1969–2017 in Sweden and 1977–2011 in Denmark) in patients with Crohn's disease and ulcerative colitis, at risk after 8 years of follow‐up or from the date of a primary sclerosing cholangitis diagnosis, and matched general population comparators. Numbers represent number of events in IBD patients/1000 person‐years of follow‐up, hazard ratio (95% confidence interval).
Article
Background Previous research indicates that the increased relative risk of colorectal cancer (CRC) in inflammatory bowel disease (IBD) is limited to young‐onset IBD. Aim To estimate risks of incident CRC and death from CRC in elderly‐onset IBD Methods Patients diagnosed with IBD at age ≥ 60 years between 1969 and 2017 were identified using Danish and Swedish National Patient Registers and histopathology data. We linked data to Cancer and Causes of Death Registers and used Cox regression to estimate hazard ratios (HRs) for CRC diagnosis and death compared to matched (by sex, age, and region) IBD‐free individuals. Results Among 7869 patients with Crohn's disease followed for 54,220 person‐years, and 21,224 patients with ulcerative colitis (UC) followed for 142,635 person‐years, 2.10% and 1.90% were diagnosed with CRC, compared to 2.26% and 2.34% of reference individuals (median follow‐up 6 and 7 years). The incidence of CRC was elevated during the first year after IBD diagnosis: 4.36 (95% CI = 3.33–5.71) in Crohn's disease and 2.48 (95% CI = 2.03–3.02) in UC, but decreased after the first year of follow‐up: 0.69 (95% CI = 0.56–0.86) and 0.78 (95% CI = 0.69–0.88). Once diagnosed with CRC, the risk of CRC death was similar for IBD patients and the general population. Conclusion The excess risk of CRC in elderly‐onset IBD was probably due to bias and not observed beyond the first year. From 2010, the HR for CRC diagnosis more than 1 year after initial IBD diagnosis was lower than in the largely unscreened reference population, supporting the benefit of endoscopic screening and surveillance in patients with IBD.
 
Intra‐epithelial peak eosinophil counts in biopsies taken at lower (A) and upper (B) oesophageal third levels in 18 paediatric and adult patients with eosinophilic oesophagitis triggered by milk with histological and clinical remission at baseline and after 8 weeks of sterilised cow's milk challenge. Changes in symptoms before and after sterilised milk challenge (measured by dysphagia symptom score) (C). Colour lines represent individual patients who tolerated or reacted to sterilised milk.
Significant changes from baseline in weekly intake of different nutrients in a cohort of patients with milk‐triggered eosinophilic oesophagitis who were fed with sterilised milk. Changes in saturated fatty acids (A), medium chain triglycerides (C) and calcium (E) weekly intake before and after sterilized milk consumption. Differences in the weekly intake of saturated fatty acids (B), triglycerides (D) and calcium (F) in patients with EoE, at Baseline and at the Final week of the study period, according to patient' status of tolerance to sterilized milk.
Health‐related quality of life (QoL) measured by the eosinophilic oesophagitis (EoE)‐QoL‐A questionnaire in patients with EoE triggered by milk at baseline (while on disease remission) and at 8 weeks after challenge with sterilised cow's milk. Median and interquartile ranges (IQR) are represented in the boxes, with whiskers (vertical lines) extending to a limit of ±1.5 IQRs. Changes in the five dimensions that compose the total EoE‐QoL‐A score are shown by patients who tolerated (A) and were reactive (B) to sterilised milk. In addition, changes from baseline scores are shown for patients who were tolerant and reactive to sterilised cow's milk (C).
Article
Background Cow's milk protein is the main food trigger for eosinophilic oesophagitis (EoE) in children and adults and should be continuously avoided once identified as such. Aim To evaluate tolerance of sterilised cow's milk (boiled instead of UHT processing) with regard to maintenance of EoE remission, health‐related quality of life (HRQoL), nutritional intake and allergic sensitisation in patients of all ages with milk‐triggered EoE Methods We prospectively recruited patients in whom cow's milk was demonstrated to trigger EoE after an empirical food elimination diet‐based study. They were given 200 ml of sterilised cow's milk twice daily for 8 weeks. Endoscopic assessment, peak eosinophil counts, oesophageal‐related symptoms, HRQoL, blood eosinophils, eosinophil cationic protein (ECP), skin prick test and serum total and specific immunoglobulin E (IgE) to major milk proteins were monitored before and after sterilised milk intake. Results Eighteen patients (13 male) in EoE remission underwent a sterilised milk challenge. Twelve maintained EoE remission (<15 eos/hpf) while EoE recurred in the remaining six. Endoscopy deteriorated in non‐tolerant patients. HRQoL scored well at baseline and was maintained among sterilised milk‐tolerant patients, but deteriorated in reactive ones. No significant changes in blood eosinophil count, ECP, tryptase and total and milk‐specific IgE serum levels were observed from baseline. However, cow's milk‐specific IgE increased slightly in non‐tolerant patients. Clinic and histological remission were maintained in patients who regularly consumed sterilised milk for 1 year. Conclusion Sterilised milk did not trigger EoE in two‐thirds of patients with documented milk‐induced EoE, either in the short term or in the long term.
 
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Javier P Gisbert
  • Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria Princesa (IIS-IP), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD)
Ancha Baranova
  • George Mason University
Nicholas Talley
  • University of Newcastle
William J Sandborn
  • University of California, San Diego
Jan Tack
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