Therapeutic Advances in Gastroenterology最新文献

Background: Treatment options for patients with refractory inflammatory bowel disease (IBD) or concomitant IBD and extraintestinal manifestations (EIM) are often limited.

Objective: This study aimed to examine the efficacy and safety of combining biologics or small molecules in patients with refractory IBD, active EIM, or active immune-mediated inflammatory disease (IMID).

Design: This was a retrospective and multicenter study.

Methods: We retrospectively collected demographics and disease characteristics from 47 patients with IBD who received dual-targeted therapy in 3 hospitals from January 2022 to June 2024. The primary endpoint was clinical remission based on the Harvey-Bradshaw index or patient-reported outcome 2 after at least 4 months of combination therapy. The secondary endpoints included clinical response, endoscopic response, and endoscopic remission, as well as all adverse events that occurred within the period of combination therapy.

Results: In total, 47 IBD patients including 37 with refractory IBD, 5 with active EIM, and 5 with active IMID received dual-targeted therapy, of which 37 achieved clinical response (78.7%) and 27 achieved clinical remission (57.4%) at a median follow-up time of 13.0 months. Among these 47 patients, 29 patients underwent endoscopic follow-up, of which 15 (51.7%) achieved endoscopic response and 8 (27.6%) achieved endoscopic remission at a median follow-up time of 9.0 months. Mild and moderate adverse events were reported in 17 (36.2%) patients within the period of combination therapy, and serious adverse events requiring hospitalization occurred in 1 patient (2.1%).

Conclusion: The combination therapy of biologics and small molecules for refractory IBD or those with concomitant EIM/IMID is effective and safe.

Background: Despite its significant health burden, there is a lack of national-level temporal patterns in gastrointestinal bleeding (GIB) mortality.

Objectives: To comprehensively decipher the annual and monthly trend of GIB-related mortality in the United States.

Design: Cross-sectional study.

Methods: We analyzed the National Vital Statistic System database, which documents more than 99% of the annual deaths in the United States for GIB-related deaths from January 2010 to May 2023. Annual and monthly age-standardized mortality rates were estimated and categorized by age, sex, and bleeding site. Joinpoint regression was performed for trend analysis. Prediction modeling was conducted to determine the GIB-associated excess mortality.

Results: A total of 529,094 and 210,641 GIB-associated deaths occurred before and after 2020, respectively. Following a stably decreasing trend between 2010 and 2019, there was an excess mortality rate during the pandemic which peaked in 2021. The monthly mortality trend showed spikes corresponding to the outbreak of variants. Importantly, excess GIB-related mortality resolved in 2023, with the convergence of predicted and observed mortality rates. Subgroup analysis showed that young males (aged 19-44 years) were affected the most during the pandemic, with excess mortality rates of 35.80%, 52.77%, and 31.46% in 2020, 2021, and 2022, respectively. While the increasing trend of upper GIB was accentuated during the pandemic, lower GIB showed a reversal of the pre-pandemic decreasing trend.

Conclusion: Our findings demonstrate the trend of GIB-related mortality, underscoring an increased excess death during the pandemic followed by a resolution in 2023. We identify subpopulations vulnerable to the pandemic.

Background: The efficacy of the 14-day esomeprazole-amoxicillin (EA) dual therapy in eradicating Helicobacter pylori (H. pylori) has been widely discussed previously. Vonoprazan, a novel potassium-competitive acid blocker, presents rapid, potent, and long-lasting acid inhibitory effects compared to esomeprazole. However, there is currently a scarcity of direct comparisons between the 10-day vonoprazan-amoxicillin (VA) and the 14-day EA dual therapy for H. pylori eradication.

Objectives: This study aimed to compare the efficacy and safety of the 10-day VA and the 14-day EA dual therapy for H. pylori first-line eradication.

Design: This study was a prospective, multicenter, open-label, randomized controlled trial.

Methods: The study was conducted at 10 hospitals in China. In total, 570 newly diagnosed H. pylori-infected patients were recruited from April 2023 to February 2024. These patients were randomly assigned to either the 10-day VA group (vonoprazan 20 mg twice daily + amoxicillin 1000 mg three times daily) or the 14-day EA group (esomeprazole 20 mg four times daily + amoxicillin 750 mg four times daily). The primary outcome was the eradication rate, with secondary outcomes including adverse events and compliance.

Results: The 10-day VA regimen outperformed the 14-day EA regimen in terms of eradication rates in intention-to-treat (ITT) analysis (85.4% vs 76.7%, p = 0.008), modified ITT analysis (90.7% vs 84.8%, p = 0.036), and per-protocol (PP) analysis (91.1% versus 85.5%, p = 0.047). The non-inferiority p-values in all three analyses were less than 0.001. No statistically significant difference was observed in the incidence of adverse events between the two groups (9.1% vs 11.7%, p = 0.308). The 10-day VA regimen demonstrated higher compliance compared to the 14-day EA regimen (p = 0.006).

Conclusion: The 10-day VA dual therapy showed a satisfactory eradication rate of 91.1% (PP analysis), demonstrating good safety and better compliance compared to the 14-day EA dual therapy as the first-line eradication.

Trial registration: This trial was registered in the Chinese Clinical Trial Registry (registration number: ChiCTR2300070475) on April 12, 2023.

Background: Early biologic intervention after diagnosis has shown improved clinical and endoscopic outcomes in patients with Crohn's disease (CD), while very little is known about the effectiveness of early versus late administration of Ustekinumab (UST).

Objectives: We aimed to compare early versus late UST use in managing CD and identify potential predictors associated with clinical and endoscopic outcomes.

Design: This was a retrospective observational study.

Methods: This study included patients with CD who started UST treatment from 2020 to 2023 in our center. Clinical and endoscopic outcomes were compared between early stage (⩽24 months) and later-stage (>24 months) groups at 6 months after starting UST therapy, and clinical predictors associated with any of the outcomes were assessed by logistic regression model. Furthermore, time-to-event analyses were applied to observe CD-related prognosis during follow-up.

Results: This study included 237 patients with CD, with 44.3% (n = 105) starting UST at the early stage and 55.7% (n = 132) at the later stage. Patients with early UST use demonstrated significantly higher rates of clinical and endoscopic remissions as compared to those with late UST use at 6 months after treatment. After adjusting for disease-related factors using multivariate logistic regression analysis, active perianal disease and severe disease were negatively associated with clinical and endoscopic remission in both early and late UST use groups. Finally, early UST administration was associated with a more favorable long-term outcome in terms of overall hospitalization and treatment escalation during follow-up.

Conclusion: Starting UST therapy in the early stage of CD especially within the first 6 months was associated with high rates of clinical and endoscopic remission and a low rate of CD-related complications.

Background: Immune checkpoint inhibitor (ICI)-induced colitis is a significant adverse event associated with ICI therapy, known to be linked to increased cytotoxic T-cell activity.

Objectives: To compare T-cell subsets based on the endoscopic features of ICI-induced colitis and to compare these findings with those of inflammatory bowel disease (IBD).

Design: Prospective cohort study.

Methods: We analyzed patients with ICI-induced colitis, confirmed through both endoscopic and histological evaluation. Biopsy specimens were examined using multiplex immunohistochemistry to assess their immune cell profile. Clinical outcomes were analyzed. Immune cell profiles were compared based on their endoscopic features and contrasted with those of patients with IBD.

Results: Seventeen patients with ICI-induced colitis were included in the study. All patients showed clinical improvement after treatment, and steroids were administered to 11 patients (64.7%). Based on endoscopic features, the patients were classified as Crohn's disease (CD)-like (n = 3, 17.6%), ulcerative colitis (UC)-like (n = 9, 52.9%), or microscopic colitis (MC)-like (n = 5, 29.4%). In ICI-induced colitis, cytotoxic T cells (Tc cells) were more predominant than helper T cells (Th cells) (p = 0.053), and this trend was most pronounced in the MC-like subtype (p = 0.020). When comparing the number of CD8+ cells infiltrating the crypts, both the UC-like and MC-like subtypes had significantly more infiltrating cells than the CD-like subtype (p = 0.008 and p = 0.016, respectively). In comparison to IBD, IBD exhibited a Th-dominant profile, whereas CD-like ICI-induced colitis had a lower Th cell density than CD (p = 0.032) and UC-like ICI-induced colitis had a higher Tc density than UC (p = 0.045).

Conclusion: Analysis of T-cell subsets of ICI-induced colitis revealed a Tc-dominant profile, contrasting with the Th dominance observed in patients with IBD. The Tc-dominant profile was evident in UC-like and MC-like subtypes, with significant crypt infiltration by CD8+ cells. Tc may play an important role in the pathophysiology of ICI-induced colitis.

Background: Relapse after corticosteroid withdrawal in eosinophilic esophagitis is not well understood.

Objectives: Budesonide oral suspension (BOS) 2.0 mg twice daily (b.i.d.) was evaluated in two consecutive phase III studies (12 and 36 weeks, respectively). For clinicopathologic responders after 12 weeks of BOS treatment, we assessed randomized treatment withdrawal for up to 36 weeks of therapy.

Design: Post hoc analysis of a phase III, double-blind, randomized withdrawal study.

Methods: Clinicopathologic responders (⩽6 eosinophils per high-power field (eos/hpf) and ⩾30% reduction in Dysphagia Symptom Questionnaire (DSQ) score from baseline) after 12 weeks of BOS were randomized to continue BOS 2.0 mg b.i.d. (BOS-BOS) or withdraw to placebo (PBO; BOS-PBO) for up to 36 weeks. Relapsers (⩾15 eos/hpf (⩾2 esophageal regions) and ⩾4 days of dysphagia (DSQ)) could reinitiate BOS 2.0 mg b.i.d. This post hoc analysis assessed a more clinically relevant relapse definition (⩾15 eos/hpf (⩾1 esophageal region) and ⩾4 days of dysphagia (DSQ)) for BOS-BOS versus BOS-PBO patients over 36 weeks. To account for BOS-PBO patients who reinitiated BOS before week 36, patients' last observations before reinitiating BOS were carried forward (last observation carried forward (LOCF)) for histologic, symptom, and endoscopic efficacy endpoints (at weeks 12 and 36).

Results: Of 48 patients included (BOS-BOS, n = 25; BOS-PBO, n = 23), significantly more BOS-PBO than BOS-BOS patients relapsed over 36 weeks using this post hoc relapse definition (60.9% vs 28.0%; p = 0.022). More BOS-BOS than BOS-PBO patients maintained histologic responses (all thresholds) and showed improvements in symptom and endoscopic efficacy endpoints.

Conclusion: More BOS-PBO than BOS-BOS patients relapsed, determined by a more clinically relevant post hoc relapse definition. Using LOCF, more BOS-BOS than BOS-PBO patients also maintained or had improvements in efficacy endpoints.

Trial registration: ClinicalTrials.gov identifiers (https://clinicaltrials.gov/): NCT02605837, NCT02736409.

Background: Colorectal adenomas (CAs) represent a significant global health issue, particularly in China, where lifestyle modifications have contributed to their increased prevalence. These adenomas are precursors to colorectal cancer. While high-fiber diets have been shown to decrease risk, the implications of food-specific serum immunoglobulin G reactivity (FSsIgGR) on CAs remain uncertain and warrant further investigation.

Objectives: To investigate the association between FSsIgGR and the occurrence of CAs in the Chinese population, assess the mediating influence of body mass index (BMI), and offer insights into potential prevention strategies.

Design: A retrospective cross-sectional study.

Methods: This study is based on 8796 individuals who underwent colonoscopy at the Second Medical Center of Chinese PLA General Hospital from 2017 to 2021. We examined the relationship between FSsIgGR and CAs using logistic regression, controlling for various confounders. Interaction effects were explored through subgroup analysis. We addressed missing data using multiple imputation and confirmed the robustness of our findings through sensitivity analysis. The role of BMI as a mediator was quantified using structural equation modeling.

Results: The cohort comprised 2703 patients diagnosed with CAs and 6093 polyp-free controls, with an average age of 50.1 years, of whom 70.1% were male. The analysis revealed a significant inverse association between FSsIgGR and the incidence of CAs (adjusted odds ratio = 0.97; 95% confidence interval: 0.95-0.99; p < 0.001). Dose-response analysis indicated a linear reduction in CAs risk correlating with an increased number of IgG-positive food items. Structural equation modeling showed that BMI mediated 6.02% of the effect on CAs risk (p = 0.038).

Conclusion: Our findings suggest that FSsIgGR correlates with a reduced risk of developing CAs, with BMI partially mediating this effect. These results add a novel dimension to CAs risk assessment and prevention, highlighting potential dietary interventions.

Background: Esophagogastric junction outflow obstruction (EGJOO) is a manometric diagnosis based on Chicago Classification version 4.0 (CC4.0) that requires confirmatory testing for clinical relevancy. However, it is still unclear which patients will respond to therapy.

Objectives: To evaluate manometric and clinical predictors of abnormal confirmatory testing for patients with EGJOO.

Design: This was a prospective observational study of patients with manometric EGJOO and chest pain or dysphagia who underwent confirmatory testing.

Methods: Patients with EGJOO on manometry were enrolled and underwent timed barium esophagram or endoFLIP. A subset of patients was given validated surveys, including Eckardt scores (ES) and PROMIS-10.

Results: For patients with a CC4.0 EGJOO diagnosis, abnormal peristalsis (OR = 7.0, 95% CI = 1.01-44.6, p = 0.04) and increases in ES (OR = 2.34 95% CI = 1.13-4.86, p = 0.02) were associated with positive confirmatory testing.

Conclusion: Patients with potentially actionable EGJOO were more likely to have an abnormal peristaltic subtype of EGJOO or higher ES.

Crohn's disease (CD) is a chronic, complex inflammatory disorder of the gastrointestinal tract that presents significant therapeutic challenges. Despite the availability of a wide range of treatments, many patients experience primary non-response, secondary loss of response, or adverse events, limiting the overall effectiveness of current therapies. Clinical trials often report response rates below 60%, partly due to stringent inclusion criteria. Emerging therapies that target novel pathways offer promise in overcoming these limitations. This review explores the latest investigational drugs in phases I, II, and III clinical trials for treating both luminal and perianal CD. We highlight promising therapies that target known mechanisms, including selective Janus kinase inhibitors, anti-adhesion molecules, tumor necrosis factor inhibitors, and IL-23 selective inhibitors. In addition, we delve into novel therapeutic strategies such as sphingosine-1-phosphate receptor modulators, miR-124 upregulators, anti-fractalkine (CX3CL1), anti-TL1A, peroxisome proliferator-activated receptor gamma agonists, TGFBRI/ALK5 inhibitors, anti-CCR9 agents, and other innovative small molecules, as well as combination therapies. These emerging approaches, by addressing new pathways and mechanisms of action, have the potential to surpass the limitations of existing treatments and significantly improve CD management. However, the path to developing new therapies for inflammatory bowel disease (IBD) is fraught with challenges, including complex trial designs, ethical concerns regarding placebo use, recruitment difficulties, and escalating costs. The landscape of IBD clinical trials is shifting toward greater inclusivity, improved patient diversity, and innovative trial designs, such as adaptive and Bayesian approaches, to address these challenges. By overcoming these obstacles, the drug development pipeline can advance more effective, accessible, and timely treatments for CD.

Background: Morphological and functional cardiac involvement is rarely described in patients with inflammatory bowel disease (IBD) but there is evidence that they have an increased risk of cardiovascular (CV) events despite the lower prevalence of traditional CV risk factors.

Objectives: Our systematic review and meta-analysis examined the relationship between IBD and cardiac function, namely the incidence of heart failure (HF) and subclinical echocardiographic changes.

Data sources and methods: Two medical databases, PubMed and Scopus, were systematically searched up to September 2022 to identify all studies reporting HF and/or echocardiographic changes in IBD patients.

Results: The qualitative analysis comprised a total of 18 studies (14 retrospective and 4 prospective studies) involving 59,838 patients. IBD was associated with subtle systolic and diastolic alterations, vascular dysfunction, increased risk for HF hospitalizations, and globally worse CV outcomes. Nine studies were included in the meta-analysis. In the IBD population, we found statistically significant reduced early to late diastolic transmitral flow (E/A), higher E to early diastolic mitral annular tissue velocity (E/e'), and decreased global longitudinal strain. Increased left atrial diameter and area were also present in IBD patients but no statistical significance was reached. Inter-atrial and right intra-atrial conduction delays were observed.

Conclusion: The IBD population has an increased risk for left ventricular and atrial dysfunction, vascular changes, arrhythmias, and HF hospitalization. Screening with sensitive imaging like speckle tracking echocardiography could identify early subclinical changes. IBD is in fact a CV risk factor and tight inflammation control may reduce CV risk.