Therapeutic Advances in Gastroenterology最新文献

Background: Eosinophilic esophagitis (EoE) is characterized by eosinophil infiltration into the esophageal tissue and esophageal dysfunction. In the United States, EoE has an estimated prevalence of 26-163 cases per 100,000 people. Real-world data concerning the clinical burden of EoE and treatment patterns in the United States are limited.

Objectives: To describe the demographics, clinical characteristics, symptoms, comorbidities, treatment pathways, and healthcare resource utilization (HCRU) and costs among patients with EoE in the United States.

Design: Retrospective analysis.

Methods: A study of pediatric and adult patients diagnosed with incident EoE (full incident EoE cohort) using Merative™ MarketScan^® health insurance claims data between January 1, 2017, and June 30, 2020. A subset of patients (matched incident EoE cohort) was matched with patients without EoE for age, sex, and payor (matched control cohort). Follow-up was 12 months after the EoE diagnosis date. All statistics are descriptive.

Results: The full incident EoE cohort included 20,290 patients (62.61% were male; median (range) age was 38 (1-93) years); 13,710 patients (matched incident EoE cohort) were matched to 54,727 patients without EoE (matched control cohort). During baseline in the full incident EoE cohort, the most common comorbidities within the Charlson Comorbidity Index (CCI) were chronic pulmonary disease (19.79%), hypertension (15.77%), and depression (9.71%); the most common non-CCI comorbidities were reflux esophagitis (38.84%), allergic rhinitis (19.14%), and depression/anxiety (19.07%). During follow-up, the most frequently reported symptoms were acid reflux/heartburn (56.02%), dysphagia (51.89%), and abdominal pain (30.50%). The most common medications first observed were proton pump inhibitors (42.51%) and oral corticosteroids (12.26%). Overall, a larger proportion of the matched incident EoE cohort had visits to any healthcare setting during baseline and follow-up than the matched control cohort. Correspondingly, the annualized, all-cause healthcare costs per patient were higher in the matched incident EoE cohort than in the matched control cohort at baseline (mean (standard deviation), $10,185 ($29,455); median, $3248 vs $4906 ($20,601); $632) and during follow-up ($15,103 ($35,484); $6708 vs $5200 ($21,314); $651).

Conclusion: Considerable disease burden is experienced by patients with EoE (before and after diagnosis), which contributes to a high level of HCRU and increased costs.

Background: Proton pump inhibitors (PPIs) use has been linked to adverse outcomes in patients with inflammatory bowel disease (IBD). However, it remains unknown whether this is due to protopathic bias (i.e., when the outcome precedes exposure).

Objectives: We aimed to conduct a propensity-weighted study of the association between PPI use and IBD-related hospitalizations and surgery in patients with IBD.

Design: Historical propensity score (PS)-weighted cohort study.

Methods: We identified all Danish residents diagnosed with IBD in 2000-2022 in the Danish National Patient Registry. We analyzed separate PPI treatment episodes allowing an individual to contribute with more than one PPI episode. We used PS-weighted Cox regression to estimate the hazard ratio (HR) for IBD-related hospitalization and surgery for current PPI-users compared with current nonusers.

Results: We identified 50,460 patients with IBD (67% with ulcerative colitis, 33% with Crohn's disease). Five years after their diagnosis, two-thirds of patients with IBD had used PPI at some point and 10% were in current treatment. The weighted HR for IBD-related hospitalizations was 1.45 (95% confidence interval (CI): 1.38-1.52) during the first year after PPI prescription, and 1.16 (95% CI: 1.05-1.28) thereafter. The weighted HR for IBD-related surgery was 1.21 (95% CI: 1.11-1.32) the first year and 1.35 (95% CI: 1.18-1.54) thereafter.

Conclusion: We observed a 20%-40% higher rate of IBD-related hospitalization and surgery, the first year after PPI prescription in patients with IBD which most likely represents a protopathic bias, yet the rate of IBD-related surgery remained elevated more than 1 year after PPI prescription.

Background: A combination of immune checkpoint inhibitors and chemotherapy has emerged as standard therapy in advanced human epidermal growth factor receptor 2-negative advanced gastric cancer (AGC). However, the clinical benefit in patients with a low combined positive score (CPS) of 1-4 remains controversial.

Objectives: To evaluate the efficacy and safety of nivolumab plus chemotherapy in AGC patients with low CPS (1-4) in a real-world clinical setting.

Design: A retrospective single-center study conducted at Samsung Medical Center.

Methods: We analyzed outcomes in AGC patients with CPS 1-4 who received nivolumab in combination with capecitabine and oxaliplatin (XELOX) or fluorouracil, oxaliplatin, and leucovorin (FOLFOX) as first-line therapy between April 2021 and December 2024. Tumor response was assessed using Response Evaluation Criteria in Solid Tumor version 1.1. Progression-free survival (PFS) and overall survival (OS) were estimated using Kaplan-Meier methods.

Results: Of 336 patients receiving first-line nivolumab plus XELOX or FOLFOX, 63 had a CPS of 1-4. Median age was 61 years, and the most common CPS was 1, found in 26 patients (41%). One patient achieved a complete response (2%), and 25 patients achieved partial response (40%), for an overall response rate of 42%. Stable disease was observed in 23 patients, a disease control rate of 76%. Median PFS was 5.8 months (95% confidence interval (CI), 4.9-6.7), and median OS was 15.0 months (95% CI, 13.2-18.7). Any-grade adverse events were reported in 92% of patients, while grade 3 or 4 treatment-related adverse events occurred in 61% of patients, most commonly anemia and neutropenia.

Conclusion: This real-world retrospective study suggests modest efficacy of AGC patients with low CPS treated with nivolumab with chemotherapy. Further studies are needed to determine the optimal treatment strategy and to identify predictive biomarkers for therapy selection in patients with low-CPS AGC.

Background: Patients with ulcerative colitis (UC) usually experience anxiety symptoms that seriously affect their quality of life, treatment, and prognosis. Dysbiosis of the gut microbiota plays an important role in UC and mental illness. However, little is known about the role of the gut microbiota in UC patients with anxiety.

Objectives: To identify the gut-microbiome and fecal metabolome profiles uniquely associated with comorbid anxiety in UC patients and to explore potential biomarkers for diagnosis.

Design: A cross-sectional, two-group comparative study.

Methods: To study the underlying association between them, we recruited 126 UC patients in this study, including 78 with anxiety and 48 without anxiety. A total of 102 fecal samples were collected for metagenomic sequencing and metabolome sequencing. Microbial diversity, differential gut microbiota, functional pathways, and metabolites were analyzed. Multivariable logistic regression was used to identify independent risk factors associated with anxiety in UC patients, while Spearman correlation was employed to explore microbe-metabolite interactions and the performance of potential biomarkers.

Results: We found that disease severity, steroid usage, and abdominal pain may promote the occurrence of anxiety. Compared to UC patients without anxiety, UC patients with anxiety had low fecal microbial community diversity, with an increase in the species Haemophilus sp. HMSC71H05 and Corynebacterium durum, and a decrease in the species Roseburia intestinalis (RI), Bifidobacterium longum (BL), and Enterococcus hirae. The metabolic pathways driven by the gut microbiota were disrupted. Moreover, the levels of most metabolites (such as L-kynurenine) were increased in the feces, while the levels of a few metabolites decreased, including indole-2-carboxylic acid, N-demethylmirtazapine, and tauroursodeoxycholic acid.

Conclusion: Our research further revealed that these gut microbiota and metabolites are highly correlated. This study provides a new perspective for understanding the occurrence and development of anxiety in UC patients, suggesting that RI and BL may serve as potential candidate biomarkers to diagnose UC patients with anxiety.

Background: Clostridioides difficile infection (CDI) is a significant complication in patients with acute severe ulcerative colitis (ASUC).

Objectives: To assess the clinical outcomes of hospitalized ASUC patients with CDI.

Design: Retrospective, single-center study.

Methods: Medical records of ASUC patients admitted from December 1, 2008, to June 1, 2018, were reviewed. Primary outcomes included hospital duration, in-hospital colectomy rates, and escalation of immunosuppression at discharge. Secondary outcomes included readmission rates and use of salvage therapy.

Results: Among 410 ASUC patients, 67 tested positive for CDI. No significant differences in hospital duration, colectomy rates, or readmission rates were found between CDI-positive and CDI-negative groups. CDI-positive patients were less likely to receive intravenous corticosteroids.

Conclusion: A positive CDI test in ASUC patients does not correlate with worse clinical outcomes. Based on these results, CDI should be ruled out and treated in hospitalized patients with severe ulcerative colitis without delaying ASUC management.

Background: The current standard treatment paradigm for patients with unresectable and non-metastatic hepatocellular carcinoma (HCC) involves transarterial chemoembolization (TACE) as the primary local therapeutic modality, followed by systemic therapy upon disease progression. Emerging evidence suggests that the concurrent integration of immunotherapy and targeted therapy with TACE may yield synergistic therapeutic effects. Recent phase III trials-including EMERALD-1, LEAP-012, and TALENTACE-have provided important insights into the efficacy and safety of this multimodal approach.

Objectives: This meta-analysis aimed to quantitatively synthesize the efficacy and safety of first-line TACE combined with immunotherapy and targeted therapy versus TACE alone in patients with unresectable, non-metastatic HCC.

Design: Systematic review and meta-analysis of phase III randomized controlled trials (RCTs).

Data sources and methods: A systematic search of PubMed and major conference proceedings was conducted up to July 6, 2025. Three phase III trials (EMERALD-1, LEAP-012, TALENTACE) were included. Pooled hazard ratios (HRs) for progression-free survival (PFS), odds ratios (ORs) for objective response rate (ORR), and risk ratios (RRs) for adverse events (AEs) were calculated using fixed-effect or random-effects models.

Results: The combination of TACE with immunotherapy and targeted therapy demonstrated superior efficacy compared to TACE monotherapy. The pooled HR for PFS was 0.69 (95% confidence interval (CI): 0.60-0.79), indicating a significant delay in disease progression. The pooled OR for ORR was 1.83 (95% CI: 1.45-2.31), reflecting a markedly improved tumor response rate. However, overall survival (OS) data remain immature, and no statistically significant difference in OS was observed at this stage. In terms of safety, the combination therapy was associated with a higher incidence of AEs. Specifically, it significantly increased the risk of grade 3-5 AEs (RR: 1.88, 95% CI: 1.48-2.40) and serious AEs (RR: 1.65, 95% CI: 1.31-2.07).

Conclusion: First-line treatment with TACE combined with immunotherapy and targeted therapy significantly improves tumor response and prolongs PFS in patients with unresectable and non-metastatic HCC, albeit at the cost of increased toxicity. This combination strategy represents a promising advancement in the therapeutic landscape for HCC, offering meaningful improvements in oncologic outcomes while highlighting the need for careful toxicity management.

Trial registration: International Prospective Register of Systematic Reviews (PROSPERO; CRD420250652613).

Background: Unlike infliximab, ustekinumab (UST) has shown inconsistent associations between drug concentration and clinical efficacy across studies, with varying cutoff therapeutic trough levels (TLs) proposed.

Objectives: Given that patients have different histories of biologic use, we aimed to evaluate whether therapeutic TLs of ustekinumab require optimization in patients with Crohn's disease.

Design: Cohort study.

Methods: To assess whether ustekinumab has a potential therapeutic cutoff value, we evaluated and compared its 1-year TLs in 14 biologic-naïve patients and in 26 patients who were prescribed the drug after experiencing a loss of response to previous biologic therapies.

Results: The mean TL in the biologic-naïve patients was 3.41 µg/mL, which was significantly higher than that in the biologic-experienced patients (1.46 µg/mL; p = 0.007). The duration of prior biologic therapy and disease activity correlated with the ustekinumab TLs. With regard to the optimal cutoff value for predicting deep remission at 1 year, the threshold was 2.34 µg/mL for the biologic-naïve patients (area under the receiver operating characteristic curve (AUC) = 0.909, p < 0.001) and 1.18 µg/mL for the biologic-experienced patients (AUC = 0.892, p < 0.001).

Conclusion: Ustekinumab TLs in patients may differ according to their prior exposure to biologic agents and disease activity. Accordingly, rather than applying a uniform threshold, ustekinumab levels should be interpreted using individualized, patient-specific strategies in clinical practice.

Background: Intestinal fibrosis-associated stricture can lead to bowel complications and subsequent surgeries in patients with Crohn's disease (CD), but there are no widely accepted biomarkers for intestinal fibrostenosis.

Objectives: This study aims to investigate the value of interleukins (IL) in detecting CD-related intestinal fibrostenosis.

Design: This is an observational study.

Methods: Transcriptomic profiling was performed from paired CD surgical resections containing non-involved and fibrostenotic segments. Data were integrated with a public dataset and a Luminex-based serum assay to identify fibrosis-related interleukins, which were further validated at mRNA and protein levels. Correlations with clinical indicators and surgical outcome were analyzed. Lastly, an in vitro assay was used to evaluate the pro-fibrotic effect of the candidate interleukin.

Results: Bulk RNA-sequencing and public dataset revealed increased expression of IL11 in the fibrostenotic intestinal segments of CD patients, which was further validated by real-time polymerase chain reaction and immunohistochemistry. The serum Luminex assay showed that serum IL11 is significantly increased in stricturing CD patients compared to that in non-stricturing CD patients. Clinically, serum IL11 was correlated with disease behavior (r = 0.343, p = 0.006), and increased IL11 expression was linked to a higher risk of subsequent surgery (log-rank p = 0.0055). Furthermore, single-cell RNA sequencing revealed that IL11 and its receptor IL11RA were mainly expressed by fibroblasts. In vitro, IL11 functionally promoted intestinal fibrosis.

Conclusion: IL11, mainly derived from fibroblasts, is enriched in fibrostenotic tissue of CD and promotes intestinal fibrosis. IL11 may serve as a potential biomarker for CD fibrostenosis.

Extra-intestinal manifestations (EIMs) commonly occur in patients with inflammatory bowel diseases (IBD) and contribute significantly to morbidity and reduced quality of life. Their management remains challenging. Recently, the development of Janus Kinase (JAK) inhibitors has expanded the therapeutic options of luminal IBD, and three JAK inhibitors, tofacitinib, upadacitinib, and filgotinib, have been approved for IBD treatment, while a growing body of evidence suggests that JAK inhibitors may be a promising therapeutic option for the management of EIMs, particularly those affecting the joints and skin. In this comprehensive review, we aim to provide the available evidence concerning the impact of JAK inhibitors on EIMs treatment and analyze their underlying mechanisms of action.

Background: Potassium-competitive acid blocker-based regimens, such as tegoprazan, have demonstrated promising efficacy for Helicobacter pylori eradication. In regions with high antibiotic resistance, such as Gansu Province, bismuth-containing quadruple therapy (BQT) remains the recommended first-line treatment. However, evidence on the efficacy and safety of high-dose tegoprazan-amoxicillin dual therapy (TA) remains limited.

Objectives: To compare the eradication rates and safety profiles of TA and BQT.

Design: Prospective, multicentre, randomised controlled trial.

Methods: Patients were enrolled from 10 centres across Gansu Province, China, between September and December 2024. Participants were randomised 1:1 to receive either BQT (esomeprazole 20 mg twice daily + bismuth potassium citrate 600 mg twice daily + amoxicillin 1000 mg twice daily + metronidazole 400 mg four times daily) or TA (tegoprazan 50 mg twice daily + amoxicillin 750 mg four times daily) for 14 days. The primary outcome was eradication rate. Secondary outcomes included adverse event (AE) rates, treatment compliance and cost-effectiveness.

Results: A total of 288 patients were randomised, with baseline characteristics well balanced between the TA and BQT groups (p > 0.05). Eradication rates for TA versus BQT were 68.06% (98/144) versus 81.25% (117/144) (difference, -13.19%; 95% confidence interval (CI): -22.95 to -3.43; p = 0.009; non-inferiority p = 0.736) in the intention-to-treat analysis; 69.01% (98/142) versus 81.82% (117/143; difference, -12.81%; 95% CI: -22.70 to -2.90; p = 0.011; non-inferiority p = 0.711) in the modified intention-to-treat analysis; and 72.59% (98/135) versus 89.31% (117/131; difference, -16.72%; 95% CI: -26.01 to -7.43; p < 0.001; non-inferiority p = 0.924) in the per-protocol analysis. AEs were less frequent with TA (8.30% vs 25.70%, p < 0.0001), with similar compliance rates (95.07% vs 91.61%, p = 0.241). Multivariate analysis indicated that long-term residence in the southern region of Gansu Province (including Longnan City and Tianshui) was significantly associated with higher eradication rates compared with the Hexi region (adjusted odds ratio = 5.46, p = 0.04), suggesting that geographical factors independently influenced treatment outcomes.

Conclusion: TA did not achieve non-inferiority to BQT and yielded significantly lower eradication rates. The inferior eradication efficacy of TA precludes its recommendation as a first-line therapy in high-resistance settings, such as Gansu.

Trial registration: This trial was registered on the Chinese Clinical Trial Registry with the registration number ChiCTR2400081873.