Therapeutic Advances in Gastroenterology最新文献

Background: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has complicated the management of inflammatory bowel diseases (IBD).

Objectives: This study aimed to assess the efficacy of different anti-SARS-CoV-2 vaccines under different treatments in IBD patients and identify predictive factors associated with lower serological response, including anti-tumor necrosis factor (anti-TNF) drug levels.

Design: A prospective, double-center study of IBD patients was conducted following messenger ribonucleotide acid (mRNA) and non-mRNA anti-SARS-CoV-2 vaccination.

Methods: Healthy control (HC) patients were enrolled to reduce bias. Baseline and control samples were obtained 14 days after the second dose to assess the impact of conventional and biological treatments. Clinical and biochemical activity, serological response level, and anti-TNF drug levels were measured.

Results: This study included 199 IBD (mean age, 40.9 ± 12.72 years) and 77 HC participants (mean age, 50.3 ± 12.36 years). Most patients (76.9%) and all HCs received mRNA vaccines. Half of the IBD patients were on biological treatment (anti-TNF 68.7%). Biological and thiopurine combined immunomodulation and biological treatment were associated with lower serological response (p < 0.001), and mRNA vaccination promoted better antibody levels (p < 0.001). Higher adalimumab levels caused lower serological response (p = 0.006). W8 persistence of anti-SARS-CoV-2 level was equal in IBD and HC groups. Vaccination did not aggravate clinical disease activity (p = 0.65).

Conclusion: Anti-SARS-CoV-2 vaccination is considerably efficacious in IBD patients, with mRNA vaccines promoting better antibody levels. The negative impact of combined biological treatment, especially with high adalimumab drug levels, on serological response to vaccination should be considered. Although midterm durability of vaccination is encouraging, more data are needed to expand the existing understanding on this issue.

Background: Readmission shortly after discharge is indicative of an increased disease severity for patients with ulcerative colitis (UC) and ineffectiveness to medical therapy, which may contribute to a dismal prognosis.

Objectives: This study aimed to explore prognostic variables with a nomogram to predict unplanned UC-related readmission within 1 year after discharge.

Design: A retrospective cohort study.

Methods: Electronic medical records of all UC patients treated at our center between 1 January 2014 and 31 June 2021 were reviewed. A comprehensive analysis of various characteristics, such as demographics, comorbidities, medical history, follow-up appointments, admission endoscopy, histopathologic features, etc., was used to determine the primary end point, which was unplanned UC-related calendar year readmission.

Results: We found that the unplanned UC-related readmission rate within 1 year was 20.8%. In multivariable cox analysis, the predictors of the Elixhauser comorbidity index [Hazard ratio (HR): 3.50, 95% confidence interval (CI): 1.93-6.37], regular follow-up (HR: 0.29, 95% CI: 0.16-0.53), any history of corticosteroid use (HR: 3.38, 95% CI: 1.83-6.27), seral level of C-reactive protein (HR: 1.01, 95% CI: 1.00-1.02), and the UC endoscopic index of severity (HR: 1.29, 95% CI: 1.05-1.57) independently predicted calendar year readmission after discharge. The established nomogram had a consistently high accuracy in predicting calendar year readmission in the training cohort, with a concordance index of 0.784, 0.825, and 0.837 at 13, 26, and 52 weeks, respectively, which was validated in both the internal and external validation cohorts. Therefore, UC patients were divided into clinically low-, high-, and extremely high-risk groups for readmission, based on the calculated score of 272.5 and 378.

Conclusion: The established nomogram showed good discrimination and calibration powers in predicting calendar year readmission in high-risk UC patients, who may need intensive treatment and regular outpatient visits.

The coronavirus disease 2019 (COVID-19) pandemic has had enormous implications for the care of patients with chronic liver disease (CLD), cirrhosis, and liver transplant (LT). Clinical outcomes of COVID-19 vary in patients with CLD and cirrhosis compared to healthy controls, and in patients with LT compared to patients without LT. Several special considerations apply to the approach to vaccination and treatment in patients with CLD and LT. The practice of liver transplantation has also been heavily impacted by the pandemic, including persistent reductions in living donor LT and increases in LT for an indication of alcohol-related liver disease. Recent medical society guidelines strive to standardize severe acute respiratory syndrome coronavirus 2 testing in donors and recipients and the approach to transplantation after recovered from COVID-19 infection, but certain controversies remain.

Background: The mainstay of treatment for microscopic colitis (MC) is budesonide. However, the optimal formulation and dosage of budesonide to induce and maintain remission has not yet been clearly demonstrated.

Objectives: To compare the data for efficacy and safety of treatments to induce and maintain remission for MC.

Design: We conducted a meta-analysis of randomised controlled trials (RCTs) comparing treatment with each other or placebo for induction and maintenance of clinical and histological remission in MC.

Data sources and methods: We searched MEDLINE (1946 to May 2021), EMBASE and EMBASE Classis (1947 to May 2021), the Cochrane central register of controlled trials (Issue 2, May 2021) and conference proceedings between 2006 and 2020. Results were reported as pooled relative risks (RRs) with 95% confidence intervals (CIs) to summarise the effect of each comparison tested, with treatments ranked according to p score.

Results: We identified 15 RCTs in total for the treatment of MC. Entocort 9 mg ranked first for clinical (RR: 4.89, CI: 2.43-9.83; p score: 0.86) and histological (RR: 13.39, CI: 1.92-93.44; p score 0.94) induction of remission, whilst VSL#3 ranked second for clinical induction (RR: 5.30, CI: 0.68-41.39; p score 0.81). Budenofalk 6 mg/3 mg alternate day dosing ranked first for clinical maintenance of remission (RR: 3.68, CI: 0.08-159.92, p-score 0.65). Entocort and Budenofalk were associated with the greatest adverse events for induction and maintenance of clinical remission, respectively, although the overall withdrawal numbers for treatment versus placebo groups were 10.9% (22/201) and 10.5% (20/190), respectively.

Conclusion: Entocort 9 mg/day ranked first among the treatment options in inducing remission and Budenofalk 6 mg/3 mg alternate day dosing for maintaining remission in the treatment of MC. Moving forward, mechanistic studies exploring the differences between Entocort and Budenofalk would be valuable whilst future RCT studies are needed in non-corticosteroidal maintenance, particularly looking into immunomodulators, biologics and probiotics.

Background: Deficient mismatch repair (dMMR) or microsatellite instability is one of the well-established molecular biomarkers in colorectal cancer (CRC). The efficiency of neoadjuvant chemotherapy (NAC) in locally advanced colorectal cancer (LACC) patients with dMMR is unclear.

Objectives: We assessed the tumor response and clinical outcome in LACC patients with dMMR received NAC.

Design: Retrospective, single-center analysis.

Methods: From 2013 to 2018, a total of 577 LACC patients with dMMR who underwent radical surgery were identified. Among them, 109 patients who received adjuvant chemotherapy were further screened out for analysis. According to whether receiving NAC or not, 109 patients were divided into two groups with the purpose of retrospectively analyzing their characteristics, treatment, and survival results, especially the 5-year disease-free survival (DFS) and 5-year overall survival.

Results: Baseline characteristics were matched between the two groups. One of 40 patients in NAC group recurred, while 13 of 69 patients in non-NAC group recurred. Univariate and multivariate analyses showed that NAC (hazard ratio: 0.115; 95% confidence interval: 0.015-0.897; p = 0.039) was independent influence factor for DFS. In NAC group, there were 13/40 (32.5%) patients for tumor regression grade 1 and 27/40 (67.5%) patients converted clinical positive N-stage into negative N-stage.

Conclusion: In this study, NAC was associated with better tumor downstaging and longer 5-year DFS in LACC patients with dMMR. Consequently, NAC might be an additional treatment choice when it comes to such patients in the future.

Background: Chromoendoscopy is preferred over high-definition white light endoscopy (HDWLE) for dysplasia surveillance in inflammatory bowel disease (IBD) patients, but is more time-consuming to perform and real-world evidence is limited. The prevalence of sessile serrated lesions (SSLs) in IBD patients is also unknown.

Objective: To determine the yield of polypoid and non-polypoid dysplasia and SSLs in IBD patients undergoing dysplasia surveillance and the associations for these lesions.

Design: A retrospective cohort study from a tertiary IBD centre.

Methods: A keyword search of the colonoscopy reporting system was performed. IBD patients with colonic disease that underwent colonoscopy for surveillance between 1 February 2015 and 1 February 2018 were included. Clinical, endoscopic and histopathological outcomes were extracted for the analysis.

Results: Of 2114 patients identified, 276 eligible colonoscopies in 126 patients were analysed. The median age at colonoscopy was 51 years (interquartile range: 42-58 years). 71/126 (56%) of colonoscopies were performed in male patients, with 57/126 (45%) having ulcerative colitis, 68/126 (54%) Crohn's colitis and 1/126 (0.79%) IBD-unspecified. The prevalence for any neoplasia was 75/276 (27%). The prevalence for all serrated lesions was 43/276 (16%). Increased age was a risk factor for finding a neoplastic lesion on both univariate and multivariate analyses. Chromoendoscopy was associated with twice the odds of finding a neoplastic lesion (odds ratio: 1.99, 95% confidence interval: 1.13-3.51, p = 0.02), on multivariate analysis. No factor was associated with an increased risk of finding a serrated lesion.

Conclusion: Significant neoplastic lesions and serrated lesions were detected in 27% and 16% of colonoscopies performed in IBD patients, respectively, with the highest yield in older patients. Chromoendoscopy significantly increased neoplasia yield compared to HDWLE and still has a robust utility in this pragmatic real-world study.

Inflammatory bowel diseases (IBD), including Crohn's disease (CD) and ulcerative colitis (UC), are lifelong diseases characterized by chronic inflammation of the gastrointestinal tract leading to its progressive and irreversible destruction. Whether early initiation of IBD-specific therapy impacts the long-term course of the disease remains unclear and has to be further explored in prospective disease-modification trials. Historically, surgery and hospitalization rates have been the surrogate markers to measure disease progression in IBD, providing an overview of the effectiveness of medical therapies. However, neither surgery nor hospitalization necessarily reflects a fail in therapeutic medical management, and many confounding factors make them biased outcomes. The Selecting Endpoints for Disease-Modification Trials consensus has defined the disease-modification endpoints required for these trials, including the impact of the disease on patient's life (health-related quality of life, disability, and fecal incontinence), the mid-term disease complications (bowel damage in CD, IBD-related surgery and hospitalizations, disease extension in UC, extra-intestinal manifestations, permanent stoma, short bowel syndrome), and the development of dysplasia/cancer and mortality in the long term. Most available data in the literature regarding the impact of current therapies on disease progression focused on anti-tumor necrosis factor agents and are based on retrospective or post-hoc studies. Thus, prospective disease-modification trials are pressingly required to explore the effectiveness of early intensified treatment in patients with severe disease or at risk for disease progression.

Background: The high-flow nasal cannula (HFNC) is a relatively recent method that provides high-flow, heated, humidified gas delivery.

Objectives: We compared HFNC (group HF) and conventional nasal cannula (NC) (group CO) during deep sedation with propofol and remifentanil for endoscopic submucosal dissection (ESD).

Design: Single-center, retrospective observational cohort study.

Methods: In this study, a total of 159 cases were analyzed (group CO, 71 and group HF, 88). We collected the data from electronic medical records from September 2020 to June 2021. The lowest oxygen saturation (SpO₂), incidence of hypoxia (SpO₂ < 90%), rescue interventions, and adverse events between the two groups were investigated.

Results: There were significant differences between the two groups in lowest SpO₂ and incidence of hypoxia [group CO versus group HF; 90.3 ± 9.7% versus 95.7 ± 9.0%, 25 (35.2%) versus 10 (11.4%); p < 0.001, p < 0.001; respectively]. Among the rescue interventions, the number of jaw thrust, patient stimulation, O₂ flow increase, and nasal airway insertion were significantly higher in the CO group than in the HF group. However, postprocedural chest X-ray showed higher rates of abnormal findings (atelectasis, aspiration, and pneumoperitoneum) in group HF than in group CO [group CO: 8 (11.3%) versus group HF: 26 (29.5%), p = 0.005]. In multivariable analysis, besides group CO, difficult type of lesion was the risk factor for hypoxia.

Conclusions: Compared to the conventional NC, HFNC provided adequate oxygenation and a stable procedure without significant adverse events during sedation for ESD. However, caution is needed to avoid complications associated with deep sedation and difficult type of lesions.

Background: Immunogenicity to antitumor necrosis factor alpha agents, such as infliximab (IFX), may lead to therapeutic failure.

Objectives: This study evaluated the relationship between free and total antibodies-to-infliximab (ATIs), trough levels (TLs) of IFX, and the response to dose intensification.

Design: We performed a prospective, observational study including pediatric patients with Crohn's disease (CD) receiving IFX maintenance therapy without dose intensification.

Methods: We compared clinical and laboratory outcomes according to the presence of free and total ATIs. Factors associated with response to IFX dose intensification were investigated by analyzing IFX TLs and free and total ATIs.

Results: Of the 98 patients, 9 patients had detectable free ATIs and 38 patients had total ATIs. Patients with free ATIs had significantly lower TLs (0.7 versus 5.1 µg/mL, p < 0.001) than patients without free ATIs. However, there was no difference in the IFX TLs according to the presence of total ATIs (p = 0.2523). Analysis of the 38 samples with total ATIs showed that response to dose intensification was significantly lower in patients with free ATIs than those without free ATIs (22.2% versus 65.5%, p < 0.001). In addition, free ATIs were the only factor with poor response to dose intensification [odds ratio (OR): 14.15, 95% confidence interval (CI): 1.31-151.97, p = 0.0140]. According to the receiver operating characteristic analysis, the optimal cutoff level indicating non-response to IFX dose intensification was 30.0 AU/mL for free ATIs concentration (area under curve, 0.792; 95% CI: 0.590-0.942; sensitivity, 60.0%; specificity, 96.7%; p = 0.0241).

Conclusion: Free ATIs, but not total ATIs, have a negative impact on the course of CD. Free ATIs are potential reliable biomarker for predicting the effect of dose intensification in patients with loss of response to IFX. Future studies based on serial and proactive therapeutic drug monitoring are required in the future.

Background: Since not all Crohn's disease (CD) patients respond adequately to ustekinumab therapy, biomarkers could aid to monitor treatment response and optimize therapeutic outcomes.

Objectives: To explore the dynamics of serum biomarker concentrations to monitor the response to ustekinumab treatment in CD patients.

Design: Retrospective, exploratory study to evaluate concentrations of serum cytokines and acute phase proteins and their relation to endoscopic remission in CD patients during ustekinumab treatment.

Methods: Serum concentrations of 16 proteins including cytokines and acute phase proteins were measured using the Mesoscale Discovery Platform in serum of healthy controls (n = 13), and CD patients (n = 61) at baseline (week 0), week 8 and week 24 during ustekinumab treatment. Endoscopic remission was defined as simple endoscopic score for CD (SES-CD) <3 after 6 months of therapy.

Results: Absolute concentrations of serum amyloid A protein (SAA; week 8), IL-6 (week 24), AGP (weeks 8 and 24), interferon (IFN)-γ (weeks 8 and 24), lipopolysaccharide binding protein (LBP; weeks 8 and 24) and IL-22 (weeks 8 and 24) were significantly lower in endoscopic remitters compared to non-responders (p-values ranging between <0.001 and <0.05). SAA (week 8) and AGP (week 24) were the biomarkers with the highest area under the ROC curve (AUROC; 0.761 and 0.760, respectively) for identifying patients in endoscopic remission, though their performance was not superior to C-reactive protein (CRP) or faecal calprotectin. AUROCs of the predictive probability of biomarker combinations showed superiority in discriminating endoscopic remitters from non-responders in comparison to single biomarker measurements, but not as compared to faecal calprotectin.

Conclusion: Although not superior to faecal calprotectin, measurement of AGP, SAA, LBF, IFN-γ, IL-6 and IL-22 concentrations, and combinations thereof with or without CRP and faecal calprotectin, during ustekinumab therapy might contribute to adequate monitoring of treatment response in CD patients.