Journal of Crohn's & colitis最新文献

Background and aims: We previously identified small molecules predicted to reverse an ileal gene signature for future Crohn's Disease (CD) strictures. Here we used a new human intestinal organoid (HIO) model system containing macrophages to test a lead candidate, eicosatetraynoic acid (ETYA).

Methods: Induced pluripotent stem cell lines (iPSC) were derived from CD patients and differentiated into macrophages and HIOs. Macrophages and macrophage-HIO cocultures were exposed to lipopolysaccharide (LPS) with and without ETYA pretreatment. Cytospin and flow cytometry characterized macrophage morphology and activation markers, and RNA sequencing defined the global pattern of macrophage gene expression. TaqMan low-density array, Luminex multiplex assay, immunohistologic staining, and sirius red polarized light microscopy were performed to measure macrophage cytokine production and HIO profibrotic gene expression and collagen content.

Results: Induced PSC-derived macrophages exhibited morphology similar to primary macrophages and expressed inflammatory macrophage cell surface markers including CD64 and CD68. LPS-stimulated macrophages expressed a global pattern of gene expression enriched in CD ileal inflammatory macrophages and matrisome-secreted products and produced cytokines and chemokines including CCL2, IL1B, and OSM implicated in refractory disease. ETYA suppressed CD64 abundance and profibrotic gene expression pathways in LPS-stimulated macrophages. Coculture of LPS-primed macrophages with HIO led to upregulation of fibroblast activation genes including ACTA2 and COL1A1, and an increase in HIO collagen content. ETYA pretreatment prevented profibrotic effects of LPS-primed macrophages.

Conclusions: ETYA inhibits profibrotic effects of LPS-primed macrophages upon cocultured HIO. This model may be used in future untargeted screens for small molecules to treat refractory CD.

Background: Intestinal ultrasound (IUS) is emerging as a valuable tool to assess treatment response in inflammatory bowel disease (IBD) clinical trials. This study details how IUS defines response and remission to evaluate treatment efficacy in IBD patients.

Methods: We conducted a comprehensive search of studies from 1984 to March 31, 2024, focusing on IUS use in assessing treatment efficacy in IBD.

Results: A total of 51 studies were included: 31 on Crohn's disease (CD), 12 on ulcerative colitis (UC) and 8 on IBD. Ileocolonoscopy was used as a reference standard in 53% of studies. IUS-defined response was reported in 47% of studies, with the majority (71%) using changes in bowel wall thickness (BWT) and color Doppler signals (CDS) as key indicators. IUS-defined remission was reported in 53% of studies, primarily using normalization of BWT to <3 mm and CDS to grades 0 or 1 as criteria. Ultrasonographic activity scores were used in 16% of studies, including the Bowel Ultrasound Score (BUSS) in two CD studies, the International Bowel Ultrasound Segmental Activity Score (IBUS-SAS) in one CD study, and the Milan Ultrasound Criteria (MUC) in one UC study The remaining four studies used unvalidated scores without clear definitions of response or remission. Assessment times varied, most commonly at weeks 8-16, and at 6, 12, and 24 months.

Conclusions: This systematic review reveals significant variability in IUS definitions of response and remission in IBD, highlighting the need to standardize eligibility criteria and outcome measures for IUS in IBD clinical trials.

Background and aims: Our objective was to compare the efficacy of novel biologics (such as vedolizumab and ustekinumab), anti-tumor necrosis factor (anti-TNF) agents, and immunomodulators (IMMs) in preventing postoperative recurrence (POR) of Crohn's disease (CD).

Methods: We searched the PubMed, Embase, and the Cochrane Library databases up to December 2023 to identify placebo-controlled, no-treatment comparison, or positive-controlled studies for the prevention of POR in CD. Endoscopic recurrence and clinical recurrence were the primary and secondary endpoints for the efficacy assessment. We conducted traditional direct and Bayesian network meta-analyses to evaluate the preventive effects of selected drugs. Additionally, we ranked interventions based on their scores under the Surface Under the Cumulative Ranking curve (SUCRA).

Results: A total of 17 studies involving 2786 patients were included. In the direct meta-analysis, anti-TNFs, vedolizumab, and IMMs showed greater efficacy in preventing endoscopic POR, compared with controls (placebo or no treatment). In preventing clinical POR, anti-TNFs and IMMs outperformed the controls. The network meta-analysis revealed that the risk of endoscopic POR was considerably lower in patients receiving anti-TNFs, vedolizumab, and ustekinumab compared with controls. Regarding the reduction of clinical POR, only anti-TNFs showed significant efficacy compared with controls. Vedolizumab and anti-TNFs were ranked as the most effective strategies in preventing endoscopic and clinical recurrence, respectively.

Conclusions: According to direct and network meta-analysis, in CD patients after surgical resection, novel biologics, especially vedolizumab, were quite effective in decreasing the risk of endoscopic POR, whereas anti-TNFs appeared to perform best in reducing the risk of clinical POR.

Background and aims: Cross-sectional imaging techniques, including intestinal ultrasonography (IUS), computed tomography enterography (CTE), magnetic resonance enterography (MRE), are increasingly used for the evaluation of inflammatory bowel diseases (IBD). We aimed to systematically review literature evidence on the assessment of disease activity, and/or severity through cross-sectional imaging in IBD patients, and to offer guidance on their most effective utilization.

Methods: We performed a systematic review of PubMed, EMBASE, and Scopus to identify citations pertaining to the assessment of disease activity and/or severity at cross-sectional imaging techniques compared to a reference standard (ie, other radiological techniques, endoscopy, histopathology, and surgery) in IBD patients published until December 2023.

Results: Overall, 179 papers published between 1990 and 2023 were included, with a total of 10 988 IBD patients (9304 Crohn's disease [84.7%], 1206 ulcerative colitis [11.0%], 38 IBD-U [0.3%], 440 unspecified [4.0%]). Of the 179 studies, 39 investigated IUS, 22/179 CTE, and 101/179 MRE. In the remaining papers, 2 techniques were addressed together. In 81.6% of the papers, endoscopy (with or without histopathology) was used as a reference standard. All studies included evaluated disease activity, while just over half (100/179, 55.8%) also evaluated disease severity of the addressed cross-sectional methodology. Pooled sensitivity, specificity, and overall accuracy of IUS, MRE, and CTE compared to the reference standard were 60%-99%, 60%-100%, and 70%-99%, respectively.

Conclusions: All cross-sectional imaging techniques demonstrated moderate-to-good accuracy in assessing disease activity and severity of IBD. This finding highlights the potential, especially for MRE and IUS to be widely utilized in managing IBD in both clinical practice and clinical trials.

Background and aims: There are few studies on the cost-effectiveness of telemedicine for inflammatory bowel diseases. We assessed the long-term cost-effectiveness of a telemedicine solution compared to standard care (sCare), as well as its efficacy according to patient-reported outcomes (PROs).

Methods: Between 2015 and 2020, we conducted a retrospective, register-based study among patients with ulcerative colitis and Crohn's disease. Direct and indirect healthcare costs over a 5-year period were obtained from Danish registers and compared to a control group. Costs were estimated on a yearly basis from 1 year before, until 5 years after, inclusion in the trial. Patients were divided into 2 groups: those not receiving biologics (Cohort 1) and those receiving biologics (Cohort 2).

Results: We recruited 574 patients with inflammatory bowel diseases. In Cohort 1 (61.5%), average total direct costs and total earnings per patient per year were €14 043 and €307 793, respectively, in telemedicine compared to €16 226 and €252 166, respectively, in sCare. In Cohort 2 (38.5%), average total direct costs and total earnings were €73 916 and €215 833, respectively, in telemedicine compared to €41 748 and €203 667, respectively, in sCare. PROs showed improved quality of life, which was higher in Cohort 1 than in Cohort 2. Disease activity among patients with Crohn's disease increased after Years 3 and 4 in Cohorts 1 and 2, respectively.

Conclusion: Telemedicine is cost-effective for patients not receiving biologics. However, treatment with biologics is more expensive for patients enrolled in telemedicine. Careful attention to PROs in telemedicine improves quality of life and could prolong the time to relapse.

Background: Endoscopic remission has emerged as an important treatment target in Crohn's disease (CD) and has been associated with improvement in long-term outcomes. We examined the relationship between achievement of endoscopic remission and hospitalizations using pooled data from 52-week Phase III maintenance trials of risankizumab and upadacitinib in patients with moderate-to-severe active CD.

Methods: Included patients received maintenance therapy after achieving a clinical response following a 12-week induction with risankizumab or upadacitinib. Endoscopic remission was defined as a Simple Endoscopic Score for Crohn's Disease (SES-CD) of no greater than 4, with at least a 2-point reduction vs induction baseline and no subscore greater than 1. All subsequent hospitalization events were recorded until completion of the maintenance trial or discontinuation. Exposure-adjusted negative binomial regression models were estimated to assess the relationship between post-induction endoscopic remission and long-term hospitalization, controlling for demographics, clinical variables, and treatment arm.

Results: Post-induction hospitalization rates were lower in patients who achieved endoscopic remission at the end of the induction period. In multivariable models, post-induction endoscopic remission was independently associated with incidence rate ratios of 0.45 (95% confidence interval [CI], 0.22-0.95, p = 0.036) and 0.71 (95% CI, 0.44-1.14, p = 0.156) for long-term disease-related and all-cause hospitalizations, respectively.

Conclusions: Week 12 endoscopic remission is independently associated with a reduction in 52-week disease-related hospitalizations. However, achieving this stringent endpoint within 12 weeks of therapy may be challenging. Endoscopic response may be a more realistic early endoscopic target in the post-induction timeframe. Additional research is needed to evaluate early achievement of alternative endoscopic endpoints in CD.

Background and aims: Large registries are promising tools to study the epidemiology of inflammatory bowel disease (IBD). We aimed to develop and validate machine learning models to identify IBD cases in administrative data, aiming to determine the prevalence, incidence, and mortality of IBD in the Netherlands.

Methods: We developed machine learning models for administrative data to identify IBD cases and classify them on subtype and incidence year. Models were developed in a population-based cohort and externally validated in a hospital cohort. Models were evaluated on Brier score, area under the receiver operating characteristic curve (AUC), calibration, and accuracy. The best models were used to determine the epidemiology of IBD in the Netherlands between 2013 and 2020.

Results: For identifying IBD cases the random forest model was best (AUC: 0.97, 95% CI [0.96; 0.97]). The gradient-boosted trees model for subtype was best (accuracy: 0.95, 95% CI [0.94; 0.95]) as was the random forest model for incidence year (0.88, 95% CI [0.86; 0.89]). The prevalence of IBD in the Netherlands was 577.6 (95% CI [566.7; 586.2]) per 100 000 on December 31, 2020, with varying prevalence across the Netherlands. Incidence of IBD was 20.1 (95% CI [18.0; 22.3]) per 100 000 in 2020 and stable over time. Mortality rates of IBD patients rose over time and were 11.6 (95% CI [10.5; 11.8]) per 1000 in 2020 as compared to 9.5 in the general population.

Conclusion: Inflammatory bowel disease cases can be accurately identified using administrative data. The prevalence of IBD in the Netherlands is increasing slower than expected, suggesting a trend towards the epidemiological stage of Prevalence Equilibrium.

Background and aims: Microbiota transplant therapy (MTT) is an emerging treatment for ulcerative colitis (UC). One proposed mechanism for the benefit of MTT is through engraftment of donor microbiota; however, engraftment kinetics are unknown. We identified SourceTracker as an efficient method both to determine engraftment and for the kinetic study of engrafting donor taxa to aid in determining the mechanism of how this therapy may treat UC.

Methods: Ulcerative colitis patients received either encapsulated (drug name MTP-101C) or placebo capsules daily for 8 weeks followed by a 4-week washout period. Amplicon sequence data from donors and patients were analyzed using the Bayesian algorithm SourceTracker.

Results: Twenty-seven patients were enrolled, 14 to placebo and 13 to MTT. Baseline Shannon and Chao1 indices negatively correlated with week 12 donor engraftment for patients treated with active drug capsules but not for placebo patients. SourceTracker engraftment positively correlated with the week 12 distance from donors measured using the Bray-Curtis similarity metric in treated patients but not with placebo. Engraftment at week 12 was significantly higher in the MTT group than in the placebo group. We identified engrafting taxa from donors in our patients and quantified the proportion of donor similarity or engraftment during weeks 1 through 8 (active treatment) and week 12, 4 weeks after the last dose.

Conclusion: SourceTracker can be used as a simple and reliable method to quantify donor microbial community engraftment and donor taxa contribution in patients with UC and other inflammatory conditions treated with MTT.

Background and aims: For pregnant women with perianal Crohn's disease (CD), major guidelines recommend delivery by caesarean section (c-section) for active disease, and that delivery mode be governed by obstetric indications for women with inactive disease. However, a significant gray zone exists between active versus inactive disease, such as for women who had a history of prior perianal surgery. We examined adverse maternal outcomes of vaginal delivery versus c-section in women with perianal CD and prior perianal surgeries.

Methods: We used the Danish national registries to collect information on singleton live births from 1997 through 2022 by mothers with CD and previous perianal surgery. Adverse postpartum maternal outcomes included new perianal or intestinal surgery within 12 months, hospital diagnosed infection or outpatient antibiotic prescription within 6 months, and major haemorrhage within 3 days. Adjusted odds ratios (aOR) were estimated in logistic regression models.

Results: There were 704 deliveries by women with CD and prior perianal surgery, including 245 vaginal deliveries (34.8%) and 459 c-sections (65.2%). Women who delivered vaginally versus by c-section had less new perianal surgery (aOR 0.47, 95% CI, 0.24-0.93) and no significant differences in intestinal CD surgery (aOR 0.87, 95% CI, 0.43-1.75), hospital diagnosed infection (aOR 0.50, 95% CI, 0.18-1.38), outpatient antibiotic prescription (aOR 0.92, 95% CI, 0.65-1.28), or major hemorrhage (aOR 0.79, 95% CI, 0.39-1.59).

Conclusions: Vaginal delivery was not associated with increased important adverse maternal outcomes in mothers with CD and prior perianal surgery.