Journal of Crohn's & colitis最新文献

Background: Randomized controlled trials (RCTs) provide high-quality evidence but often lack generalizability to real-world populations. Although real-world evidence (RWE) studies help to bridge this gap, retrospective design and heterogeneous outcome measures still limit their standardization in Crohn's disease (CD). Building on the recent ECCO Position Paper, this study aimed to identify the most relevant outcomes for real-world CD studies.

Methods: An international panel of inflammatory bowel disease (IBD) specialists participated in a structured two-round Delphi e-survey using the RAND/UCLA Appropriateness Method. Experts rated outcomes across eight domains, including disease activity, patient-reported outcomes, and treatment safety. Agreement was assessed using the Disagreement Index (DI), where DI > 1 indicated disagreement, and DI ≤ 1 indicated agreement or no disagreement. Weighted scoring prioritized key outcomes.

Results: A total of 51/85 experts (60%) completed Round 1 and 48/51 (94%) Round 2. No disagreement was observed (DI < 1) in both rounds. The highest-ranked outcomes were Abscess or Fistula (10.6%), Endoscopic Remission (10.3%), Corticosteroid-Free Clinical Remission (8.9%), Disease Progression (6.7%), and Colorectal Cancer (5.9%). The top 10 outcomes accounted for 61.5% of the weighted score. For combinations, the top four outcomes, Corticosteroid-Free Clinical Remission (16.2%), Endoscopic Remission (15.6%), Disease Progression (14.1%), and Health-Related Quality of Life (11.9%), represented 57.8% of selections. When considering the top five and top six outcomes, the cumulative proportions were 55.4% and 57.6%, respectively.

Conclusions: This expert-driven Delphi study provides a standardized framework for selecting outcomes in CD RWE studies, improving consistency and comparability across future research in this field.

Background and aims: We assessed placebo rates and associated factors using individual patient data (IDP) from randomized clinical trials (RCTs) in ulcerative colitis (UC).

Methods: We conducted an IPD meta-analysis using Vivli and Yale University Open Data Access data-sharing platforms. Phase 2 and 3 RCTs of advanced biologics in adults with moderate-to-severe UC published since 2010 were included. Pooled placebo rates and 95% CIs were estimated using one- and two-stage meta-analytical approaches. Significant patient-level factors (P < .05) were identified using regression analyses. Primary outcomes were clinical response and remission.

Results: Data were available for 1703 patients from nine studies. For induction trials, overall placebo response and remission rates were 33% (95% CI 29%-38%) and 9% (95% CI 7%-11%). Overall placebo response and remission rates in maintenance trials were 28% (95% CI 18%-41%) and 14% (95% CI 9%-20%). A lower body mass index reduced the odds of placebo response and remission, while higher baseline albumin levels and left-sided (compared to extensive) UC increased the odds of these outcomes. A 1-point increase in the Mayo Clinic Score (MCS) and adapted MCS was associated with a 26% and 27% reduction in odds of clinical remission. For induction trials, prior biologic exposure was associated with lower odds of response and remission. Multicenter trials have lower placebo effects than single-center trials.

Conclusions: These results enable future trials to incorporate design elements that reduce placebo rates as well as a precise benchmark for expected rates in clinical trials that do not include placebo.

Background & aims: The optimal management of inflammatory bowel disease (IBD) patients with a partial response after intravenous (IV) vedolizumab (VDZ) induction remains unclear.

Methods: PRIVEDO was an observational, non-randomized, open-label, prospective cohort study conducted within the Sicilian Network for IBD. It compared subcutaneous (SC) VDZ (108 mg every 2 weeks) versus intensified IV VDZ (300 mg every 4 weeks) in Crohn's disease (CD) or ulcerative colitis (UC) patients with a partial response at Week 14 post-induction. Partial response was defined as: (1) clinical remission with fecal calprotectin >250 µg/g and/or steroid use, or (2) a reduction in the Harvey-Bradshaw Index by ≥3 points (for CD) or in the Partial Mayo Score by ≥2 points (for UC) from baseline, without fulfilling clinical remission criteria. The primary endpoint was steroid-free clinical remission with fecal calprotectin <250 µg/g at Weeks 26 and 52. The secondary endpoints were clinical benefit (remission or partial response), regardless of calprotectin values, and treatment persistence.

Results: 107 patients were enrolled (CD: 58/107, 54.2%; UC: 49/107, 45.8%), allocated to SC (n = 52) or IV (n = 55) groups. The primary endpoint was met more often with SC VDZ at Week 26 (30/52, 57.7% vs. 14/55, 25.5%; P < 0.001; odds ratio [OR]: 3.57, P = 0.004 at multivariable analysis) and at Week 52 (25/52, 48.1% vs. 14/55, 25.5%; P = 0.016; OR: 3.05, P = .029 at multivariable analysis). Clinical benefit was also higher in the SC group at both timepoints, though not statistically significant. Treatment persistence was comparable between the 2 groups (log-rank test, P = .225).

Conclusions: In IBD patients with partial response to IV VDZ induction, switching to SC VDZ may lead to more profound remission than continuing IV optimization.

Background and aims: Colitis-associated cancer (CAC) is the most severe complication of inflammatory bowel disease (IBD). We hypothesized that chronic inflammation activates endogenous anti-inflammatory mechanisms that promote dysplasia by undermining immunosurveillance. Our aim was to determine chronic inflammation-induced immune cell reprogramming in IBD patients at risk for developing CAC.

Methods: This cohort study utilized GeoMx digital spatial profiling and imaging mass cytometry in 11 patients with either CAC or sporadic colorectal cancer (SCRC). Results from this discovery cohort were validated using immunohistochemistry/immunofluorescence in an independent cohort of CAC and SCRC patients (n = 10 and n = 14, respectively), as well as in an independent cohort of IBD patients with (n = 6) and without dysplasia (n = 18).

Results: Histologically uninflamed colon from patients who developed CAC displayed upregulated metabolism and stress response pathways as compared to SCRC patients, indicating ongoing epithelial stress-responses. Endogenous anti-inflammatory mechanisms included increased IL-10 expression by lamina propria IgA+ plasma cells and CD163+ macrophages. T cell recruitment and effector pathways were downregulated in CAC, which was associated with a decrease in CD8+ intraepithelial T cells (IELs) and reduced levels of granzyme B within CD8+ IELs. Decreased CD8+ IEL density was associated with CAC susceptibility, as IBD patients who developed dysplasia showed significantly lower levels of CD8+ IELs than IBD patients who never developed dysplasia.

Conclusions: Chronic inflammation induces endogenous mechanisms to protect from inflammation-induced damage, including increased anti-inflammatory cytokine production and decreased levels of CD8+ IELs. While this may limit inflammation, these mechanisms may also reduce immunosurveillance, favoring the development of CAC.

Background and aims: The submucosa is the most responsive bowel wall layer on intestinal ultrasound (IUS) when assessing treatment response in ulcerative colitis (UC). Submucosal thickening with hyper-echogenicity is observed. This study aimed to quantify echogenicity and understand transmural changes in UC.

Methods: In total, 118 patients were studied in two cohorts. Cohort 1 included colectomy patients: 19 UC patients and 52 controls without inflammatory bowel disease. Cohort 2 included 47 UC patients in a prospective cohort starting anti-inflammatory treatment. In Cohort 1, submucosal inflammation, and fat and collagen deposition were scored by two pathologists using a semi-quantitative scale (0-3). For UC patients in Cohort 1, histopathology and IUS of the sigmoid were location matched. Relative submucosal echogenicity (RSE) was assessed, quantified in grayscale values. In Cohort 2, baseline sigmoid RSE was compared between endoscopic responders (≥1 point decrease in endoscopic Mayo score after 8-26 weeks) and non-responders.

Results: In all colectomized UC patients with preserved wall layer stratification (n = 12, 63%), submucosal fat (score ≥1) was present; in those with loss of stratification (n = 7, 37%), fat was absent (score = 0). RSE was higher when fat was present [95.5 (IQR 86.5-116.9) vs 8.1 (IQR 5.8-23.0) grayscale values, P < .001], with no significant differences for inflammation and collagen. In Cohort 2, RSE was higher in non-responders (n = 17) compared to responders (137.1 ± 50.9 vs 88.3 ± 49.6 grayscale values, P = .003). An RSE of >108 grayscale values predicted non-response [OR: 0.07 (95% CI: 0.01-0.44), P = .004].

Conclusion: Submucosal hyper-echogenicity on IUS indicates fat deposition and predicts non-response in UC.

Background: External validation of predictors of anti-tumor necrosis factor (TNF) outcomes remains limited, particularly in children. We conducted a systematic review of the literature to identify predictors of therapeutic success and validated them in a prospective pediatric cohort.

Methods: We searched PubMed and Embase for studies reporting clinical and laboratory predictors of anti-TNF outcomes in Crohn's disease (CD). Identified predictors were evaluated in a prospective cohort of 186 children with CD initiating anti-TNF. Univariable logistic regression assessed individual predictors, and previously published multivariable models were validated using the area under the curve (AUC).

Results: Of the 4840 studies screened, 42 were included; seven (17%) focused on children and only four were rated as low risk of bias. We identified 24 individual predictors and five multi-item models. Of these, prior corticosteroid use (odds ratio [OR], 2.84, 95% CI, 1.12-7.15) and immunomodulator combination therapy (OR 6.36, 95% CI, 2.39-17.10) were associated with increased risk of primary non-response. Disease activity at 4 months, reflected by C-reactive protein and disease activity indices, predicted remission at 12 months. Loss of response was associated with elevated inflammatory markers at 4 months and with partial clinical response. The five multivariable models demonstrated varying performance in children (AUC 0.54-0.76).

Conclusion: Only a few of the variables suggested to predict response to anti-TNF showed acceptable performance in pediatric CD, mainly those that included post-induction indicators. These findings highlight the limited generalizability of existing predictors and the importance of external validation before clinical implementation of prediction rules.

Background and aims: Not all patients, as with other inflammatory bowel disease (IBD) treatments, respond to modulation of kinase activity. To improve the precision of therapeutic interventions, a better understanding of the mucosal inflammatory environment is essential. This study investigates mucosal kinase activity and cytokine/chemokine profiles in IBD and in relation to tofacitinib response.

Methods: Paired inflamed and non-inflamed colonic biopsies were collected from patients with Crohn's disease (CD, n = 16), ulcerative colitis (UC, n = 16), and non-IBD controls (n = 4) to assess IBD-associated kinase activity and cytokine/chemokine profiles. Additionally, colonic samples were collected from UC patients before the start of tofacitinib treatment (cohort 1, n = 12) and both before and after 8 weeks of treatment (cohort 2, n = 16), to assess tofacitinib response-related kinase activity profiles.

Results: The kinase activity profiles exhibited significant differences between inflamed and non-inflamed mucosa, with more pronounced alterations observed in UC compared to CD. The increase in kinase activity was most pronounced in the tyrosine kinase families. Responders to tofacitinib demonstrated higher baseline mucosal kinase activity, although only two predicted kinases (DCLK1 and ATR) were consistently identified. In responders, mucosal kinase activity significantly decreased after 8 weeks of treatment.

Conclusion: Mucosal kinase activity profiles are associated with inflammation in IBD, with distinct differences between UC and CD. Baseline kinase activity appears to predict response to tofacitinib, with a marked reduction in kinase activity observed after 8 weeks of treatment in responders. These findings highlight the potential of kinase activity profiling in optimizing therapeutic strategies for IBD.

Background and aims: Most patients with Crohn's disease (CD) who have undergone ileocolonic resection experience recurrent inflammation within 1 year after surgery. We examined the molecular basis underlying gastrointestinal inflammation in postoperative CD across 3 common anatomic locations of recurrence.

Methods: To characterize spatial transcriptomic signatures, this study utilized biopsies from the colon, neo-terminal ileum, and anastomosis of patients with postoperative CD in the PREDICT-OR study. Sample analyses were performed with 10X Genomics Visium CytAssist system V2.0, and data analyses with R.

Results: Histologically inflamed biopsies from all locations shared transcriptional signatures across 3 cellular niches (myeloid, B, T cells) and a specialized epithelial cell type expressing inflammation-associated genes. Differentially expressed genes overexpressed inflammatory pathway activity across the 3 locations, whereas hypoxic pathways were less apparent. In addition to genes for known treatment targets, epidermal growth factor receptor and mitogen-activated protein kinase pathways were upregulated. Cellular niches shaped inflammatory microenvironments through endoplasmic reticulum stress and extracellular matrix remodeling signaling.

Conclusions: Application of spatial transcriptomics revealed a common disease signature for postoperative CD across the colon, neo-terminal ileum, and anastomosis. Inflamed biopsies from all locations demonstrated similar immune cell and inflammatory gene expression patterns as opposed to hypoxic pathways, and unique inflammatory pathways were revealed.

Background and aims: Crohn's disease (CD) is a chronic, immune-mediated inflammatory disorder. Its pathophysiology involves dysregulation of both innate and adaptive immune responses, which can occur in clonal hematopoiesis of indeterminate potential (CHIP) individuals. Therefore, we hypothesize that CHIP may influence CD incidence. However, no study has explored the association between CHIP and incident CD. We analyzed UK Biobank data to investigate the association between CHIP and incident CD.

Methods: CHIP was defined based on whole-exome sequencing data. The outcome was incident CD. Cox regression models were used to calculate hazard ratios (HRs) with 95% confidence intervals (CIs) for CD in relation to CHIP.

Results: This study included 461 913 participants, of whom 14 339 (3.1%) had CHIP. The incidence rate of CD was 21.6 and 37.7 per 100 000 person-years for individuals without and with CHIP, respectively. We found a statistically significant increased risk of CD among individuals with CHIP (HR, 1.68; 95% CI, 1.30-2.16), compared with the reference group. This association was particularly stronger in individuals with JAK2-mutant CHIP (HR, 7.28; 95% CI, 1.82-29.13), ASXL1-mutant CHIP (HR, 3.07; 95% CI, 1.74-5.44), and DNMT3A-mutant CHIP (HR, 1.73; 95% CI, 1.24-2.42). Additionally, the association did not vary greatly by demographic, socioeconomic, lifestyle factors, CHIP clone size, or cancer comorbidity.

Conclusions: CHIP was associated with a markedly increased risk of subsequent CD. The association was particularly stronger in JAK2-mutant CHIP, ASXL1-mutant CHIP, and DNMT3A-mutant CHIP. The findings of this study may offer potential insights for future investigations into the mechanistic underpinnings of CD.