Journal of Crohn's & colitis最新文献

Introduction: Ulcerative colitis (UC) is a chronic inflammatory disease that impairs health-related quality of life (HRQoL). We evaluated the effect of approved therapies on HRQoL in adults with moderate-to-severe UC.

Methods: We systematically searched Medline, Embase, CENTRAL, and gray literature through December 2024 for randomized controlled trials (RCTs) of approved therapies. The primary outcome was change in Inflammatory Bowel Disease Questionnaire (IBDQ) score during induction and maintenance. Secondary outcomes included changes in Short Form-36 (SF-36) Mental and Physical Component Scores, Work Productivity and Activity Impairment in UC (WPAI-UC), and rates of IBDQ response (≥16-point increase) and remission (score ≥170). Minimal clinically important differences were prespecified. Subgroup analyses based on prior biologic exposure were performed for primary outcome. Frequentist random-effects network meta-analyses were conducted, and confidence in estimates was assessed using the CINeMA (Confidence In Network Meta-Analysis) framework.

Results: Twenty-eight RCTs were included; 26 reported HRQoL outcomes during induction and 15 during maintenance. During induction, clinically meaningful improvements in IBDQ were observed with upadacitinib, filgotinib, and guselkumab. During maintenance, upadacitinib 30 mg and vedolizumab showed HRQoL benefits, although clinical meaningfulness was not consistently demonstrated. SF-36 improvements were modest overall, with upadacitinib and vedolizumab showing selective advantages, while WPAI-UC benefits were observed with upadacitinib, vedolizumab, and ustekinumab. Upadacitinib consistently ranked highest in IBDQ response and remission, while other therapies showed variable efficacy across outcomes.

Discussion: Advanced therapies vary in their impact on HRQoL, with some demonstrating clinically meaningful improvements in UC. These findings support integrating HRQoL into treatment selection and shared decision-making.

Background: Internalized stigma impacts the wellbeing of inflammatory bowel disease (IBD) patients and has complex relationships with experiences of discrimination and disease disclosure.

Methods: We surveyed 1263 IBD Partners e-cohort participants. Discrimination and internalized stigma were measured using the Everyday Discrimination Scale (EDS) and the Paradox of Self Stigma (PaSS-24) scale. IBD disclosure was measured using a modified "outness" scale.

Results: Overall, 48.8% of respondents reported discrimination, and there was a strong association between discrimination and internalized stigma (Pearson rho = 0.436, P < .001). Individuals who experienced discrimination were significantly more likely to be female, sexual or gender minorities (SGM), younger, and non-white. EDS score had a weak negative correlation with IBD disclosure (Pearson rho = -0.152, P< 0.001), indicating higher reported levels of discrimination correlated with lower rates of IBD disclosure. Internalized stigma was common and significantly associated with active disease (median PaSS-24 score 53 for respondents with active disease vs a score of 43 for respondents in remission; P < .001). Internalized stigma had a moderate negative correlation with disclosure of IBD (Pearson rho = -0.397, P < .001), indicating that more disease disclosure correlated with lower levels of internalized stigma. In a mediation analysis, disease disclosure was a significant mediator of the effect of discrimination on internalized stigma, mediating 15% of the overall estimated effect (P < .001).

Conclusions: In this large cohort of adults with IBD, experiences of discrimination and internalized stigma were common and associated with active disease. Disease disclosure may mediate the relationship between discrimination and internalized stigma. This emphasizes the importance of psychosocial support for individuals with IBD.

Background: Oral corticosteroids remain the treatment of choice for moderately active ulcerative colitis (UC), achieving clinical remission in 30%-60% of patients.

Objective: To compare the rates of steroid-free clinical-endoscopic remission at weeks 8 and 54 in patients treated with 3 methyl-prednisolone pulses before oral corticosteroids in moderately active UC versus those only receiving oral corticosteroids.

Design: Prospective, open, multicentre, randomized, controlled trial. Patients with left/extensive, moderately active UC, naive to immunosuppressants and biological agents, were randomized to receive conventional treatment (CT) with oral prednisone 60 mg/day or the same regimen preceded by an additional daily pulse (AP) of 500 mg of methyl-prednisolone for 3 days. All patients who responded started oral mesalazine and were followed up until month 12 or clinical relapse.

Results: Seventy-five patients were randomized: 39 were allocated to the CT arm and 36 to the AP arm. Overall, 21 patients achieved clinical-endoscopic remission (28%; 95% confidence interval [CI]: 23%-33%) at both weeks 8 and 54 without needing rescue treatments, being not significantly different between both study groups (23% [95%CI: 14%-32%] CT vs. 33% [95%CI: 21%-45%] AP; P = 0.323). Patients in the AP group had higher rates of clinical response at day 3 and remission at day 7. No significant differences in adverse events were observed. Due to early termination, the study was underpowered, and findings should be interpreted as exploratory.

Conclusions: The addition of 3 pulses of high-dose corticosteroids to a conventional regimen of oral prednisone does not improve medium and long-term clinical outcomes in moderately active UC.

Trial registration codes: EudraCT number 2016-001170-15; ClinicalTrials.gov identifier NCT02921555.

Background and aims: Loss of response (LoR) is a major limitation of anti-tumor necrosis factor (anti-TNF) therapy in inflammatory bowel disease (IBD). It can result from immunogenicity or other, less well-defined mechanisms. Specific HLA alleles have been linked to immunogenicity, but their association with LoR are not fully understood. In this study, we aimed to assess the relationship between HLA alleles and LoR, and investigate the impact of concomitant immunomodulator use.

Methods: LoR and sustained response to infliximab or adalimumab were defined in 25 642 IBD patients from the IBD BioResource. We applied multivariable Cox proportional hazards models to assess the effect of HLA alleles on time to LoR. The effect of concomitant immunomodulator use was also evaluated. Significantly associated alleles were further tested in patients treated with ustekinumab and vedolizumab.

Results: HLA-DQA1*05:01 was associated with reduced time to LoR in infliximab-treated patients (P = 5.34E-07), while HLA-DQA1*05:05 was associated with reduced time to LoR in adalimumab-treated patients (P = 3.20E-05). Neither allele was associated with LoR to ustekinumab or vedolizumab. Concomitant use of immunomodulators conferred a protective effect against LoR to infliximab and adalimumab in carriers of HLA-DQA1*05:01 and HLA-DQA1*05:05, respectively. However, this protective effect was not observed in adalimumab-treated patients who carried neither allele subtype (P = .11).

Conclusions: Our findings highlight distinct associations between HLA-DQA1*05 allele subtypes and time to LoR of infliximab and adalimumab in IBD-treated patients. The protective effect of immunomodulator use is allele-specific for adalimumab. These results provide a rationale for incorporating HLA testing into personalized anti-TNF management to optimize treatment durability.

Background and aims: Chronic background mucosal inflammation contributes to colorectal cancer (CRC) development in ulcerative colitis (UC), but its prognostic impact is unclear. We evaluated whether background mucosal inflammation documented at cancer diagnosis is associated with oncologic outcomes.

Methods: This retrospective study analyzed 1,189 UC patients diagnosed with CRC using a nationwide, multicenter database in Japan. Patients were classified as CRC within the UC-involved area (within-area) or outside the UC-involved area (outside-area), based on tumor location relative to the UC disease extent documented endoscopically at cancer diagnosis. The primary endpoint was 5-year recurrence-free survival (RFS), and the secondary endpoint was 5-year cancer-specific survival (CSS). In within-area cases, inflammation severity was assessed using the Mayo Endoscopic Score (MES), stratified as Inactive, Mild-Moderate, and Severe.

Results: Of 723 eligible patients, 683 had within-area and 40 outside-area CRC. Five-year RFS was significantly lower in within-area than outside-area CRCs (75.1% vs 87.6%, P = 0.022). Multivariable Cox regression analysis of RFS revealed this classification as an independent prognostic factor (HR = 2.99, 95% CI: 1.09-8.18, P = 0.030). A significant difference was also observed in 5-year CSS (P = 0.038). Among within-area cases, higher MES was associated with stepwise declines in RFS (P = 0.150), and a similar, statistically significant gradient in CSS (P = 0.048).

Conclusions: Background mucosal inflammation at cancer diagnosis is associated with significantly worse prognosis of CRC in UC patients. Systematic endoscopic assessment at cancer diagnosis may aid prognostic stratification and inform management.

Background and aims: The necessity of diverting loop-ileostomy after staged ileoanal pouch for ulcerative colitis remains unclear. This study aimed to compare postoperative outcomes between modified-2-stage and 3-stage ileoanal pouch procedures for ulcerative colitis.

Methods: This retrospective cohort study included patients ≥18 years with ulcerative colitis or unclassified inflammatory bowel disease who underwent modified-2-stage or 3-stage ileoanal pouch surgery from 2016-2021 in six European centres, with a follow-up of more than 12 months. Primary outcome was stoma-free rate at the end of follow-up. Secondary outcomes included perioperative practice, length of hospital stay, anastomotic leakage rate and timing of diagnosis and treatment.

Results: Overall, 370 patients were included of which 228 (61.6%) underwent a modified-2-stage approach and 142 (38.4%) a 3-stage approach. The median length of follow-up was 3.6 years (range: 1.0-7.7). Stoma-free rate was 93.8% (213/227) in modified-2-stage patients and 91.5% (130/142) in 3-stage patients (p = 0.404). Notably, 78.4% of modified-2-stage patients never required an ileostomy, while the remaining 21.6% did receive a secondary ileostomy. While median length of hospital stay for pouch surgery was longer in the modified-2-stage group, total median length of hospital stay after one year was shorter (median 7.0 days (IQR 6.0-11.0) versus 9.0 days (IQR 7.0-12.5), p = 0.015). The Clavien-Dindo score was higher than II in 22.6% of modified-2-stage patients and in 8.7% of 3-stage patients (p < 0.001). Anastomotic leakage rate was higher after modified-2-stage (18% versus 5%, p < 0.001), but diagnosis and treatment occurred earlier (86% within 21 days versus 43%, p = 0.009).

Conclusions: Both approaches have comparable high stoma-free rates at the end of follow-up. Modified-2-stage avoids a temporary stoma in more than 75% of patients, but has a significantly higher rate of anastomotic leakages. Active and early surveillance of the anastomosis after 3-stage procedures could improve postoperative outcomes in this group.

Background: Disease duration is associated with lower treatment response and accrual of bowel damage in Crohn's disease (CD), but not in ulcerative colitis (UC). We aimed to understand intestinal transcriptomic changes associated with disease duration in CD and UC.

Methods: We analyzed intestinal tissue RNA sequencing data from two independent prospective cohorts of CD and UC patients, the Mount Sinai Crohn's and Colitis Registry (MSCCR; nCD = 498, nUC = 421), and the Study of a Prospective Adult Research Cohort with Inflammatory Bowel Disease (SPARC IBD; nCD = 777, nUC = 440). We conducted differential expression analysis and subsequent pathway analyses of significantly up- or down-regulated genes, and examined cell type-specific expression of significant genes and pathways in ileal single-cell RNA sequencing data from CD patients (n = 18). We then assessed the association of significant pathways with treatment response in an infliximab-treated CD cohort.

Results: Significantly more genes were differentially expressed with increasing disease duration in CD compared to UC in both cohorts (MSCCR: nCD = 1472, nUC = 227; SPARC: nCD = 1248, nUC = 25; q-value < 0.05). A shared gene signature with 263 down- and 135 up-regulated genes in longer standing disease was identified. Pathway analyses revealed significant enrichment in pathways related to oxidative phosphorylation, mitochondrial dysfunction, cholesterol biosynthesis, liver X receptor/retinoid X receptor (LXR/RXR) activation, and protein modifications. Pre-treatment intestinal gene expression of four disease duration-related pathways were associated with non-response to infliximab.

Conclusion: Disease duration influences intestinal gene expression in CD but significantly less so in UC. The identified pathways and genes may inform development of differing biomarkers and treatment strategies in shorter versus longer standing CD.

Background: Placebo response rates in ulcerative colitis (UC) trials are highly variable. It is uncertain whether adding objective measures of inflammation, such as fecal calprotectin (FC) or histologic activity, to conventional eligibility criteria could reduce placebo response and strengthen treatment effect estimates. This study evaluated whether applying baseline FC or histology thresholds would alter outcomes in UC clinical trials.

Methods: We conducted a post-hoc pooled analysis of individual patient-level data from five phase 3, randomized, placebo-controlled trials including 1918 patients on active therapy and 1149 on placebo. Baseline FC thresholds (>150, >200, >250, >500 µg/g) and Geboes histological thresholds (≥3.1, ≥3.2) were applied as hypothetical inclusion criteria. Outcomes assessed were post-induction clinical remission (CR: modified Mayo score with stool frequency ≤1 and ≥1-point decrease, rectal bleeding = 0, and endoscopic subscore ≤1) and endoscopic improvement (EI: endoscopic subscore ≤1).

Results: Applying FC or Geboes thresholds did not meaningfully reduce placebo response rates or increase treatment-placebo differences for CR or EI. For example, for vedolizumab, the CR difference vs placebo was 11% (95% CI: 3.5-18.5) in the unrestricted population and 10.4%-13% with thresholds applied, with up to 91 (33.6%) of participants excluded. For upadacitinib, EI differences were 36.2% (95% CI: 28.5-43.8) unrestricted and 35.9%-37.3% with restrictions, with up to 248 (38.7%) of participants excluded. Results were consistent across therapies and in subgroup analyses.

Conclusion: Restricting trial enrollment based on elevated FC or histological activity did not meaningfully lower placebo response rates in phase 3 UC trials.

Background: Prior studies showed worse outcomes in obese inflammatory bowel disease (IBD) patients, especially those related to hospitalizations, surgery, and steroid-free remission. Glucagon-like peptide-1 receptor agonists (GLP1-RAs) have demonstrated significant metabolic benefits for patients with type 2 diabetes mellitus (T2DM) and obesity. Hence, GLP1-RAs may improve clinical outcomes in patients with IBD, especially those with obesity. The objective was to systematically evaluate the impact of GLP1-RAs on clinical outcomes in patients with IBD.

Methods: A comprehensive literature search was performed using the databases PubMed, Embase, Web of Science, and Cochrane Library from inception to March 15, 2025. Studies reporting outcomes related to GLP1-RAs in patients with IBD were included. Primary outcomes included weight loss and various IBD-related co-endpoints such as hospitalizations, surgery, corticosteroid use, and advanced therapy initiation.

Findings: In total, 11 studies with 16 242 patients with IBD treated with GLP1-RAs were included. Weight loss was achieved using semaglutide (-9.6 kg, 95% confidence interval [CI]: -12.0; -7.2), liraglutide (-9.4 kg, 95% CI: -13.0; -5.8), and tirzepatide (-11.8 kg, 95% CI: -18.3; -5.4) after 3 months of follow-up. In meta-analyses, GLP1-RAs were associated with lower risk of surgery for effect sizes (logHR: 0.61 [95% CI: 0.44-0.84], I 2 = 0%) and event frequencies (odds ratio [OR]: 0.46 [95% CI: 0.32-0.67], I 2 = 42%). Sensitivity analysis for body mass index (BMI) showed a lower risk of hospitalizations and surgery in patients with obesity (BMI ≥ 30).

Interpretation: Patients with IBD and obesity using GLP1-RAs were able to achieve significant weight loss and had lower risks of surgery and hospitalizations. Our findings require confirmation in prospective trials of GLP1-RAs in IBD.