Journal of Crohn's & colitis最新文献

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: 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.

Introduction: While ileocolic resection is the most common surgical procedure for Crohn's disease (CD), many physicians prefer to initiate pharmacotherapy before considering surgery. This study aimed to compare early ileocolic resection (EICR) with medical treatment (MT) for localized ileocolic CD.

Methods: A systematic search was conducted across PubMed, Cochrane, Embase, and Google Scholar. Inclusion criteria required studies to compare EICR (performed within 18 months of initial diagnosis) without the use of biologics to MT, with primary outcomes being the need for CD-related surgery and the use of biologics.

Results: Five studies involving 1770 patients, both pediatric and adult, were included in this analysis. The data showed that in the EICR cohort, which comprised 740 patients, the rate of CD-related surgery within 5 years of initial treatment was 2.43%. In contrast, the MT cohort, consisting of 1030 patients, had a much higher surgery rate of 20.58% (P < 0.001). Additionally, at a mean follow-up of 5 years, the long-term use of biologics was significantly lower in the EICR cohort compared to the MT cohort, with rates of 18.38% and 72.91% respectively (P < 0.001).

Conclusion: An EICR operation for localized ileocolic CD was associated with longer and more stable remission, resulting in improved long-term outcomes compared to medical therapy alone. In cases of localized ileocolic CD where MT fails to improve disease activity after several months, early surgical intervention may provide a safe and effective way to achieve disease remission and enhance the overall quality of life for patients.

Objective: Identifying proteomic signatures in treatment-naïve individuals newly diagnosed with inflammatory bowel disease (IBD) may provide insights into the underlying pathophysiological mechanisms of the disease and aid in distinguishing Crohn's disease (CD) from ulcerative colitis (UC).

Design: In the discovery phase, label-free quantitative proteomics was performed to analyze proteomic profiles in serum extracellular vesicles (EVs), serum, urine, and intestinal tissue from 100 newly diagnosed IBD patients (50 CD and 50 UC), and 51 healthy controls (HC). Serum candidate biomarkers were validated using ELISA in a separate subset cohort (87 CD, 134 UC, and 99 HC), and immunohistochemistry was performed on biopsies from the discovery cohort to confirm findings.

Results: We identified 419 proteins in serum EVs, 468 in serum, 683 in urine, and 2603 in intestinal tissue. ELISA results showed lower levels of TTR and APOC3 and higher levels of ATRN in UC patients compared to HC. Similarly, CD patients showed lower TTR and higher ATRN levels compared to HC. Moreover, serum protein S10A9 was differentially upregulated in CD vs UC. Immunohistochemistry revealed increased PRDX4 and AZU1 expression in the ileum of CD patients, whereas AOFB expression was lower in the ileum of CD and in the left colon of both CD and UC compared to HC.

Conclusion: This comprehensive proteomic study has identified a set of proteins differentially expressed in IBD, which may contribute to a better understanding of its mechanisms and hold promise as candidate biomarkers. Although these findings are preliminary, they warrant further investigation to evaluate their diagnostic and therapeutic relevance.

Background: Upper gastrointestinal Crohn's disease (UGICD) is an uncommon phenotype with limited management guidelines. We reviewed evidence on the safety and efficacy of pharmacological interventions for UGICD.

Methods: We searched MEDLINE, Embase, and Cochrane CENTRAL (1990-2025) for randomized controlled trials (RCTs) and comparative observational studies evaluating pharmacological or dietary interventions for UGICD, including esophagus to jejunum. Two reviewers screened studies, extracted data, and assessed bias (Newcastle-Ottawa Scale). Primary outcomes were clinical remission and response. Due to limited, heterogeneous evidence, data are summarized descriptively.

Results: Of 1207 citations, 11 observational studies (nine retrospective, two prospective) and post-hoc analyses from two RCTs met the criteria, involving 387 patients. Most had ileocolonic involvement (280/387; 72.3%); only 8.5% (33/387) had isolated UGICD. Five studies (137 patients) reported esophageal CD. Follow-up ranged from 6 weeks to 28 years. Interventions and outcomes varied. Anti-tumor necrosis factor (anti-TNF) drugs and corticosteroids, alone or combined with other treatments, were associated with improvements in clinical outcomes, endoscopic healing, and histology, but controlled data are lacking. Other therapies, including proton pump inhibitors, H2-receptor antagonists, enteric nutrition, immunomodulators, anti-integrins, and anti-interleukin12/23, showed moderate to minimal improvement.

Conclusions: Our systematic review highlights a paucity of evidence to inform therapeutic strategies in UGICD. Positive outcomes were reported for corticosteroids and anti-TNF, but from small observational and uncontrolled studies. Data for most advanced therapies remain limited, highlighting a large unmet need to inform clinical practice.

Background and aims: Inflammatory bowel disease (IBD) often coincides with pregnancy, and disease activity during pregnancy increases the risk of adverse outcomes. We aimed to determine how disease course before conception influences relapse risk during pregnancy, adjusting for established risk factors.

Methods: In this multicenter, retrospective cohort study, we included adult women with IBD who were pregnant during treatment at one of three university hospitals between 2017 and 2022. Using generalized estimating equations, we evaluated associations between relapse during pregnancy and pre-conceptional flares, categorized into three time intervals. Analyses were adjusted for phenotype, disease duration, surgical history, biologic use, smoking, and assisted reproduction. Interaction analyses were conducted with matched non-pregnant women.

Results: We included 386 women (63.4% Crohn's disease, 36.6% ulcerative colitis) with 476 pregnancies. Pre-conceptional flares were significantly associated with relapse if they occurred <3 months [adjusted odds ratio (aOR) 5.289, 95% CI 2.6-10.8, P < .001] or 3-6 months prior to conception (aOR 2.910, 95% CI 1.0-8.2, P = .043), but not 6-12 months prior (aOR 1.636, 95% CI 0.8-3.2, P = .146). Other predictors were not significantly associated with relapse. There was no significant interaction between pregnancy and pre-conceptional disease activity.

Conclusions: This large multicenter study demonstrates that disease activity within 6 months before conception significantly increases the risk of relapse during pregnancy in women with IBD. Our study is the first to assess both the pre-conceptional disease course and a broad set of known risk factors in a real-world cohort.

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.