Journal of Crohn's & colitis最新文献

Background & aims: We conducted this nationwide study to evaluate the association between peripheral blood eosinophilia (PBE) and long-term outcomes in children and adults with inflammatory bowel diseases (IBD).

Methods: Data from the epi-IIRN cohort, a validated population-based IBD database, included patients diagnosed between 2005-2020 who had an eosinophil count at diagnosis, and those of non-IBD controls. PBE was defined as an eosinophil count of >0.5 X109/L Severe disease course was defined as corticosteroid dependency, use of ≥2 biologics from different classes, or surgery. Time-to-outcomes, including severe disease course, was determined by Cox proportional hazard models.

Results: Included were 28,133 patients (15,943 Crohn's disease [CD] and 12,190 ulcerative colitis [UC]), and 28,724 non-IBD controls. The prevalence of PBE was 13% in the IBD group and 5% in controls (P < .001). PBE was more prevalent in UC (16.1%) compared to CD (10.6%, OR=1.52 (95%CI 1.42-1.63); P < .001) and in pediatric-onset (23.5%) compared to adult-onset (11%) IBD (OR=2.14 (1.97-2.31); P <.001). In a multivariate analysis, PBE was a predictor of severe disease course in IBD (hazard ratio [HR]=1.49, 95%CI 1.38-1.62, P < .001). PBE also predicted time-to-hospitalization (HR=1.24, 95%CI 1.19-1.30), use of corticosteroids (HR=1.32, 95%CI 1.28-1.36), corticosteroid dependency (HR=1.37, 95%CI 1.31-1.43), and need of biologics (HR=1.27, 95%CI 1.21-1.33).

Conclusion: In this largest nationwide study, PBE predicted severe IBD course. These findings support the use of PBE as a marker of adverse outcome of IBD and as a potential target for future therapies.

Background and aims: Switching from the intravenous to the subcutaneous biosimilar infliximab (SC-IFX) has been shown to safely maintain clinical remission and increase drug levels in patients with Crohn's disease (CD) and ulcerative colitis (UC). The aim of this study was to evaluate long-term outcomes after switching from intravenous IFX (IV-IFX) to SC-IFX, the drug concentration thresholds for maintaining remission and other predictors for loss of response after the switch.

Methods: Multicenter observational study involving CD and UC patients who were in clinical remission for at least 24 weeks and scheduled to switch from IV-IFX to SC-IFX.

Results: Two hundred and twenty patients were included [74 UC (34%) and 146 (66%) CD]. IV-IFX was administered for 52.5 months [range 25-89]. Pre-switch, 106 (49%) patients were receiving intensified IV-IFX. While SC-IFX levels significantly increased following the switch from IV to SC-IFX, clinical parameters, C-reactive protein and faecal calprotectin remained unchanged during follow-up. SC-IFX levels were significantly higher between patients receiving the standard IV-IFX dose than those with the intensified dose. Immunomodulator therapy at baseline and perianal disease had no effect on IFX trough levels, whereas higher body mass index was associated with increased levels. The suggested optimal SC-IFX cut-off concentration for clinical and biochemical remission based on ROC analysis was 12.2 μg/mL (AUC: 0.62) at week 12 and 13.2 μg/mL (AUC: 0.57) at week 52. Drug persistence was 92% at week 52, with a good safety profile.

Conclusion: Switching from IV-IFX to SC-IFX safely maintains long-term remission in patients with CD and UC. In maintenance, the optimal cut-off point associated with remission was 12-13 μg/mL.

Background & aims: Anti-tumor necrosis factor (anti-TNF) therapies are commonly prescribed treatments for Crohn's Disease (CD) and Ulcerative Colitis (UC). Many patients treated with anti-TNF therapy eventually develop anti-drug antibodies (ADA). Understanding the factors associated with immunogenicity in anti-TNF treated patients can help guide treatment. The Humira SERENE studies were phase 3 trials studying adalimumab induction regimens in CD and UC patients.

Methods: We imputed alleles for 7 HLA genes in 1100 patients from the SERENE CD and SERENE UC trials. We tested these alleles for association with time to immunogenicity. We then tested loci significantly associated with immunogenicity for association with patients that had consistently low drug-serum concentrations.

Results: This study replicated the association of HLA-DQA1*05 with time to immunogenicity (Hazard Ratio (HR) 1.42, P=2.22E-06). Specifically, HLA-DQA1*05:05 was strongly associated (HR 1.76, P=2.02E-10) and we detected a novel association represented by HLA-DRB1*01:02 (HR 3.16, P=2.92E-07). Carriage of HLA-DQA1*05:05 and HLA-DRB1*01:02 were both associated with patients who experienced consistently low adalimumab trough concentrations (HLA-DQA1*05:05 OR 1.98, P=0.0049; HLA DRB1*01:02 OR 7.06, P=7.44E-05).

Conclusions: We found a significant association between alleles at genes in the human HLA locus and the formation of adalimumab immunogenicity and low adalimumab drug-serum concentrations in large clinical studies of CD and UC patients. This work extends previous results in Crohn's disease to ulcerative colitis and directly shows a genetic association in patients with low drug concentrations. This work builds on existing literature to suggest genetic screening as a useful tool for clinicians concerned with patient anti-TNF immunogenicity.

Introduction: Inflammatory bowel disease [IBD] patients have a relapsing-remitting disease course, and amongst environmental factors that aggravate the disease course, common drugs aside from non-steroidal anti-inflammatory drugs have not been studied in detail. While the microbiome is considered to play a significant role on the disease course, the impact of antibiotics is poorly understood. This study investigated the potential impact of different classes of antibiotics on the course of disease in IBD using the Danish National Patient Registry.

Methods: Danish IBD patients were studied using two nested case-control cohorts exploring associations between antibiotic types and IBD flare-ups, defined as IBD-related hospitalizations and/or high-dose systemic steroid exposure. Multivariate logistic regression and eXtreme Gradient Boosted decision tree [GBDT] machine learning methods evaluated antibiotic risks.

Results: Two cohorts with 15 636 and 5178 patients were analysed for risk of hospitalization and course of steroids, respectively. The risk of a flare-up was significantly increased with antecedent exposure to quinolones (ATC:J01M; odds ratio [OR]: 3.04-3.82), antimycotics [ATC:J02A; OR: 1.50-2.30], agents against amoebiasis and protozoal infections [ATC:P01A; OR: 1.95-3.18], intestinal anti-infectives [ATC:A07A; OR: 2.09-2.32], and beta-lactam antibiotics [ATC:J01C; OR: 1.36]. The GBDT models achieved an area under the curve of 0.71-0.85 for predicting flare-ups, with the same above-mentioned antibiotics being in the ten most important variables.

Conclusion: We found distinctive antibiotics to be significantly associated with an increased risk of IBD flare-ups. Our findings are corroborated by our GBDT machine learning models. Healthcare providers should be aware of the deleterious potential of specific antibiotic groups in patients with IBD only using these agents in a restrictive manner or preferentially consider alternative antibiotic groups.

Background and aims: Intestinal fibrotic stenosis is a major reason for surgery in Crohn's disease [CD], but the mechanism is unknown. Thus, we asked whether intestinal adipocytes contribute to intestinal fibrosis. Adipocytes were found to transdifferentiate into myofibroblasts and confirmed to be involved in mesenteric fibrosis in our recent study. Here, we investigated the role and possible mechanisms of intestinal adipocytes in intestinal fibrosis in CD.

Methods: The intestinal tissue of patients with CD with or without fibrotic stenosis [CDS or CDN] and normal intestinal tissue from individuals without CD were obtained to assess alterations in submucosal adipocytes in CDS and whether these cells transdifferentiated into myofibroblasts and participated in the fibrotic process. Human primary adipocytes and adipose organoids were used to evaluate whether adipocytes could be induced to transdifferentiate into myofibroblasts and to investigate the fibrotic behaviour of adipocytes. LPS/TLR4/TGF-β signalling was also studied to explore the underlying mechanism.

Results: Submucosal adipocytes were reduced in number or even absent in CDS tissue, and the extent of the reduction correlated negatively with the degree of submucosal fibrosis. Interestingly, submucosal adipocytes in CDS tissue transdifferentiated into myofibroblast-like cells and expressed collagenous components, possibly due to stimulation by submucosally translocated bacteria. Lipopolysaccharide [LPS]-stimulated human primary adipocytes and adipose organoids also exhibited transdifferentiation and profibrotic behaviour. Mechanistically, TLR4-mediated TGF-β signalling was associated with the transdifferentiation and profibrotic behaviour of intestinal adipocytes in CDS tissue.

Conclusions: Intestinal adipocytes transdifferentiate into myofibroblasts and participate in the intestinal fibrosis process in CD, possibly through LPS/TLR4/TGF-β signalling.

Background and aims: Fistula formation is a major complication in Crohn's disease [CD] and the role of the immune cell compartment remains to be elucidated. Thus, we compared the immune cell compartment of CD fistula to inflammatory CD colitis using imaging mass cytometry [IMC] and immunofluorescence.

Methods: A 36-marker panel including structural, functional, and lineage markers for use in IMC was established. This panel was applied to analyse paraffin-embedded CD fistula tract [n = 11], CD colitis [n = 10], and colon samples from non-inflamed controls [n = 12]. Computational methods for cell segmentation, dimensionality reduction, and cell type clustering were used to define cell populations for cell frequency, marker distribution, and spatial neighbourhood analysis. Multiplex immunofluorescence was used for higher resolution spatial analysis.

Results: Analysis of cell frequencies in CD fistulas compared to CD colitis and control colonic samples revealed a significant increase in neutrophils, effector cytotoxic T cells, and inflammatory macrophages in CD fistula samples, whereas regulatory T cells were decreased. Neutrophils in CD fistula expressed significantly more matrix metalloproteinase 9 [MMP9], correlating with extracellular matrix remodelling. Neighbourhood analysis revealed a strong association between MMP9+ neutrophils and effector cytotoxic T cells in both CD fistulas and colitis.

Conclusions: This study presents the first highly multiplexed single cell analysis of the immune cell compartment of CD fistulas and their spatial context. It links immune cell dynamics, particularly MMP9+ neutrophils, to extracellular matrix remodelling in CD fistulas, offering insights into the complex network of cellular interactions and potential therapeutic targets for CD complications.

Background: We aimed to evaluate outcomes of robotic versus conventional laparoscopic colorectal resections in patients with inflammatory bowel disease [IBD].

Methods: Comparative studies of robotic versus laparoscopic colorectal resections in patients with IBD were included. The primary outcome was total post-operative complication rate. Secondary outcomes included operative time, conversion to open surgery, anastomotic leaks, intra-abdominal abscess formation, ileus occurrence, surgical site infection, re-operation, re-admission rate, length of hospital stay, and 30-day mortality. Combined overall effect sizes were calculated using a random-effects model and the Newcastle-Ottawa Scale was used to assess risk of bias.

Results: Eleven non-randomized studies [n = 5566 patients] divided between those undergoing robotic [n = 365] and conventional laparoscopic [n = 5201] surgery were included. Robotic platforms were associated with a significantly lower overall post-operative complication rate compared with laparoscopic surgery [p = 0.03]. Laparoscopic surgery was associated with a significantly shorter operative time [p = 0.00001]. No difference was found in conversion rates to open surgery [p = 0.15], anastomotic leaks [p = 0.84], abscess formation [p = 0.21], paralytic ileus [p = 0.06], surgical site infections [p = 0.78], re-operation [p = 0.26], re-admission rate [p = 0.48], and 30-day mortality [p = 1.00] between the groups. Length of hospital stay was shorter following a robotic sub-total colectomy compared with conventional laparoscopy [p = 0.03].

Conclusion: Outcomes in the surgical management of IBD are comparable between traditional laparoscopic techniques and robotic-assisted minimally invasive surgery, demonstrating the safety and feasibility of robotic platforms. Larger studies investigating the use of robotic technology in Crohn's disease and ulcerative colitis separately may be of benefit with a specific focus on important IBD-related metrics.

There is a knowledge gap on the epidemiology of inflammatory bowel disease in Africa. To begin to address this issue we formed a case reporting network of practitioners with an interest in inflammatory bowel disease across sub-Saharan Africa. Here we report a series of 175 cases from 12 countries over 2 years.

Background and aims: Pragmatic studies designed to test interventions in everyday clinical settings can successfully complement the evidence from registration and explanatory clinical trials. The European consensus project PRACTICE-IBD was developed to identify essential criteria and address key methodological issues needed to design valid, comparative, pragmatic studies in inflammatory bowel diseases [BDs].

Methods: Statements were issued by a panel of 11 European experts in IBD management and trial methodology, on four main topics: [I] study design; [II] eligibility, recruitment and organisation, flexibility; [III] outcomes; [IV] analysis. The consensus process followed a modified Delphi approach, involving two rounds of assessment and rating of the level of agreement [1 to 9; cut-off ≥7 for approval] with the statements by 18 additional European experts in IBD.

Results: At the first voting round, 25 out of the 26 statements reached a mean score ≥7. Following the discussion that preceded the second round of voting, it was decided to eliminate two statements and to split one into two. At the second voting round, 25 final statements were approved: seven for study design; six for eligibility, recruitment and organisation, flexibility; eight for outcomes; and four for analysis.

Conclusions: Pragmatic, randomised, clinical trials can address important questions in IBD clinical practice, and may provide complementary, high-level evidence, as long as they follow a methodologically rigorous approach. These 25 statements intend to offer practical guidance in the design of high-quality, pragmatic, clinical trials that can aid decision making in choosing a management strategy for IBDs.