Journal of Crohn's & colitis最新文献

Background and aims: We conducted a prospective study (FAVOUR) of patients with ulcerative colitis (UC) commencing vedolizumab to investigate fecal vedolizumab loss and its impact on serum levels and treatment outcomes.

Methods: FAVOUR recruited patients with moderate-to-severe UC commencing vedolizumab. Fecal vedolizumab levels (FVL) were measured at days 1, 4, and 7 and at weeks 2, 6, and 14. Trough serum vedolizumab levels (SVL) were measured at weeks 2, 6, and 14.

Results: In total, 36 patients were recruited, of whom 33 completed induction therapy. Fecal vedolizumab was detectable in 80/203 (39%) samples. Statistically significant, positive correlations were observed between FVL and clinical, biochemical, baseline endoscopic, and histologic disease activity at day 1, 4, and 7 as well as weeks 2 and 6. Week 14 clinical non-responders had higher FVL than responders at that timepoint (median 1.0 vs 0.0 µg/g, P = .004) but not at other timepoints. Area-under-the-curve analysis of FVL was used to quantify cumulative vedolizumab stool loss. This demonstrated significant differences between week 14 clinical responders and non-responders (44 µg/g/day, 95% CI: 0-128 vs 233 µg/g/day, 95% CI 0-1139, P < .0001), as well as between endoscopic responders and non-responders (48 µg/g/day, 95% CI 0-142 vs 179 µg/g/day, 95% CI 0-142, P = .0017), with non-responders having a higher rate of cumulative loss.

Conclusions: Active UC results in fecal loss of vedolizumab. This correlates with lower SVL and decreased response to treatment. Fecal loss of vedolizumab may be a marker of disease activity and/or result in lower rates of drug exposure at a tissue level, negatively impacting response.

Introduction: Clinicians have several imaging options to evaluate suspected or confirmed small bowel Crohn's disease (SB-CD), including computed tomography enterography (CTE), magnetic resonance enterography (MRE), intestinal ultrasound (IUS), and video capsule endoscopy (VCE).

Methods: Direct head-to-head comparative analysis and network meta-analysis were conducted on all available modalities using a random effects model. Furthermore, each modality was ranked using the surface under the cumulative ranking curve approach (P-score).

Results: The present review included 29 studies with a total population of 2609 individuals. The pooled sensitivity, specificity, and diagnostic accuracy for the detection of SB-CD were 89.6%, 86.2%, and 71.5% for VCE; 82%, 71.6%, and 67.9% for MRE; 79.6%, 82.7%, and 52.3% for CTE; and 89.3%, 72%, and 71% for IUS, respectively. The network meta-analysis found that VCE exhibited superior diagnostic accuracy compared to CTE and MRE, while demonstrating comparable performance between VCE and IUS, as well as among MRE, CTE, and IUS. Further, the ranking analysis positioned VCE (P-score .97) as the most effective diagnostic modality for SB-CD, followed by IUS, MRE, and CTE. Subgroup analysis showed that VCE had significantly better diagnostic accuracy than the other modalities for detecting proximal SB-CD. Regarding adverse events, VCE was associated with capsule retention in 3.3% of the cases in these studies.

Conclusions: VCE exhibited superior diagnostic performance for detecting established proximal SB-CD compared to other imaging modalities. Clinicians should weigh the benefits and risks, and incorporate other modalities, such as MRE and IUS to optimize diagnosis and management.

Background and aims: Outcomes of patients admitted with acute severe ulcerative colitis (ASUC) in the post biologic era are under explored, as well as the ability of scoring indices to predict early steroid non-response.

Methods: This retrospective cohort study included adults hospitalized with ASUC (2010-2022) at London Health Sciences Centre, Canada. Steroid response, need for rescue therapy, colectomy during index hospitalization, and colectomy and hospitalization at 3- and 12-months following discharge was assessed. Logistic regression identified predictors of steroid non-response, defined as need for rescue therapy or colectomy during hospitalization.

Results: Of 261 adults hospitalized with ASUC (male: 51.7%, mean age: 40.6 years), 71.2% had extensive colitis. After intravenous corticosteroid therapy during index admission, 55.7% (n = 147) had a response, 37.9% (n = 99) received rescue therapy (infliximab: 98, tofacitinib: 1, and cyclosporine: 0), and 8% (21/261) underwent colectomy. Additionally, 11.6% (28/240) of patients discharged from hospital underwent colectomy within the first 12 months (8.3% at 3-months and 3.3% between 3 and 12 months). There was no difference between steroid responders and non-responders for colectomy (11% vs 12.6%) or hospitalization (33.5% vs 32.6%) at 12 months. The overall cumulative probabilities of colectomy for the entire cohort at 1 year, 3 years, and 5 years were 13.5%, 16.1%, and 17.4%, respectively. On multivariate analysis, Day 3 Oxford criteria was the only factor found to be statistically significant in predicting steroid non-response (odds ratio 4.70, 95%CI [1.06-20.80]).

Conclusions: Day 3 Oxford criteria was an independent predictor of steroid non-response. The risk of colectomy remains substantial after discharge despite low in-hospital colectomy rates following an episode of ASUC. Initial steroid response did not affect long-term colectomy rate at 12 months.

Background and aims: Intestinal fibrosis in Crohn's disease (CD) frequently leads to stricture formation, with current treatment options limited to endoscopic balloon dilation and surgery. This underscores the urgent need for anti-fibrotic therapies. Our objective was to identify therapeutic targets and compounds capable of reversing the fibrotic gene expression profile of mucosal fibroblasts in CD.

Methods: We derived a fibrotic gene signature via fibroblasts isolated from stricturing CD tissue and conducted a meta-regression analysis across three publicly available transcriptomic datasets, to identify key differentially expressed genes (DEGs) in fibrostenotic CD. Drug repurposing platforms (iLINCS, L1000, CLUE-io) were implemented to screen compounds with high druggability, for their potential to reverse this pro-fibrotic profile. Transcription factors, microRNAs, and drugs targeting the fibrostenotic signature were identified using the TRRUST, miRWalk, and DGIdb databases, ultimately forming a drug-gene interaction network. The STITCH platform was used to predict compound-protein binding affinities. Promising compounds were subsequently evaluated in vitro, using mucosal fibroblasts derived from fibrostenotic CD patients, and the effect on the expression of selected protein targets was measured via ELISA and immunofluorescence staining.

Results: The top upregulated DEGs included fibroblast activation protein (FAP), IL-7 receptor, and transcription factor AP-2 gamma. The drug-gene interaction network analysis identified IL-6 among the most druggable targets. Of 6783 pharmaceutical agents, PI3K inhibitors and histone deacetylase blockers were the most effective in reversing the fibrotic signature via a FAP- and IL-6-dependent mechanism.

Conclusion: This integrative approach identified potential anti-fibrotic compounds and molecular targets in CD-associated fibrostenosis, supporting future development of effective therapies.

Background and aims: Intestinal ultrasound (IUS) is increasingly used to monitor treatment efficacy in inflammatory bowel disease (IBD) trials. However, standardized definitions for response, remission, and optimal assessment timing remain undefined. An international expert consensus meeting was held to establish IUS endpoints for clinical trials.

Methods: A panel of 35 international gastroenterologists and radiologists participated in a modified Delphi process, reviewing the literature and developing consensus statements. Agreement was defined as at least 75% consensus.

Results: Consensus was reached on 150 statements across four domains: general IBD (30 statements), luminal Crohn's disease (CD) (43), perianal CD (51), and ulcerative colitis (UC) (26). For luminal CD and UC, ultrasound response was defined by: (1) a ≥25% reduction in bowel wall thickness (BWT) from baseline, or (2) multifactorial improvement, combining BWT reduction with ≥1 grade decrease in color Doppler signal (CDS) or another IUS parameter. Assessments were set at weeks 4-8 for the colon and week 12 for the terminal ileum. Ultrasound remission in luminal CD was defined as: (1) BWT normalization (≤3 mm) or (2) normalization of multiple parameters, including BWT, CDS, and all other IUS parameters. Similar remission criteria were proposed for UC, but the sigmoid BWT normal range (3-4 mm) remained uncertain. The bowel ultrasound score (BUSS) for CD and the Milan ultrasound criteria (MUC) for UC were supported as standardized scoring systems for trials.

Conclusion: This consensus provides standardized IUS definitions to enhance consistency in IBD trials, supporting the integration of IUS in future research.

Background and aims: This study aims to evaluate the real-life durability of biologic therapies and to identify factors associated with biologic persistence in pediatric inflammatory bowel disease (IBD).

Methods: We analyzed data from the IBD-registry of the Italian Society of Pediatric Gastroenterology, Hepatology, and Nutrition (SIGENP) of patients initiating biologics between 2009 and 2022 and ≥1-year follow-up.

Results: A total of 1184 patients (747 with Crohn's disease [CD], 437 with ulcerative colitis or IBD unclassified [UC/IBD-U]) were included, accounting for 1709 treatment courses. The median follow-up was 43 months (interquartile range 28-64). Overall, 33% received a second-line biologic, 9% third-line, and 2% fourth-line. First-line biologic durability was significantly lower in UC/IBD-U vs CD, with inferior persistence at 1, 2, and 3 years (61%, 51%, and 44% vs 88%, 75%, and 67%; hazard ratios [HR]: 1.5, 95% confidence interval [CI] 1.2-1.9, P = .002). In CD, infliximab had inferior durability then adalimumab (72%, 59%, and 50% vs 91%, 82%, and 77%; HR 2.0, 95% CI, 1.5-2.7, P < .0001). In both CD and UC/IBD-U, age <6 years was a risk factor for treatment discontinuation (HR 1.8, 95% CI, 1.2-2.7, P < .01) while therapeutic drug monitoring (TDM) emerged as protective (HR 0.5, 95% CI, 0.4-0.7, P < .0001). Combination with an immunomodulator had no significant impact on durability (HR 0.9, 95% CI, 0.8-1.2, P = .54).

Conclusions: Biologic persistence varied by disease type and biologic agent. TDM was associated with longer treatment durability, while combination therapy had a limited effect. Further prospective studies are needed to refine biologics optimization strategies in pediatric IBD.

Background and aims: Janus kinase inhibitors (JAKi) provide effective treatment for ulcerative colitis (UC), but inadequate response (IR) or intolerance occurs frequently. This study aimed to assess the effectiveness of a second JAKi in a real-world UC cohort.

Methods: A retrospective multicenter cohort study encompassing 19 UK hospitals was undertaken. Primary outcome was clinical remission (Simple Clinical Colitis Activity Index/partial Mayo Score ≤ 1) at weeks 8 and 24, based on available assessments. Biochemical (CRP ≤ 5mg/L and fecal calprotectin ≤ 200µg/g) and endoscopic (Ulcerative Colitis Endoscopic Index of Severity/Mayo Endoscopic Subscore ≤ 1) remission were also assessed.

Results: A total of 131 patients with active UC were included. The majority (60%) had exposure to ≥3 advanced therapies and 50% required corticosteroids at induction. Clinical remission rates were 59% and 51% at weeks 8 and 24. Biochemical and endoscopic remission rates were 61% and 60% at week 8, and 47% and 32% at week 24. All disease activity parameters significantly reduced by week 8 (P < .001). At week 24 no difference was detected in clinical remission rates between those with primary non-response (42%) or secondary loss of response (52%) to their first JAKi (P = .518). Clinical remission did not differ between upadacitinib (54%) and filgotinib (36%), P = .253. Adverse events occurred in 27% of patients, and serious adverse events in 8%.

Conclusions: In this highly refractory cohort with active UC a second JAKi effectively achieved remission following IR to first JAKi. Type of first JAKi failure did not appear to influence clinical remission. No new safety signals were found.