Journal of Crohn's & colitis最新文献

Background and aims: Immunogenicity and the development of an undetectable drug level is a modifiable cause of anti-tumor necrosis factor (anti-TNF) treatment failure. We modeled the clinical utility of pre-treatment HLA-DQA1*05:01 and HLA-DQA1*05:05 allele subtype testing to guide immunomodulator use in patients with Crohn's disease treated with an anti-TNF.

Methods: The Personalised Anti-TNF Therapy in Crohn's Disease study is a UK-wide, prospective observational study of infliximab and adalimumab in anti-TNF-naïve patients with active Crohn's disease. Rates of drug-clearing antibody development, defined by the presence of anti-TNF antibodies and undetectable drug levels, were estimated using the Kaplan-Meier method. Genetic association tests were performed using Cox proportional hazards regression.

Results: About 40% of participants carried an actionable HLA-DQA1*05 allele subtype. HLA-DQA1*05:01 (hazard ratio [HR] 1.87 [95% CI: 1.37-2.53], P < .0001) and HLA-DQA1*05:05 (HR 2.45 [95% CI: 1.32-4.54], P = .004) were the most significant allele subtypes associated with the development of drug-clearing antibodies in infliximab- and adalimumab-treated patients, respectively. Immunomodulator use increased the time to drug-clearing antibodies in all patients treated with infliximab. In adalimumab-treated patients, only individuals who carried the HLA-DQA1*05:05 allele subtype benefited from combination immunomodulator use with a number needed to treat of 4.6 (95% CI: 2.4-20.5) to prevent one episode of a drug-clearing antibody.

Discussion: Pre-treatment four-digit HLA testing informs on anti-TNF treatment choice and immunomodulator use. In HLA-DQA1*05:01 carriers, adalimumab monotherapy should be used and infliximab avoided. In HLA-DQA1*05:05 carriers, infliximab or adalimumab can be used with a concomitant immunomodulator. In patients who do not carry either HLA-DQA1*05:01 or HLA-DQA1*05:05, adalimumab monotherapy or infliximab with a concomitant immunomodulator are recommended.

Background: With the increasing number of effective therapies for inflammatory bowel diseases (IBD), determining optimal treatment sequences is challenging. Given the impracticality of conducting randomized head-to-head trials for every comparison, this study assessed whether phase 3 placebo-controlled trials can reliably predict outcomes of published head-to-head studies.

Methods: Three randomized head-to-head trials without placebo arms were analyzed alongside their corresponding phase 3 placebo-controlled trials. Effect sizes for clinical and endoscopic endpoints were extracted for comparison.

Results: In the VARSITY trial, vedolizumab achieved an 8.8% higher clinical remission rate than adalimumab at week 52 in patients with ulcerative colitis. Placebo-controlled studies estimated a 17.3% advantage for vedolizumab; however, differences in trial design and patient populations between GEMINI-1 and ULTRA-2 limit the robustness of this indirect comparison.In Crohn's disease, indirect comparisons of IM-UNITI, CLASSIC-II, and CHARM suggested an 11.6-18.6% higher efficacy for adalimumab compared with ustekinumab in biologic-naïve patients, yet the SEAVUE head-to-head trial found no significant difference at week 52.Most recently, the SEQUENCE trial demonstrated a + 15.6% superiority of risankizumab over ustekinumab in endoscopic remission at week 48 among bio-exposed Crohn's disease patients, whereas indirect comparisons between FORTIFY and IM-UNITI were confounded by clinically relevant population differences.

Conclusion: Significant heterogeneity in trial design, populations and outcome reporting limits the predictive value of placebo-controlled trials. Randomized head-to-head trials remain essential for optimizing IBD therapeutic strategies.

Introduction: The IBD U.K. Benchmarking surveys, conducted in 2019 and 2023 collected repeated data regarding the quality of inflammatory bowel disease (IBD) care across the U.K. using both service self-assessments and patient-reported experience measures (PREMs). We aimed to assess variation between patient and provider perspectives.

Methods: All U.K. hospitals offering specialist IBD services were invited to complete online surveys. Patients were invited through social media, charities, and clinical services. This study compared changes over the four-years and examined alignment between healthcare-reported and patient-reported assessments.

Results: From 26,760 patient responses and 154 service assessments, patient perceived care quality (PPCQ) declined between 2019 and 2023 (P <0.001). Male sex and older age were associated with higher PPCQ. Greater disease severity was associated with lower PPCQ (P <0.001). More patients reported IBD symptoms to impact activities of daily living in 2023 (P <0.001). Factors associated with higher PPCQ included rapid diagnosis, being supported by an IBD team and having knowledgeable IBD nurses. Access, information, communication and empowerment were identified by patients as needing improvement (P <0.001). Services with lowest quartile quality scores in 2019, demonstrated significant improvement over time, whilst those with highest 2019 scores demonstrated significant deterioration in PPCQ (P <0·001). Services reported better performance than patients (P <0.001).

Conclusions: This data underscores the importance of assessing lived experience and the care quality perception gap between patients and service providers. Regular benchmarking including PREMs should be used to drive and assess service-level, national and international quality improvement initiatives.

Background and aims: Faecal microbiota transplantation (FMT) is a promising therapy for ulcerative colitis, but variable responses and unclear mechanisms limit its efficacy. We aimed to compare nasogastric versus colonic FMT delivery and define the microbial and immunological changes associated with clinical response.

Methods: In this prospective, open-label, randomised pilot trial (STOP-Colitis), 30 adults with active ulcerative colitis were randomised to receive multi-dose FMT via nasogastric tube or colonoscopy with subsequent enemas. Key endpoints were clinical outcomes at week 8 and longitudinal multi-omic analyses of stool and biopsies to define changes in microbial composition (16S rRNA and shotgun metagenomics), short-chain fatty acids, mucosal T-cells, and host gene expression.

Results: Colonic FMT was superior to nasogastric delivery, with a higher clinical response rate at week 8 (75% [9/12] vs 25% [2/8]; RR 2·94, 95% CI 0·84-10·30-per protocol analysis). Response was underpinned by successful microbial engraftment, leading to significantly increased faecal microbial diversity and enrichment of SCFA-producing taxa, including Oscillospiraceae and Christensenellaceae. This correlated with reduced faecal calprotectin. Responders showed a significant increase in mucosal regulatory T cells (P = 0·01), with a concurrent decrease in Th17 (P = 0·03) and CD8 + T cells. This anti-inflammatory shift was confirmed by mucosal transcriptomics, which revealed upregulation of metabolic pathways and downregulation of proinflammatory defence pathways in responders. (Trial registration: ISRCTN13636129).

Conclusion: Colonic FMT is a more effective delivery route than nasogastric administration. Clinical response is driven by the engraftment of immunomodulatory bacteria that restore a healthy host-microbe dialogue, providing rationale for developing targeted microbial therapeutics.

Background: Filgotinib, a Janus kinase 1-preferential inhibitor, is approved for the treatment of moderately to severely active ulcerative colitis (UC).

Aim: To assess the effects of filgotinib on endo-histological outcomes and tissue RNA sequencing data from the SELECTION trial (NCT02914522).

Methods: This analysis assessed single and composite endo-histological improvement and remission endpoints at week (W) 10 and W58 in patients with moderately to severely active UC receiving once-daily filgotinib 200 mg (FIL200) or 100 mg, or placebo. Post hoc RNA sequencing analysis was performed on colonic mucosal biopsies from baseline and W10. Comparisons were made between patients who did and did not achieve endo-histological outcomes at W10 and treatment arms.

Results: Greater proportions of patients achieved single and composite endo-histological improvement and remission endpoints with FIL200 than placebo at W10 and W58 (endo-histological remission, W10: 6.7% vs 1.8%; P = 0.0021; W58: 12.1% vs 5.1%; P = 0.0485). Differentially expressed genes between baseline and W10 that were associated with histologic remission at W10 had upregulated and downregulated expression opposite to that of an active UC signature. Patients treated with FIL200, achieving endoscopic improvements or histological remission, exhibited reduced neutrophil-related gene expression (eg, neutrophil migration, P <0.0001) and enriched gene expression for mitochondrial activity and epithelial repair compared with those without (eg, PADI2, log2(fold change) = 2, P <0.0001).

Conclusions: Filgotinib improved endo-histological outcomes in patients with UC, with a dose-dependent effect on transcription. Gene expression changes and enriched pathways suggest that achieving endoscopic and histological endpoints in patients receiving FIL was associated with the restoration of mucosal homeostasis.

Background: Crohn's disease (CD) is characterized by epithelial barrier dysfunction and mucosal immune dysregulation. Dietary interventions have gained increasing attention as important therapeutic strategies. We evaluated whether an intermittent ketogenic diet (IKD), which elevates β-hydroxybutyrate (BHB), ameliorates CD via lysine β-hydroxybutyrylation (Kbhb) and elucidated the underlying mechanisms.

Methods: IL-10 knockout mice were allocated to three groups: continuous KD (ketogenic diet), IKD, or a normal diet. Disease activity index (DAI), histopathological changes, cytokine levels, and epithelial barrier integrity were evaluated. Regulatory T cells (Tregs) and Foxp3 expression were assessed by flow cytometry and quantitative real-time PCR (qRT-PCR). To elucidate the underlying mechanisms, we conducted metabolomic and transcriptomic analyses, pyrosequencing, and additional experiments.

Results: Both KD and IKD alleviated colonic inflammation, but IKD better prevented epithelial senescence. IKD increased colonic Treg infiltration and Foxp3 expression. Metabolomics revealed elevated BHB in IKD colons. BHB reduced inflammation and promoted Treg differentiation in a dose-dependent manner. Mechanistically, BHB induced Kbhb of S-adenosylhomocysteine hydrolase (AHCY), inhibiting its activity, leading to S-adenosylhomocysteine (SAH) accumulation, downregulating DNA methyltransferase 1 (DNMT1), and promoting Foxp3-TSDR demethylation to enhance Foxp3 transcription and Treg differentiation. IKD also enriched Akkermansia muciniphila, supporting gut and systemic BHB levels.

Conclusions: In an IL-10 knockout model, IKD improves intestinal barrier function and reshapes the gut microbiota. It is associated with BHB-induced Kbhb-mediated inhibition of AHCY, leading to SAH accumulation and DNMT1 downregulation, thereby promoting Treg differentiation. These findings suggest protective effects of IKD in the IL-10 knockout colitis model.