Inflammatory Bowel Diseases最新文献

Inflammatory bowel disease (IBD), namely Crohn's disease (CD) and ulcerative colitis (UC), are defined by chronic, non-resolving inflammation of the intestinal mucosa. Neutrophils are the first responders in inflammation, executing various effector functions, including chemotaxis, phagocytosis, degranulation and the release of cytokines, reactive oxygen species (ROS) and neutrophil extracellular traps (NETs). Amongst all neutrophil functions, emerging evidence increasingly suggests that NET release may be particularly relevant in underpinning the pathogenesis of IBD. NETs are extracellular structures composed of chromatin, antimicrobial proteins, and oxidative enzymes released by neutrophils to trap and neutralize pathogens. In this review, we discuss the protective roles of NETs in intestinal health and how, under tight physiological regulation, they can prevent pathogenic invasion, exert anti-inflammatory effects, and play an important role in wound healing and intestinal tissue repair. Conversely, we consider how inflammation-driven changes in neutrophil activation, phenotype and immunometabolism can cause dysregulation in NET production and clearance and lead to harmful intestinal effects that can prolong intestinal and chronic inflammation in IBD. Specifically, we explore how uncontrolled NET production can damage intestinal epithelial integrity, increase bacterial translocation and increase thromboembolic risk, ultimately linking NETs to the pro-inflammatory pathogenesis of IBD.

Background: Pediatric Inflammatory Bowel Disease (IBD) is a chronic condition characterized by persistent intestinal inflammation in children. It often presents with distinct clinical phenotypes and is more frequently linked to rare monogenic variants affecting epithelial barrier function or mucosal immunity. Although over 100 genes are associated with monogenic IBD, their roles in the intestinal epithelium remain poorly defined. This study aimed to improve our understanding of epithelial dysfunction in early-onset IBD through molecular and cellular analyses to uncover patient-specific phenotypes and potential therapeutic targets.

Methods: We generated intestinal epithelial organoids (IEOs) from 94 pediatric IBD patients, including those with monogenic variants (BTK, TTC7A, IL10RA, LRBA, STXBP2, TRNT1, SKIV2L), along with 46 non-IBD controls. RNA sequencing was performed on 38 patient and 20 control lines, under both baseline conditions and after immunological stimulation, yielding a valuable dataset for studying epithelial responses in IBD.

Results: IEOs effectively initiated inflammation upon bacterial lysate stimulation, regardless of disease status, origin, or genotype. Inflammatory stimulation triggered upregulation of IBD-linked genes SERPINA1 and LIFR in IBD organoids, suggesting their role in epithelial innate immunity. However, network analysis showed no consistent transcriptional signatures across all IBD cases. Instead, specific genotypes (TTC7A, STXBP2, LRBA) revealed responses, with STXBP2 and LRBA showing shared upregulation of IL-1 and SLC30-mediated zinc trafficking pathways.

Conclusions: These findings underscore the potential of IEOs as a valuable model for studying IBD and offer key insights that could guide the development of targeted therapies for both monogenic and non-monogenic forms of IBD.

Background: Previous reviews for Crohn's disease (CD) treatment have rarely considered advanced and immunomodulator medical therapies together. Our aim was to compare all therapies for efficacy and safety in induction of remission.

Methods: We searched databases up to June 2025. Our outcomes were clinical remission and response, endoscopic remission, and safety outcomes. We performed network meta-analyses and estimated risk ratios (RR) and 95% CIs. We used GRADE to assess certainty of results, and surface under the cumulative ranking curve for ranking treatments.

Results: A total of 79 RCTs with 20 724 participants were included. Interventions ranged from 2 to 30 weeks. There was moderate GRADE certainty of effectiveness over placebo for clinical remission for combination of adalimumab with thiopurines (RR, 2.87; 95% CI, 1.99-4.14; RD (Risk difference)  = 35.3%; NNT (Number needed to treat) = 3, large magnitude), guselkumab (RR, 2.5; 95% CI, 1.95-3.21; RD = 28.4%; NNT = 4, moderate magnitude, adalimumab (RR, 2.46; 95% CI, 1.84-3.29; RD = 27.6% NNT = 4, moderate magnitude), combination of infliximab with thiopurines (RR, 2.43; 95% CI, 1.71-3.44; RD = 27%; NNT = 4, moderate magnitude), and ustekinumab (RR, 2.04; 95% CI, 1.69-2.46; RD = 19.6% NNT = 5, small magnitude). For endoscopic remission, there was moderate GRADE certainty of effectiveness for risankizumab (RR, 3.48; 95% CI, 2.18-5.58; RD = 17.4%, moderate magnitude). The certainty on safety varied, but treatments appear generally safe in the short term.

Conclusion: Combination of anti-tumor necrosis factors (anti-TNFs) and immunomodulators followed by anti-TNF monotherapy had large effect size with moderate certainty for the induction of clinical remission. More novel therapies appear to have similar effect sizes but with increased imprecision of the estimates.

Background: The effect of sarcopenia on clinical outcomes in children with Crohn's disease (CD) is unknown. We investigated whether sarcopenia at the diagnosis impacts the outcomes of children with CD.

Methods: This was a retrospective, single-center, case-control study of newly diagnosed children with CD undergoing magnetic resonance (MR) within 1 month from the diagnosis, from 2011 to 2022. Sarcopenia was assessed by measuring total psoas muscle area (tPMA) at L3-L4 level on the MR and defined as z-score values ≤2 SDs. Children with and without sarcopenia were compared for the risk of disease flares, CD-related hospitalization, complications, need for step-up treatment, and courses of steroids over a 2-year follow-up.

Results: Seventy-eight children were included (median age 10.7 years), 46 (59%) with sarcopenia and 32 (41%) without. The risk of clinical relapse was higher in patients with sarcopenia at 6 [19.5% vs 3%, odds ratio (OR) 7.5 (95% CI, 1.5-85)] and 12 months [30% vs 6%, OR 6.5 (95% CI, 1.4-30.4)]. Kaplan-Meier analysis showed lower survival free from relapses in children with sarcopenia (log rank P = .01, hazard ratio 2.7, 95% CI, 1.4-4.5). Multivariate analysis identified sarcopenia as independent predictors of clinical relapses (OR 1.7, 95% CI, 1-3.1, P = .045). No other independent predictor of unfavorable outcome was detected.

Conclusions: The presence of sarcopenia at the diagnosis increases the risk of clinical relapses in the first year of diagnosis. Magnetic resonance evaluation of the tPMA could therefore help identify children at higher risk of worse outcomes.

Background: The systematic review and meta-analysis (SRMA) evaluates the safety and effectiveness of combining biologics and/or small molecules in treating refractory inflammatory bowel diseases (IBD).

Methods: Our 2022 SRMA identified 13 studies published until November 3, 2020. An updated systematic search was completed from May 2020 through January 31, 2024. Random-effects inverse variance model was used to calculate pooled estimates for adverse events (AEs) and clinical and endoscopic-radiologic response/remission rates in IBD patients.

Results: Twenty-seven eligible studies had 619 patients and 631 therapeutic trials (TTs). Upadacitinib (UPA) + vedolizumab (VDZ) and tofacitinib (Tofa) + anti-TNF (aTNF) had the lowest AEs rate (0%, 2 TTs) and (9.2%, 33 TTs), respectively. Higher AE rates were seen in natalizumab (NAT) + aTNF (92.3%, 52 TTs) and aTNF + guselkumab (63.4%, 71 TTs). No serious AEs (SAEs) were observed in NAT + aTNF (52 TTs), Tofa + ustekinumab (UST) (23 TTs), and UPA + VDZ (2 TTs). The highest rate of SAEs was observed in UPA + UST (23%, 17 TTs). UPA + UST and UPA + VDZ had 100% clinical response rates and the highest clinical remission rates (83.3%, 12 TTs) and (100%, 2 TTs), respectively. High clinical response rates were also seen in Tofa + aTNF (82.7%, 34 TTs), UST + aTNF (82.1%, 63 TTs), and VDZ + UST (82.0%, 71 TTs).

Conclusions: Combining biologics and/or small molecules may be effective for IBD patients who fail to achieve remission with monotherapy; however, safety profiles need to be carefully considered prior to implementing these strategies in clinical practice.