Inflammatory Bowel Diseases最新文献

Background: Historically, randomized controlled trials (RCTs) have been criticized for being poorly generalizable to patients with ulcerative colitis (UC) evaluated in routine care. We aimed to evaluate the proportion of patients with UC starting an advanced therapy who would be eligible to participate in phase 3 registrational UC RCTs.

Methods: We conducted a retrospective cohort analysis of UC patients starting vedolizumab, ustekinumab, or tofacitinib at 2 IBD clinics at the University of Calgary. Patient charts, endoscopy reports, and laboratory results were reviewed, and compared against the inclusion and exclusion criteria from 5 RCTs (GEMINI-I, UNIFI, OCTAVE, ELEVATE, and LUCENT). The proportion of patients who would have been deemed eligible versus ineligible for trial participation at the time of starting a new advanced therapy was determined.

Results: A total of 125 patients with UC were included: 78 (62.4%) would have been eligible for at least one of the considered RCTs. Trial-eligible patients were younger, less likely to be exposed to prior immunosuppressants, and had higher C-reactive protein and fecal calprotectin. The most common reason for trial ineligibility was having inadequate disease activity at baseline (Mayo endoscopy subscore <2 or absence of rectal bleeding). A significantly greater proportion of patients would have been eligible for LUCENT (45.6%) compared to GEMINI-I (24.8%), OCTAVE (35.2%), or ELEVATE (35.2%) (P < .01 for all comparisons).

Conclusions: Half of patients with UC starting advanced therapy in routine care may be eligible for participation in phase 3 RCTs. Disease activity is the primary reason for trial exclusion.

Background: Ulcerative colitis (UC) is a heterogeneous disease composed of different endotypes. It is important to develop useful biomarkers for endotyping UC; however, available biomarkers are insufficient. We have already established that periostin is a surrogate biomarker of type 2 inflammation. In this study, we examined the usefulness of periostin as a biomarker of UC and the role of periostin in its pathogenesis.

Methods: We examined periostin expression in the colons of UC patients. We next investigated serum periostin in UC patients and its correlation with eosinophilic infiltration in their colons. We then examined whether serum periostin could predict the efficacy of oral prednisolone. Finally, we investigated the role of periostin in UC pathogenesis by creating its genetic deficiency using dextran sulfate sodium (DSS)-treated mice.

Results: Periostin expression and serum periostin were significantly high in UC patients compared to healthy controls; however, both were diverse, showing heterogeneity of the underlying mechanism of UC. Both serum periostin and tissue periostin expression, but not blood eosinophils, were significantly associated with eosinophil infiltration. Type 2-dominant UC patients as defined by serum periostin showed significantly higher clinical remission rates for the treatment with oral prednisolone. Genetic deficiency in periostin improved colonic inflammation in a DSS-treated mouse model.

Conclusions: Periostin can be a useful biomarker to stratify type 2-dominant UC patients, thereby predicting the efficacy of oral prednisolone. Moreover, periostin plays an important role in the setting of type 2-dominant UC.

Background: Fecal microbiota, live-jslm (RBL; REBYOTA®), is the first single-dose, broad consortia, microbiota-based live biotherapeutic approved by the US Food and Drug Administration to prevent recurrent Clostridioides difficile infection (rCDI) in adults following standard-of-care antimicrobials. Inflammatory bowel disease (IBD) is a common risk factor for rCDI, yet patients with IBD are often excluded from prospective trials. This subgroup analysis of PUNCH CD3-OLS (NCT03931941) evaluated the safety and efficacy of RBL in participants with rCDI and IBD.

Methods: Participants with IBD (ulcerative colitis [UC], Crohn's disease [CD], or unspecified) who had rCDI were included. Treatment-emergent adverse event (TEAE) data were collected for up to 6 months following RBL administration. Efficacy outcomes included treatment success at 8 weeks and sustained clinical response at 6 months.

Results: Overall, 793 participants were enrolled, and 697 received RBL; 74 had IBD (UC: n = 45; CD: n = 25; unspecified IBD: n = 4). TEAEs within 8 weeks of administration were reported by 45.9% and 47.5% of participants with and without IBD, respectively; most were mild or moderate gastrointestinal symptoms. Serious TEAEs within 8 weeks of administration were reported by 1.4% and 4.2% of participants with and without IBD, respectively. The treatment success rate at 8 weeks was 78.9%, and the sustained clinical response rate at 6 months was 91.1% in participants with IBD, similar to rates in participants without IBD (73.2% and 91.0%, respectively).

Conclusions: The results of this subgroup analysis of PUNCH CD3-OLS suggest RBL is safe and efficacious in patients with IBD.

Background: We previously identified circulating and MRI biomarkers associated with the surgical management of Crohn's disease (CD). Here we tested associations between these biomarkers and ileal resection inflammation and collagen content.

Methods: Fifty CD patients undergoing ileal resection were prospectively enrolled at 4 centers. Circulating CD64, extracellular matrix protein 1 (ECM1), GM-CSF autoantibodies (GM-CSF Ab), and fecal calprotectin were measured by ELISA. Ileal 3-dimensional magnetization transfer ratio (3D MTR), modified Look-Locker inversion recovery (MOLLI) T1 relaxation, diffusion-weighted intravoxel incoherent motion (IVIM), and the simplified magnetic resonance index of activity (sMaRIA) were measured by MRI. Ileal resection specimen acute inflammation was graded, and collagen content was measured quantitatively using second harmonic imaging microscopy. Associations between biomarkers and ileal collagen content were tested.

Results: Median (interquartile range [IQR]) age was 19.5 (16-33) years. We observed an inverse relationship between ileal acute inflammation and collagen content (r = -0.39 [95% confidence interval {CI}: -0.61, -0.10], P = .008). Most patients (33 [66%]) received biologics, with no variation in collagen content with treatment exposures. In the univariate analysis, CD64, GM-CSF Ab, fecal calprotectin, and sMaRIA were positively associated with acute inflammation and negatively associated with collagen content (P < .1). The multivariable model for ileal collagen content (R2 = 0.31 [95% CI: 0.11, 0.52]) included log CD64 (β = -.27; P = .19), log ECM1 (β = .47; P = .06), log GM-CSF Ab (β = -.15; P = .01), IVIM f (β = .29, P = .10), and IVIM D* (β = 1.69, P = .13).

Conclusions: Clinically available and exploratory circulating and MRI biomarkers are associated with the degree of inflammation versus fibrosis in CD ileal resections. With further validation, these biomarkers may be used to guide medical and surgical decision-making for refractory CD.

Background and aims: Inflammation can generate pathogenic Th17 cells and cause an inflammatory dysbiosis. In the context of inflammatory bowel disease (IBD), these inflammatory Th17 cells and dysbiotic microbiota may perpetuate injury to intestinal epithelial cells. However, many models of IBD like T-cell transfer colitis and IL-10-/- mice rely on the absence of regulatory pathways, so it is difficult to tell if inflammation can also induce protective Th17 cells.

Methods: We subjected C57BL6, RAG1-/-, or JH-/- mice to systemic or gastrointestinal (GI) Citrobacter rodentium (Cr). Mice were then subjected to 2.5% dextran sodium sulfate (DSS) to cause epithelial injury. Fecal microbiota transfer was performed by bedding transfer and co-housing. Flow cytometry, qPCR, and histology were used to assess mucosal and systemic immune responses, cytokines, and tissue inflammation. 16s sequencing was used to assess gut bacterial taxonomy.

Results: Transient inflammation with GI but not systemic Cr was protective against subsequent intestinal injury. This was replicated with sequential DSS collectively indicating that transient inflammation provides tissue-specific protection. Inflammatory Th17 cells that have a tissue-resident memory (TRM) signature expanded in the intestine. Experiments with reconstituted RAG1-/-, JH-/- mice, and cell trafficking inhibitors showed that inflammation-induced Th17 cells were required for protection. Fecal microbiota transfer showed that the inflammation-trained microbiota was necessary for protection, likely by maintaining protective Th17 cells in situ.

Conclusion: Inflammation can generate protective Th17 cells that synergize with the inflammation-trained microbiota to provide host resiliency against subsequent injury, indicating that inflammation-induced Th17 TRM T cells are heterogenous and contain protective subsets.

Background: Although most inflammatory bowel disease (IBD) medications are considered safe during pregnancy, their impact on microRNAs (miRNAs) in breast milk is largely unknown. MiRNAs in milk, carried by milk-derived extracellular vesicles (MDEs), are transmitted to the newborn's gut to regulate genes. Aberrant miRNA expression profiles have been found in IBD within tissue, blood, and feces, but data on mother's milk are scarce.

Methods: We collected breast milk samples from 32 mothers with Crohn's disease (CD), 14 mothers with ulcerative colitis (UC), and 44 healthy controls. We analyzed miRNA expression through qualitative real-time polymerase chain reaction and Affymetrix miRNA chips. Target genes of differentially expressed miRNAs were predicted using miRATBase. Statistical analyses were conducted using GraphPad Prism software with Mann-Whitney tests.

Results: Milk-derived extracellular vesicles from mothers with IBD showed altered miRNA profiles compared to controls. Specifically, miR-21 and miR-320 were downregulated, while Let-7a was upregulated in IBD mothers. The expression patterns varied between CD and UC, with significantly lower MiR-21 in UC and higher Let-7a in CD. Additionally, anti-tumor necrosis factor treatment during pregnancy was associated with reduced miR-21 and miR-148a levels in MDEs. Pathway analysis revealed that these miRNAs are involved in immune regulation, particularly interleukin signaling pathways.

Conclusions: This study highlights that miRNAs in breast milk are differentially expressed in mothers with IBD, influenced by the disease and its treatments. These findings emphasize the impact of maternal health on milk composition and potential implications for infant immune development. Understanding these findings may guide personalized treatment strategies for mothers and promote breastfeeding among mothers with IBD.

Background and aims: Patients with very early-onset inflammatory bowel disease (VEO-IBD), with an age of onset < 6 years, can present with severe manifestations and may require biologic therapy. Infliximab and adalimumab are approved for induction and maintenance in pediatric IBD patients but are licensed only above the age of 6 years. Effectiveness and safety data on adalimumab in this patient population are lacking. We assessed the therapeutic response to help close this gap.

Methods: This retrospective study involved 30 sites worldwide. Demographic, clinical, and laboratory data were collected from patients with VEO-IBD who commenced adalimumab therapy before the age of 6 years.

Results: Seventy-eight patients (37 Crohn's disease, 26 ulcerative colitis, and 15 with IBD-unclassified) were included. Median age of IBD onset was 2.6 (1.3-4.1) years, with 30 (38.5%) patients diagnosed at age <2 years. Median age at adalimumab initiation was 4.2 (2.8-5.1) years. Adalimumab was used as second-line biologic therapy in 45 (57.7%) patients after infliximab. The median time to last follow-up was 63 (22-124) weeks. Significant improvement in clinical scores, CRP, fecal calprotectin, and weight Z-score were observed by Week 52. Adalimumab durability rates were 61.9%, 48.1%, and 35.6% after 1, 2, and 3 years, respectively. Drug discontinuation rates were not dependent on IBD type, age, prior anti-TNF exposure, or concomitant immunomodulatory treatment. Four (5.1%) patients developed serious infections, including 1 patient with TTC7A deficiency who died following adenovirus sepsis.

Conclusion: Adalimumab therapy is a viable therapeutic option in patients with VEO-IBD with an acceptable safety profile.

Background: Extraintestinal symptoms (EIS) in inflammatory bowel diseases, including fatigue, depression and anxiety, are highly prevalent, but poorly understood. Alterations of brain function may contribute to EIS, but their association with disease activity is unclear. This study analyzed intrinsic neural activity (INA) of individuals with Crohn's disease (CD) in different disease states and examined the relationship between INA and EIS.

Methods: Patients with CD (n = 92) and healthy controls (n = 41) underwent functional magnetic resonance brain imaging and completed symptom-specific psychometry. Temporal (amplitude of low-frequency fluctuations, ALFF) and spatial (regional homogeneity, ReHo) markers of INA were compared between CD and controls and between active (patients with active Crohn's disease [aCD]) versus remitted (rCD) disease. Regression analyses explored disease-state-dependent associations between INA and EIS.

Results: Patients exhibited aberrant INA in frontotemporal, occipital, and thalamic regions. Patients with aCD exhibited lower ALFF in left subcallosal cortex and inferior temporal gyri compared to rCD. Regional homogeneity in aCD was lower in left medial orbital gyrus and higher in right superior frontal, left inferior temporal, and left precentral gyrus. Compared to rCD, aCD showed higher ALFF predominantly in superior, ventro-, and dorsolateral prefrontal regions. Distinct associations between INA and EIS were detected in patients, particularly in the remitted state.

Conclusions: Intrinsic brain function in patients with CD varies by disease state, with prominent frontal cortex changes in active disease. These brain activity changes are at least partly related to the magnitude of neuropsychiatric symptoms and highlight a role of disturbed brain-gut interactions in the development of EIS especially in rCD.