Inflammatory Bowel Diseases最新文献

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.

We studied the mucosal bacterial population in patients with active Crohn's disease and intestinal tuberculosis. Significant differences were noted in the composition and predicted function of the gut microbiota between the two conditions. Microbial dysbiosis was more severe in intestinal tuberculosis than in Crohn's disease and could differentiate between the two conditions with good accuracy.

Background: We evaluated the efficacy and safety of ozanimod after 5-aminosalicylic acid (5-ASA) failure in advanced therapy (AT)-naive patients with moderate ulcerative colitis (UC) in True North and its open-label extension (OLE).

Methods: True North was a randomized, 52-week, phase 3 trial with an optional OLE. Efficacy was assessed in True North and the OLE; safety was assessed through OLE week 190.

Results: Overall, 203 AT-naive True North patients had moderate UC (Mayo endoscopic subscore of 2 + modified Mayo score of 4-6 + rectal bleeding subscore ≥1). Of these, 139 were also immunomodulator-naive and not receiving corticosteroids (5-ASA-exposed only) at baseline. Patients with moderate UC receiving ozanimod vs placebo achieved greater efficacy rates for all week 10 and week 52 outcomes, regardless of prior immunomodulator/corticosteroid use (eg, week 10 clinical remission: AT-naive = 36.8% vs 10.6%; 5-ASA-exposed only = 37.9% vs 17.2%). Higher symptomatic response rates were achieved by week 2 with ozanimod in AT-naive patients with moderate UC vs the overall AT-naive population (50.5% vs 38.7%); similar trends were observed in patients exposed only to 5-ASA. Efficacy was maintained through OLE week 190 in patients who entered OLE as True North week 52 ozanimod clinical responders. Of those entering OLE as True North week 10 ozanimod clinical nonresponders, 69.0% of AT-naive patients and 68.4% of patients exposed only to 5-ASA achieved symptomatic response by week 5. No new safety signals emerged.

Conclusions: Ozanimod was safe, effective, and durable up to ∼5 years in AT-naive patients with moderate UC who failed conventional therapy. ClinicalTrials.gov: NCT02435992, NCT02531126.

Background: Ulcerative colitis (UC) is a chronic inflammatory disease of the colonic mucosa, extending proximally from the rectum. However, the segmental pattern of healing in UC remains unclear. Endoscopic improvement (EI), a key therapeutic endpoint, is typically assessed using the Mayo endoscopic score (MES), which scores the worst affected area and may miss partial/segmental healing. This study evaluates healing patterns in UC and compares conventional MES with a 3-segment MES approach for detecting treatment effects in clinical trials.

Methods: A post hoc analysis of HIBISCUS I/II and GARDENIA trials was conducted in UC patients with moderate-to-severe disease (MES >2 up to the descending colon). The primary outcome was the proportion of anti-tumor necrosis factor-treated participants achieving MES ≤1 in the descending colon, sigmoid colon, and rectum at week 10. Secondary outcomes included conventionally measured EI, segmental MES improvements, clinical response, and Patient-Reported Outcome 2 (PRO2) normalization. Outcomes were compared between adalimumab, infliximab, and placebo groups.

Results: Among 300 participants, 217 received infliximab or adalimumab, while 83 received placebo. Healing followed a proximal-to-distal pattern, with the highest EI in the descending colon and the lowest in the rectum. Infliximab-treated patients continued this trend at week 54. Anti-tumor necrosis factor therapy significantly improved EI vs placebo (42.9% vs 19.3%; P < .001). No segmental MES approach outperformed conventional MES for detecting treatment effects. Combined endpoints (MES ≤1 + PRO2 normalization) better captured therapeutic benefits than PRO2 alone (28.6% vs 13.3%; P = .006).

Conclusions: UC healing follows a proximal-to-distal pattern. Conventional MES remains superior for detecting treatment effects over segmental MES. Further studies should explore alternative endoscopic scoring methodologies.

Background: Inflammatory bowel diseases (IBDs), including ulcerative colitis (UC) and Crohn's disease (CD), have complex pathologies requiring precise diagnostic tools. We evaluated the clinical utility of anti-integrin αvβ6 antibodies in diagnosing UC, focusing on differences between a U.S. cohort (self-reported White) and a Japanese cohort, and additionally assessed whether combining anti-αvβ6 with anti-EPCR improved diagnostic performance.

Methods: Serum anti-αvβ6 antibody levels were measured in 1138 participants (514 in the U.S. cohort, 624 in the Japanese cohort), including 1093 IBD cases and 45 healthy control subjects. Positivity rates and titers were compared between cohorts, and associations with clinical subphenotypes and anti-EPCR were examined.

Results: Anti-αvβ6 positivity was significantly higher in UC patients (85.4%) than in CD patients (16.4%) or control subjects (0%). Within UC, high positivity was observed across all disease extents, with only minor cohort differences. Longer disease duration was associated with lower positivity in both cohorts. In CD, the U.S. cohort showed higher positivity (23.4%) than the Japanese cohort (10.1%), particularly in colonic CD. Absence of ileal involvement, strictures, or perianal disease was associated with higher positivity. Anti-αvβ6 and anti-EPCR levels were strongly correlated, but their expression patterns differed in primary sclerosing cholangitis-associated IBD. Combining anti-αvβ6 and anti-EPCR improved UC diagnostic accuracy (area under the curve, 0.98; 95% confidence interval, 0.95-1.00) over either antibody alone (P = .00264).

Conclusions: Anti-αvβ6 is a valuable biomarker for UC diagnosis. However, this study demonstrated differences in its behavior between U.S. and Japanese cohorts, particularly in CD. Cohort-informed interpretation and combined antibody testing may improve diagnostic precision and disease stratification in IBD.

Background: Despite the transformative impact of biologics on the treatment of inflammatory bowel disease (IBD) in recent years, a substantial proportion of patients remain unresponsive to these advanced therapies. Overcoming resistance remains a significant clinical challenge, largely due to the incomplete understanding of its underlying mechanisms. This study explores the role of extracellular matrix (ECM) remodeling in the development of resistance to anti-TNFα therapy.

Methods: Using public single-cell and bulk transcriptomic datasets, combined with in vitro primary cell experiments and multiplex immunofluorescence validation, we investigated key factors contributing to therapy failure.

Results: Transcriptomic analysis revealed that ECM-related pathways were enriched in Crohn's disease patients and associated with resistance to anti-TNFα therapy. Single-cell analysis identified Fibroblast 2 (CD81+ fibroblasts) as the major ECM-related stromal subpopulation, exhibiting the highest capacity for ECM secretion and degradation. Matrix metalloproteinase-2 (MMP2) was identified as a key protease highly expressed in this subset, showing close interaction with macrophages. Co-culture of primary fibroblasts and macrophages led to increased release of inflammatory mediators such as TNFα and IL-6, which was partially reduced by MMP2 inhibition, suggesting a potential regulatory role of MMP2 in fibroblast-macrophage crosstalk. Spatial transcriptomics and multiplex immunofluorescence further supported the spatial colocalization and interaction of fibroblasts, macrophages, and MMP2 within the tissue microenvironment.

Conclusions: This study highlights the association of pathogenic fibroblasts and ECM remodeling in anti-TNFα therapy failure, identifies MMP2 as a potential target, and suggests that combination therapy may offer a potential strategy for patients with treatment resistance.