Journal of Crohn's & colitis最新文献

Background and aims: While there is increasing interest in microbiome-directed therapies for patients with ulcerative colitis (UC), the identification of microbial targets remains elusive, underlining the need for novel approaches.

Methods: Utilizing metagenomic data from the Study of a Prospective Adult Research Cohort with Inflammatory Bowel Disease, available via the IBD Plexus Program of the Crohn's & Colitis Foundation, we used a tree-based dichotomous approach to assemble distinct clusters of species-level bacterial co-abundance groups (CAGs). We evaluated the abundance of bacterial CAGs and fungal taxa during remission (n=166) and activity (n=46). We examined if the bacterial CAGs identified in our cohorts were conserved in 2 healthy cohorts and in a Korean UC cohort.

Results: CAG3 and CAG8, dominated by bacteria from family Lachnospiraceae, were associated with remission. Low CAG8 and elevated Candida genus were predictive of active UC. Constituents from CAG8 were influential hub species of the remission-associated microbial UC network, including Ruminococcus gnavus, Erysipelatoclostridium ramosum, Blautia and Dorea species. These hub species interactions were preserved in 2 healthy cohorts and were partially recapitulated in a Korean UC cohort. CAG8 abundance correlated with the secondary bile acid production pathway. Bacterial CAGs did not correlate with Candida, however Bifidobacterium adolescentis and Alistipes putredinis were negatively associated with Candida.

Conclusions: Lachnospiriceae-dominated bacterial CAGs were associated with remission in UC, with key bacterial interactions within the CAG also observed in 2 healthy cohorts and a Korean UC cohort. Bacterial CAG-based analyses may help to inform the design of candidate consortia for microbiome-based therapeutics.

Background and aims: During early phases of inflammation, activated neutrophils extrude neutrophil extracellular traps (NETs) in a PAD4-dependent manner, aggravating tissue injury and remodelling. In this study, we investigated the potential pro-fibrotic properties and signalling of NETs in Crohn's disease (CD).

Methods: NETs and activated fibroblasts were labelled on resected ileum from CD patients by multiplex immunofluorescence staining. NETs-treated human primary intestinal fibroblasts were analysed by bulk RNA-sequencing to uncover cell signalling pathways, and by high-throughput imaging to assess collagen production and migratory activity. Consequentially, TLR2/NF-kB pathway was evaluated by transfection of CCD-18Co fibroblasts with NF-kB-luciferase reporter plasmid, incorporating C29 to block TLR2 signalling. A chronic DSS mouse model was used to define the specific role of PAD4 deletion in neutrophils (MRP8-Cre, Pad4fl/fl).

Results: Immunofluorescence showed spatial co-localisation of NETs and activated fibroblasts in ileal ulcerations of CD patients. Transcriptomic analysis revealed upregulation of pro-fibrotic genes and activation of TLR-signalling pathways in NETs-treated fibroblasts. NETs treatment induced fibroblast proliferation, diminished migratory capability, and increased collagen release. Transfection experiments indicated a substantial increase in NF-kB expression with NETs, whereas C29 led to decreased expression and release of collagen. In line, a significantly reduction in collagen content was observed in the colon of MRP8-Cre, Pad4fl/fl mice subjected to chronic DSS colitis.

Conclusions: NETs potentially serve as an initial stimulus for pathological activation of fibroblasts within the intestine via the TLR2/NF-kB pathway. Given their early involvement in inflammation, inhibition of PAD4 might offer a strategy to modulate both inflammation and fibrogenesis in CD.

Background and aims: Fecal calprotectin (FC) is known to be a sensitive biomarker of colonic inflammation but to a lesser degree of small bowel (SB) inflammation. Moreover, data on FC's diagnostic levels in different SB segments are scarce. We aimed to examine FC's diagnostic levels along the SB-axis in CD.

Methods: This was a post-hoc aggregated analysis of five prospective studies of adult CD patients, who underwent FC testing and SB video capsule endoscopy (VCE). Lewis score (LS) inflammation in different SB segments was tested for correlation with FC level after exclusion of colonic disease. The diagnostic levels of FC for SB inflammatory topographical-gradient were assessed using a receiver operating characteristic.

Results: 214 patients were included (age:30 [24-43] year-old, males-57%). For a similar SB inflammatory-activity (LS≥135), FC levels incrementally increased from proximal to distal SB segments (63 [30-121] versus 190 [78-549], p=0.005) and from distal SB segment to the colon (190 [78-549] versus 542 [185-1000], p=0.010). The best FC cutoffs to identify isolated mild proximal/distal SB-inflammation (LS≥135) were 77μgg and 123μgg, respectively. A cutoff of 234μgg was best to detect more significant proximal inflammation (LS≥350) when only mild distal SB-inflammation was present. In sensitivity analyses, this proximal-to-distal FC gradient was maintained when LS≥350 and LS≥790 were used as the inflammatory reference-values. Unlike FC, the magnitude of CRP elevation was unrelated to the topography of inflammation along the SB-axis.

Conclusions: FC may serve as a topographical biomarker of CD-activity, with its sensitivity to identify mucosal inflammation increases from proximal to distal SB segments.

Background and aims: There are few studies on the cost-effectiveness of telemedicine for inflammatory bowel diseases (IBD). We assessed the long-term cost-effectiveness of a telemedicine solution (eCare) compared to standard care (sCare), as well as its efficacy according to patient-reported outcomes (PRO).

Methods: Between 2015 and 2020 we conducted a retrospective, register-based study among patients with ulcerative colitis (UC) and Crohn's disease (CD). Direct and indirect healthcare costs over a five-year period were obtained from Danish registers and compared to a control group. Costs were estimated on a yearly basis from one year before, until five years after, inclusion in the trial. Patients were divided into cohorts of those not receiving (cohort 1), and those receiving (cohort 2), biologics.

Results: We recruited 574 IBD patients. In cohort 1 (61.5%), average total direct costs and total earnings per patient per year were €14,043 and €307,793 in eCare compared to €16,226 and €252,166 in sCare, respectively. In cohort 2 (38.5%), average total direct costs and total earnings were €73,916 and €215,833 in eCare compared to €41,748 and €203,667 in sCare, respectively. PRO showed increasing quality of life and was higher in cohort 1 than cohort 2. Disease activity among CD patients increased after years 3 and 4 in cohorts 1 and 2, respectively.

Conclusion: Telemedicine is cost-effective for patients not receiving biologics. However, treatment with biologics is more expensive for patients enrolled in eCare. Careful attention to PRO in eCare improves quality of life and could prolong time to relapse.

Background and aims: STRIDE-II recommends early biomarker targets for treatment optimization to achieve treat-to-target [T2T] endoscopic remission [ER] in Crohn's disease [CD]. The predictive capabilities of intestinal ultrasound [IUS] for T2T ER remain unknown. We aimed to evaluate IUS response to predict ER in children with CD.

Methods: This was a prospective longitudinal cohort study of children with ileal [TI] CD initiating biologic therapy undergoing IUS, clinical disease activity, and C-reactive protein [CRP] assessments at baseline, week 8, 6 months, and T2T within 1 year. The primary outcome was the accuracy of optimal cut-points to predict TI ER [SES-CD ≤ 2] for change in bowel wall thickness [BWT] on IUS from baseline to week 8, and BWT at week 8. Area under the receiver operating curve [AUROC] analysis was performed and univariate analysis tested associations.

Results: In total, 44 children (median age 13 [IQR 12-17] years, 29 [66%] biologic naïve) were included, and 29 [66%] achieved ER. A ≥18% decrease in TI BWT at week 8 predicted ER with an AUROC of 0.99 [95% CI 0.98-1.00], 100% sensitivity, 93% specificity, 97% positive predictive value, and 100% negative predictive value, superior to a ≥46% decrease in PCDAI (AUROC 0.67 [95% CI 0.49-0.84]) and ≥84% decrease in CRP (AUROC 0.49 [95% CI 0.31-0.67]) at week 8.

Conclusions: Early change in TI BWT on IUS is highly predictive of ER in children with CD and superior to symptoms and CRP. Our findings suggest that IUS could be used for treatment optimization and tight control to guide T2T strategies.

Background: Mesenchymal stromal cells are suggested to play a critical role in Crohn's disease [CD]-associated fibrosis. MAPKAPK2 [MK2] has emerged as a potential therapeutic target to reduce inflammation in CD. However, the cell-specific pattern of phospho-MK2 activation and its role in CD-associated fibrosis are unknown. The objectives of this study were to evaluate cell-specific changes in MK2 activity between predominantly inflammatory CD vs CD with fibrotic complications and define the role of stromal cell-specific MK2 activation in CD-associated fibrosis.

Methods: CD tissue, CD tissue-derived mesenchymal stromal cells known as myo-/fibroblasts [CD-MFs], and fibroblast-specific MK2 conditional knockout [KO] mice were used.

Results: In the inflamed area of predominantly inflammatory CD, high MK2 activity was equally distributed between mesenchymal and haematopoietic cells. By contrast, in CD with fibrotic complications, high MK2 activity was mostly associated with mesenchymal stromal cells. Using ex vivo CD tissue explants and an IL-10KO murine colitis model, we demonstrated that pro-fibrotic responses are significantly reduced by treatment with the MK2 inhibitor PF-3644022. Inhibition of MK2 activity in primary cultures of CD-MFs significantly reduced basal and TGF-β1-induced profibrotic responses. Using fibroblast-specific MK2 knockout mice in chronic dextran saline sulphate colitis, we demonstrated that fibroblast intrinsic MK2 signalling is among the key processes involved in the chronic inflammation-induced profibrotic responses.

Conclusions: Our data suggest that activation of MK2 within fibroblasts contributes to the chronic inflammation-induced fibrosis in CD and that targeting MK2 has potential for the development of novel therapeutic approaches for fibrosis in CD.

Background and aims: Previously published long-term safety data reported a favourable ustekinumab safety profile for the treatment of inflammatory bowel disease [IBD]. We present the final cumulative safety data from pooled ustekinumab IBD phase 2/3 clinical studies through 5 years in Crohn's disease [CD] and 4 years in ulcerative colitis [UC].

Methods: In phase 3 studies, patients received a single intravenous placebo or ustekinumab [130 mg or ~6 mg/kg] induction dose followed by subcutaneous maintenance doses of placebo or ustekinumab [90 mg q8w or q12w]. Analyses included all patients who received one dose of study treatment and included patients who were biologic-naïve and patients with a history of biologic failure. Safety outcomes are summarized and presented using number of events per 100 patient-years of follow-up and corresponding 95% confidence intervals.

Results: In this final pooled safety analysis, 2575 patients were treated with ustekinumab with 4826 patient-years of follow-up. Rates of key safety events, including major adverse cardiac events and malignancies, were similar between placebo and ustekinumab or not higher for ustekinumab. Opportunistic infections, including tuberculosis, and malignancies were reported infrequently. Rates of key safety events in the IBD group were no higher in the ustekinumab group than in the placebo group for both patients who were biologic-naïve or who had a history of biologic failure. No lymphomas or cases of posterior reversible encephalopathy syndrome [formerly known as reversible posterior leukoencephalopathy syndrome] were reported.

Conclusion: The final cumulative ustekinumab safety data through 5 years in CD and 4 years in UC demonstrated favourable safety compared to placebo and continue to support the well-established safety profile across all approved indications.

Clinical trials.gov numbers: NCT00265122, NCT00771667, NCT01369329, NCT01369342, NCT01369355, NCT02407236.

Background and aims: Despite the development of medical therapy, nearly 50% of patients with Crohn's disease [CD] undergo surgery during their lifetime. Several studies have suggested some risk factors for postoperative morbidity [POM] after ileocolic resection [ICR]. However, the impact of surgical hospital volume on POM in CD has not been extensively studied. This study aimed to assess the impact of surgical hospital volume on POM after ICR for CD.

Methods: All patients with CD who underwent ICR in France between 2013 and 2022 were identified in the French Database, Programme de Médicalisation des Systèmes d'Information. Using the Chi-square automatic interaction detector, we determined the cut-off value to split high-surgical-volume [≥6 ICRs/year] and low-surgical-volume centres [<6 ICRs/year]. The primary outcome was the evaluation of major POM during hospitalization. POM was evaluated according to the surgical volume centre. The Elixhauser comorbidity index [ECI] was used to categorize the comorbidities of patients.

Results: A total of 4205 patients were identified, and the major POM during hospitalization was significantly [p = 0.0004] lower in the high-surgical-volume [6.2%] compared to low-surgical-volume centres [9.1%]. After multivariate analysis, independent factors associated with major POM were surgical hospital volume [p = 0.024], male sex [p = 0.029], ECI ≥ 1 [p < 0.001], and minor POM [p < 0.001].

Conclusion: Major POM after ICR for CD is closely associated with surgical hospital volume. Centralization of surgery for CD is desirable, especially in patients with major comorbidities.

Background: Azathioprine [AZA] effectively prevents postoperative endoscopic recurrence [ER] in Crohn's disease [CD]. However, the efficacy of AZA emerges after 3 months. Exclusive enteral nutrition [EEN] can maintain remission in CD. The present trial investigates whether AZA plus postoperative 3-month EEN is superior to AZA alone in preventing ER of CD.

Methods: In total, 84 high-risk CD patients undergoing intestinal resection received AZA alone or AZA plus 3 months of EEN [AZA + EEN] postoperatively. The primary endpoint was the rate of ER at 12 months. Secondary endpoints included the rate of ER at 3 months, clinical recurrence [CR], CD activity index [CDAI] scores, faecal calprotectin [FC], and C-reactive protein [CRP]. Quality of life was assessed using Short Form-36 [SF-36] and the Inflammatory Bowel Disease Questionnaire [IBDQ].

Results: Patients in the AZA + EEN group exhibited significantly lower rates of ER compared to the AZA group at both 12 months (33.3% [13/39] vs 63.2% [24/38], P = 0.009) and 3 months (8.6% [3/35] vs 28.1% [9/32], P = 0.037) post-surgery. The rates of CR between the two groups at 3 and 12 months were similar. CDAI scores, FC, albumin level, and CRP were all comparable between the two groups. Quality of life was significantly higher in the AZA group than in the AZA + EEN group at 3 months but became comparable from 5 to 12 months postoperatively.

Conclusion: In high-risk CD patients, combining AZA with postoperative 3-month EEN reduces 1-year ER but may temporarily impact quality of life. Further large-scale, long-term studies are warranted.

Trial number: NCT05214430.