Journal of Crohn's & colitis最新文献

Background and aims: The association of inflammatory bowel disease (IBD) with other immune-mediated inflammatory diseases (IMIDs) in the same patient is well known. We aimed to evaluate the degree of knowledge that patients with IBD have regarding the coexistence of other IMIDs and to analyze the factors associated with the concordance between self-reported and confirmed medical information.

Methods: Patients with IBD at a tertiary hospital answered a questionnaire on the presence of 54 IMIDs (self-reported diagnosis), and their IMID diagnosis was confirmed in their medical records (reference diagnosis). Agreement between the self-reported IMID and the IMID according to medical records was evaluated. The association between concordance and different predictors was evaluated using logistic regression models.

Results: A total of 1,620 patients were included. Six hundred and twenty-six (39%) patients were diagnosed with at least one IMID, and 177 (11%) with two or more. Overall agreement between patients´ self-report and medical records was k:0.61. When we grouped IMIDs according to affected organs or systems, agreement on rheumatic IMIDs was moderate (k:0.58), whereas agreement on cutaneous (k:0.66), endocrine (k: 0.74) and ocular (k:0.73) IMIDs was substantial. Among patients who had IMIDs, the factor associated with greater concordance was female gender, while lower concordance was associated with a lower educational level and the fact that the IMID had been diagnosed at the same time or later than IBD.

Conclusion: The knowledge that patients with IBD have regarding the coexistence of other IMIDs is poor, especially in rheumatic IMIDs.

Background and aim: Bromodomain-containing protein 4 (BRD4), one of the components of the bromodomain and extraterminal domain (BET) family, is a transcriptional and epigenetic regulator of cellular proliferation and cytokine production. In this study, we assessed whether BRD4 regulates the cytokine response in inflammatory bowel diseases (IBD).

Materials and methods: BRD4 expression was analyzed in intestinal mucosal samples of patients with ulcerative colitis (UC), patients with Crohn's disease (CD), normal controls (CTRs), and mice with chemically-induced colitis by real-time PCR, Western blotting, and confocal microscopy. Cytokine production was evaluated in lamina propria mononuclear cells (LPMCs) of IBD patients and mucosal tissues of colitic mice treated with BRD4 inhibitors. Finally, we evaluated the effect of JQ1, an inhibitor of the BRD4 signaling pathway, on the course of murine colitis.

Results: BRD4 RNA and protein expression was up-regulated in the inflamed mucosa of patients with UC and patients with CD as compared to the uninvolved areas of the same patients and CTRs, and in the inflamed colon of colitic mice. Knockdown of BRD4 with a specific antisense oligonucleotide in IBD LPMCs led to reduced expression of TNF-α, IL-6, IFN-γ, and IL-17A. Administration of JQ1 to colitic mice inhibited the inflammatory cytokine response and attenuated the ongoing colitis.

Conclusions: This is the first study showing the up-regulation of BRD4 in IBD and suggesting the role of such a protein in the positive control of the inflammatory cytokine response in the gut.

Background & aims: Biomarkers that integrate genetic and environmental factors and predict outcome in complex immune diseases such as inflammatory bowel disease (IBD; including Crohn's disease [CD] and ulcerative colitis [UC]) are needed. We showed that morphologic patterns of ileal Paneth cells (Paneth cell phenotype [PCP]; a surrogate for PC function) is one such cellular biomarker for CD. Given the shared features between CD and UC, we hypothesized that PCP is also associated with molecular/genetic features and outcome in UC. Because PC density is highest in the ileum, we further hypothesized that PCP predicts outcome in UC subjects who underwent total colectomy and ileal pouch-anal anastomosis (IPAA).

Methods: Uninflamed ileal resection margins from UC subjects with colectomy and IPAA were used for PCP and transcriptomic analyses. PCP was defined using defensin 5 immunofluorescence. Genotyping was performed using Immunochip. UC transcriptomic and genotype associations of PCP were incorporated with data from CD subjects to identify common IBD-related pathways and genes that regulate PCP.

Results: The prevalence of abnormal ileal PCP was 27%, comparable to that seen in CD. Combined analysis of UC and CD subjects showed that abnormal PCP was associated with transcriptomic pathways of secretory granule maturation and polymorphisms in innate immunity genes. Abnormal ileal PCP at the time of colectomy was also associated with pouch complications including de novo CD in the pouch and time to first episode of pouchitis.

Conclusions: Ileal PCP is biologically and clinically relevant in UC and can be used as a biomarker in IBD.

Introduction: The disease severity index (DSI) encapsulates the inflammatory bowel disease (IBD) burden but requires endoscopic investigations. This study developed a non-invasive DSI using faecal calprotectin (DSI-fCal) and faecal myeloperoxidase (DSI-fMPO) instead of colonoscopy.

Methods: Adults with IBD were recruited prospectively. Baseline biomarker concentrations were used to develop DSI-fCal and DSI-fMPO, and these were correlated with the original DSI, IBD-symptoms, endoscopic activity, and quality-of-life (QoL). Area under the receiver-operating-characteristics curves (AUROC) assessed DSI-fCal/DSI-fMPO as predictors of clinical and biochemical remission at six months (symptom remission and fCal <150 μg/g, respectively), and a complicated IBD-course at 24 months (disease relapse needing escalation of biologicals/immunomodulators/recurrent corticosteroids, IBD-hospitalisations/surgeries). Multivariable logistic regression assessed the utility of DSI-fCal/DSI-fMPO in predicting a complicated IBD-course at 24 months.

Results: In total, 171 patients were included (Crohn's disease=99, female=90, median age=46y (IQR 36-59)). DSI-fCal and DSI-fMPO correlated with the original DSI (r>0.9, p<0.001), endoscopic indices (r=0.45-0.49, p<0.001), IBD-symptoms (r=0.53-0.58, p<0.001) and QoL (r=-0.57-0.58, p<0.001). Baseline DSI-fCal (AUROC=0.79, 95% CI 0.65-0.92) and DSI-fMPO (AUROC=0.80, 95% CI 0.67-0.93) were associated with 6-month clinical and biochemical remission. DSI-fCal (AUROC=0.83, 95% CI 0.77-0.89) and DSI-fMPO (AUROC=0.80, 95% CI 0.73-0.87) performed similarly in predicting a complicated IBD-course to the original DSI (pdifference>0.05). The non-invasive DSI was independently associated with a complicated IBD-course on multivariable analyses (DSI-fCal28, aOR=6.04, 95% CI 2.42-15.08; DSI-fMPO25, aOR=7.84, 95% CI 2.96-20.73).

Conclusions: The DSI-fCal and DSI-fMPO perform similarly in prognosticating the longitudinal disease course as the original DSI, whilst avoiding a need for an endoscopic assessment.

Background and aims: Reliable and easily accessible objective markers of disease activity to predict long-term treatment outcomes in severe ulcerative colitis (UC) are missing. We aimed to investigate if intestinal ultrasound (IUS) might predict long-term outcomes in hospitalized patients with severe UC treated with intravenous corticosteroids.

Methods: Hospitalized patients with severe UC and IUS inflammation (bowel wall thickness (BWT)>3.0mm) starting IV corticosteroids were recruited at three university hospitals in Denmark. IUS was performed before treatment, 48±24 hours (h), 6±1 days, and 3 months after treatment initiation. Time until colectomy or need for new interventions was registered together with Mayo score at 3 months and partial Mayo score (pMayo) at 12-months. Follow-up time was 12 months.

Results: Fifty-six patients were included in the final analysis. Forty-five (80%) patients needed intervention, including 9 colectomies, during the 12-month follow-up. After 48±24h: No patient with a BWT<3mm needed a colectomy, p=0.04. BWT≥4mm showed an increased risk of colectomy (odds ratio 9.5 (95%CI 1.5-186), p=0.03), while a BWT≥3mm showed an increased risk of intervention (3.6 (1.1-12.5), p=0.03). A BWT≥4mm resulted in a significantly shorter time until both colectomy, p=0.03, and treatment intensification (mean days 75 (95%CI24-127) vs. 176 (119-233), p=0.005. However, neither IUS parameters nor pMayo score, CRP, hemoglobin, or p-albumin could predict remission at 3- and 12-months.

Conclusion: BWT assessed at 48h post intravenous corticosteroid initiation in patients hospitalized with severe UC may identify patients with an increased risk of short- and long-term colectomy and predict a more aggressive short-term disease course.

Background & aims: The Lemann Index (LI), an endpoint to measure cumulative structural bowel damage in Crohn's disease (CD), has been recently updated and validated. We applied this to investigate predictors of bowel damage in a real-world cohort.

Methods: We performed a retrospective study (2008-2022) involving two tertiary referral IBD centers in the US. MR or CT enterographies were reviewed by study radiologists and endoscopy reports by study gastroenterologists, to calculate LI. Baseline and follow-up LI were calculated. We defined high bowel damage as LI ≥2. Factors associated with high LI were identified in patients with ≥2 LI scores using multivariate logistic regression and then assessed for a change in LI (increase vs. no change/decrease) using a multivariate linear mixed-effects model.

Results: 447 patients with CD had a median first LI of 7 [IQR, 1.25-14.55]. Median LI scores were significantly different when categorized by disease duration; 2.0 [IQR, 0.6-5.9] for <2 years, 2.6 [IQR, 0.6-9.6] for ≥2 and <10 years, and 12.5 [IQR, 6.4-21.5] for ≥10 years with a p <0.01. Disease duration, presence of perianal disease, elevated C-reactive protein, and Harvey-Bradshaw index, were associated with a high LI at inclusion and increase in LI during follow-up (all p <0.01).

Conclusions: The updated LI quantified cross-sectional and longitudinal cumulative bowel damage in a real-world cohort of patients with CD with predictors identified for a longitudinal increase in LI. Further studies for prospective validation of LI and identification of multi-omic predictors of bowel damage are needed.

Background: Clinical trial recruitment for patients with inflammatory bowel disease (IBD) has become more challenging over time. We aimed to develop recommendations for broadening IBD clinical trial eligibility to improve the inclusion of a more representative patient population in a more efficient timeline.

Methods: We applied the RAND/UCLA Appropriateness Method focused on broadening IBD clinical trial eligibility. A literature review was performed for 7 domains, each representing a different area related to trial recruitment. Based on these domains, 32 statements were developed. A questionnaire was sent to IBD specialists to anonymously vote on each statement with regards to its appropriateness and feasibility. After the first round of voting, participants met for a moderated discussion to review all statements. At the end of the discussion a second round of anonymous voting led to the final recommendations.

Results: The final round of voting resulted in 26 statements. All were rated as feasible and 25 of 26 rated as appropriate. Recommendations generally are to be more inclusive of complicated disease phenotypes, more liberal around safety criteria, to recognize the importance of non-invasive imaging and biomarkers, to minimize the washout period and to not enforce a minimum or maximum number of prior medications, to allow a recently recorded colonoscopy to count as a baseline study, and to be less restrictive of age.

Conclusion: Recommendations to broaden clinical trial eligibility were found to be both appropriate and feasible with a high degree of agreement amongst an international group of IBD specialists.

Background and aims: To demonstrate that administration of 7500 Trichuris suis ova every second week over 24 weeks would reduce the intestinal inflammation in moderate ulcerative colitis.

Methods: A single-centre, randomized, double-blinded, placebo-controlled, phase 2b clinical trial of 7500 Trichuris suis ova every two weeks for 24 weeks compared to placebo in moderate activity of ulcerative colitis (Mayo score 6-10) were performed. Primary outcome: Clinical remission. Secondary outcomes: Clinical response at 24 weeks, complete corticosteroid-free clinical remission, endoscopic remission, symptomatic remission at 12 and 24 weeks and partial Mayo score over time.

Results: 119 patients were randomized to Trichuris suis ova (n=60) and placebo (n=59). At week 24, clinical remission was achieved in 30% of Trichuris suis ova-treated vs. 34% of placebo-treated (RR=0.89; CI:0.52-1.50; p=0.80, ITT). No difference was found in clinical response in any of the clinical response subgroups. However, in patients who did not need treatment with corticosteroids during the trial, a temporary effect of TSO was seen in the analysis of symptomatic remission of week 12 (p=0.01), and the partial Mayo score at week 14 and week 18 (p<0.05 and p=0.02).

Conclusions: Compared to placebo, Trichuris suis ova was not superior in achieving clinical remission at week 24 in ulcerative colitis or in achieving clinical Mayo score reduction, complete corticosteroid-free clinical remission or endoscopic remission. However, Trichuris suis ova treatment induced symptomatic temporary remission at week 12.

Introduction: 30-40% patients with acute severe ulcerative colitis (ASUC) fail intravenous (IV) steroids requiring medical rescue therapy/colectomy. Low baseline albumin predicts steroid non-response, and exclusive enteral nutrition (EEN) has been shown to improve steroid response and albumin levels. Albumin infusion due to its anti-inflammatory and anti-oxidant properties might further improve steroid response in ASUC, which was evaluated in present study.

Methods: In this open-label randomized controlled trial, patients with ASUC were randomized in 1:1 ratio to albumin + standard of care (SOC) + EEN vs. SOC + EEN (Jan2021 - Feb2023). Both arms received 5 days of EEN with 400 mg IV hydrocortisone/day. Patients in albumin arm were administered 5 days of 20% w/v intravenous albumin (100 ml). Primary outcome was 1) steroid failure (need for rescue medical therapy or colectomy) and 2) proportion of patients with adverse events.

Results: Sixty-one patients (albumin-30, SOC-31)(mean age-31.6±0.4 years, male-57.4%), were included. Baseline characteristics were comparable. There was no difference in steroid failure between albumin and SOC arm(10/30(33.33 %) vs 13/31(41.94 %), p=0.49). No adverse events were reported with albumin infusions. Colectomy rate(10% vs 9.68%, P=1), response to salvage medical therapy (88.89% vs 76.92%, P=0.62) and median duration of hospitalization (10.5(7-16) vs 10(7-20), P=0.43) were also comparable. Long-term composite outcome of colectomy and re-admission rates was numerically higher in the albumin than SOC arm (37.04% vs 17.86%, p>0.05), although it did not reach statistical significance.

Conclusion: There was no benefit of intravenous albumin infusion as an adjunct to IV steroids and EEN in patients with ASUC.

Background and aims: Etrasimod is an oral, once daily, selective sphingosine 1-phosphate [S1P]1,4,5 receptor modulator for the treatment of moderately to severely active ulcerative colitis [UC]. This subgroup analysis evaluated the efficacy and safety of etrasimod 2 mg once daily vs placebo by prior biologic/Janus kinase inhibitor [bio/JAKi] exposure in ELEVATE UC 52 and ELEVATE UC 12.

Methods: Pre-defined efficacy endpoints were assessed at Weeks 12 and 52 in ELEVATE UC 52 and Week 12 in ELEVATE UC 12 in bio/JAKi-naïve and -experienced patients, and at Week 12 [pooled] based on prior advanced therapy exposure mechanism.

Results: In the ELEVATE UC 52 and ELEVATE UC 12 analysis populations, 80/274 [29.2%] and 74/222 [33.3%] patients receiving etrasimod and 42/135 [31.1%] and 38/112 [33.9%] patients receiving placebo, respectively, were bio/JAKi-experienced. In both bio/JAKi-naïve and -experienced patients, a significantly greater proportion receiving etrasimod vs placebo achieved clinical remission (p<0.05) in ELEVATE UC 52 at Weeks 12 [naïve: 30.9% vs 9.7%; experienced: 17.5% vs 2.4%] and 52 [naïve: 36.6% vs 7.5%; experienced: 21.3% vs 4.8%]; in ELEVATE UC 12, this was observed only for bio/JAKi-naïve patients [naïve: 27.7% vs 16.2%, p=0.033; experienced: 18.9% vs 13.2%, p=0.349]. Similar patterns were observed for most efficacy endpoints. Among patients with prior anti-integrin exposure [N=90], a significantly greater proportion achieved clinical response [54.1% vs 27.6%, p=0.030], but not clinical remission [9.8% vs 3.4%, p=0.248], with etrasimod vs placebo.

Conclusions: Bio/JAKi-naïve and -experienced patients had clinically meaningful induction and maintenance treatment benefits with etrasimod vs placebo.