Simple Endoscopic Score For Crohn's Disease Research Articles

P1044 Mirikizumab Pharmacokinetics and Exposure-Response in a Phase 2 Study in Patients With Moderately to Severely Active Crohn’s Disease

Abstract Background Mirikizumab (miri) is a humanized anti–interleukin-23-p19 monoclonal antibody approved for the treatment of ulcerative colitis (UC) and under development for Crohn’s disease (CD). This analysis characterises miri pharmacokinetics (PK) and the relationship between miri exposure and efficacy response using data from a phase 2 trial in adults with moderately to severely active CD. Methods AMAG was a randomised, double-blind, placebo-controlled trial conducted in 14 countries. Patients received placebo, miri 200 mg, 600 mg, or 1000 mg as induction regimens administered intravenously (IV) every 4 weeks (Q4W) through Week 12, followed by 36 weeks of maintenance treatment with continuous treatment of miri 200 mg, 600 mg, or 1000 mg IV or miri 300 mg administered subcutaneously (SC) Q4W. PK parameters were analysed by non-linear mixed-effects modelling. Covariate effects on miri exposure were evaluated using simulation-based estimations. Exposure-response (ER) for patients achieving endoscopic response by Simple Endoscopic Score for Crohn’s Disease (SES-CD) at Weeks 12 and 52 were assessed using logistic regression models. Results 186 patients were included. The estimated systemic clearance (CL), central volume of distribution (V), and SC bioavailability (F) were 0.022 L/hr, 3.31 L, and 33.4%, respectively. Lower baseline values for SES-CD (indicative of a less severe CD) were associated with reduced CL. Lower body weight and higher albumin levels were also associated with reduced CL. Higher body weight was associated with higher V and lower baseline body mass index correlated with higher SC F. Impacts on PK parameters were small relative to random variability and not considered clinically relevant. The model-based ER analyses for endoscopic response probability at Week 12 detected a significant treatment effect relative to placebo (p<0.001) and a significant ER (p=0.001) in a dose range of 200-1000 mg. The ER analyses indicated near maximal efficacy for IV dose between 600 mg and 1000 mg during the Induction Period. There was no significant relationship between miri exposure and the probability of achieving endoscopic response by SES-CD at Week 52, indicating exposures produced by the maintenance doses provided similar efficacy. Conclusion Miri PK characteristics in adults with active CD were consistent with miri UC studies. Overall, none of the covariates identified as being significantly correlated with miri PK parameters were considered clinically relevant. No patient factors evaluated in this analysis justify dose adjustment. These findings support the miri induction dose 900 mg IV Q4W and maintenance dose 300 mg SC Q4W selected for phase 3 CD study.

P845 Vedolizumab induces endoscopic healing uniformly irrespective of disease location: post-hoc analysis of the LOVE-CD trial

Abstract Background Vedolizumab (VDZ) is a gut-selective anti–α4β7-integrin monoclonal antibody approved for the treatment of Crohn's disease (CD). We performed a post-hoc analysis of the LOVE-CD trial to evaluate the effect of disease location on endoscopic healing. Methods LOVE-CD is a prospective multicentre study of VDZ therapy in adult patients with moderate-severe CD (Crohn's Disease Activity Index (CDAI) >220 and presence of ulcers at endoscopy). Patients received VDZ 300 mg infusions at weeks 0-2-6 followed by 8 weekly infusions up to week 52. An additional infusion at week 10 was given to patients without clinical response (CDAI decrease <70 points). Corticosteroids had to be withdrawn by week 26. Ileocolonoscopies were performed at weeks 0, 26, and 52, recorded, and centrally scored by 2 independent readers using the Simple Endoscopic Score for Crohn's Disease (SES-CD). The primary endpoint for this analysis was the proportion of patients, stratified by disease location (according to Montreal classification), with ulcer-free endoscopy (absence of any ulceration; SES-CD ulcer score 0) at week 52. Key secondary endpoints at week 52 were the proportion of patients, stratified by disease location, with endoscopic remission (SES-CD <4 for L2/L3 CD or <2 for L1 CD, and no subscores >1), with combined steroid-free clinical and endoscopic remission (CDAI<150 and endoscopic remission), the segmental healing rates, and ulcer healing rates stratified by disease duration. Results 186 patients were included in this intention to treat (ITT) analysis: 42 (22.6%) with L1, 52 (28.0%) with L2, and 92 (49.5%) with L3 disease. Baseline characteristics are shown in table 1. At week 52, the primary endpoint (absence of all ulcerations) was attained in 15/42 patients with L1 (35.7%), 20/52 with L2 (38.5%) and 25/92 with L3 CD (27.2%) (ITT, NRI (p=0.327)). Endoscopic remission was observed in 12/42 patients with L1 (28.6%), 20/52 with L2 (38.5%), and 29/92 with L3 disease (31.5%) (ITT, NRI (p=0.558)). The combined endpoint of clinical-endoscopic remission was reached in 9/42 L1 (21.4%), 16/52 L2 (30.8%), and 23/92 L3 patients (25.0%) (ITT, NRI (p=0.571)). Resolution of ileal ulcers was achieved in 15/40 L1 patients (37.5%) and 37/90 L3 patients (41.1%) (ITT, NRI (p=0.698)), resolution of colonic ulcers in 21/52 L2 (40.4%) and 45/90 L3 patients (50.0%) (ITT, NRI (p=0.268). Patients with early CD (disease duration <2 years) had higher ulcer healing rates than patients with late CD (47.5% versus 24.8%) (ITT, NRI (p=0.002)). Conclusion This post-hoc analysis of LOVE-CD shows that disease location does not affect endoscopic healing rates with VDZ in CD. However, early CD is associated with significantly higher endoscopic remission rates compared to late CD.

P477 Performance of bowel preparation quality scales in patients with Crohn’s disease

Abstract Background The performance of bowel preparation (BP) in patients with Crohn’s disease (CD) is unknown and may be suboptimal due to the presence of mucosal inflammation, strictures, pseudopolyps and bowel resection. We evaluated the reliability and validity of available BP scales in patients with CD. Methods Bowel preparation, in colonoscopy videos (N=50) from patients with CD (N=40) that represented a range of bowel preparation quality and endoscopic disease activity, was independently rated twice, separated by at least 2 weeks, by 3 central readers using the Boston Bowel Preparation Score (BBPS), modified BBPS, Harefield Cleansing Scale (HCS), Food and Drug Administration bowel cleansing assessment scale (FDA BCAS), and a 100-mm visual analogue scale (VAS) of bowel cleanliness. Endoscopic activity was assessed with the Simple Endoscopic Score for CD (SES-CD). All assessments were on endoscope insertion and withdrawal and in the ileum, right colon, transverse colon, left colon, and rectum to facilitate evaluation of the relationship between BP and SES-CD scores. Reliability of BP assessment was quantified using the intraclass correlation coefficient (ICC) and interpreted with benchmarks defined by Landis and Koch.1 Validity was assessed by within-patient correlation between each BP scale and the VAS across segments using mixed effect models. Correlation between BP quality and SES-SD scores by location was assessed using Spearman’s rho. Results Substantial (ICC ≥0.61) inter-rater reliability was observed for all BP scales and the VAS during insertion and withdrawal, except for the FDA BCAS, which had moderate (ICC ≥0.41) inter-rater reliability on insertion (Table 1). Intra-rater reliability was similarly substantial for all BP scales and almost perfect (ICC ≥0.81) for the VAS during insertion and withdrawal. Coefficients for the validity of all BP scales based on correlation with the VAS of bowel cleanliness exceeded 0.58 on both insertion and withdrawal. BP and endoscopic disease activity were negatively correlated in the colon, particularly in the left colon, suggesting that lower BP scores in this segment may result in higher SES-CD scores (Table 2). Conclusion Existing scales are reliable for the assessment of BP in patients with CD. These results provide a framework for scoring of BP quality in clinical trials for CD and support the inclusion of patients with CD for the evaluation of novel BP agents. Reference: 1. Landis J.R. and Koch G. G. Biometrics. 1977:33;159-74

OP12 Mirikizumab improves fatigue, bowel urgency, and quality of life in patients with moderately to severely active Crohn’s Disease: Results from a phase 3 clinical trial

Abstract Background Mirikizumab (miri), an anti-IL-23p19 antibody, is approved for the treatment of ulcerative colitis and under development for Crohn’s disease (CD). We investigated how miri impacted fatigue, bowel urgency, and health-related quality of life (HRQoL) through 52 weeks in patients with moderately to severely active CD in the Phase 3 VIVID-1 study. Methods In the treat-through VIVID-1 (NCT03926130) study, patients (N=1065) with moderately to severely active CD and a Simple Endoscopic Score for CD (SES-CD) score ≥7 (or ≥4 for patients with isolated ileal disease) and failure to biologic and/or conventional therapy were randomized in a 6:3:2 ratio to receive miri (N=579) (a single 900mg intravenous (IV) dose at W0, W4, and W8 followed by a subcutaneous (SC) dose of 300 mg at W12 and then every 4 weeks), ustekinumab (N=287) (6mg/kg IV at W0 and SC dose of 90mg at W8 and then every 8 weeks), or PBO (N=199). At W12 PBO responders continued PBO to W52; PBO-non-responders received the same blinded miri regimen as described above. This analysis focuses on results in patients randomized to either miri or PBO. The change from baseline for Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F), Urgency Numeric Rating Scale (UNRS), and Inflammatory Bowel Disease Questionnaire (IBDQ) total and domain scores (bowel symptoms, systemic symptoms, emotional function, social function) were analyzed through W52. IBDQ response (≥16-point improvement from baseline) and remission (total score ≥ 170) rates were also analyzed at W12 and W52. For binary variables, adjusted risk differences were compared between miri and PBO using the Cochran-Mantel-Haenszel (CMH) test. For continuous variables, least squares mean changes from baseline were compared between treatment groups using ANCOVA. Results Significant improvement in mean change from baseline to W12 and W52 were observed with miri for FACIT-F, UNRS, and IBDQ total and domain scores (all p<0.000001 at W52) (Figure 1&2). Miri-treated patients showed improved UNRS scores versus PBO as early as W8 with statistical significance sustained to W52 (Figure 1B). At W12 and W52, a greater percentage of miri-treated patients achieved IBDQ response (W12: p<0.000001; W52: p<0.000001) and remission (W12: p<0.000001; W52: p<0.000001) compared to PBO (Figure 2A&B). Conclusion Treatment with miri resulted in improvements in fatigue, bowel urgency, and HRQoL at W12 and W52 in patients with moderately to severely active CD.

DOP18 Efficacy of risankizumab versus ustekinumab by baseline Crohn’s Disease location: post-hoc analysis of the SEQUENCE head-to-head trial

Abstract Background In Crohn’s disease (CD), disease location may impact treatment effect. This post-hoc analysis of the SEQUENCE head-to-head trial (NCT04524611) compared the efficacy of risankizumab (RZB), an interleukin (IL)-23 p19 inhibitor, versus ustekinumab (UST), an IL-12/23 p40 inhibitor, by CD location. Methods SEQUENCE was an open-label, efficacy assessment-blinded, randomized controlled trial, which enrolled patients (pts) with moderate to severe CD who previously failed ≥1 anti-tumor necrosis factor (TNF) therapy. Pts included in the primary efficacy analysis were randomised 1:1 to receive RZB (selected dosing: intravenous 600 mg induction dose administered at weeks (wks) 0, 4, and 8, followed by subcutaneous 360 mg maintenance dose every 8 wks starting at wk 12) or UST (a single weight-based induction dose administered at wk 0, followed by subcutaneous 90 mg maintenance dose every 8 wks starting at wk 8. A mandatory steroid taper began at wk 2. The primary endpoints were clinical remission (CD Activity Index <150) at wk 24 and endoscopic remission (Simple Endoscopic Score for CD ≤4 and at least a 2-point reduction versus baseline and no subscore >1 in any individual variable, as scored by a central reviewer blinded to treatment allocation) at wk 48. In this post-hoc analysis, both endpoints were evaluated in 100% of pts included in the primary efficacy analysis, stratified by baseline CD location subgroups (ileal only, colonic only, ileal-colonic). Nominal P-values were reported for treatment differences within subgroups. Results At baseline, majority of pts had either ileal-colonic (225 [43.3%]) or colonic (208 [40%]) CD; 87 (16.7%) pts had isolated ileal disease. At wk 24, numerically greater proportions of pts achieved clinical remission with RZB versus UST, regardless of disease location (treatment difference [95% confidence interval], P-value: ileal only, Δ0.8 [-20.1, 21.7], P=0.941; colonic only, Δ22.4 [9.2, 35.5], P=0.001; ileal-colonic, Δ18.2 [5.3, 31.0], P=0.007) (Figure). Pts randomized to RZB with colonic only disease had numerically higher rates of clinical remission relative to pts with ileal only or ileo-colonic disease. At wk 48, RZB-treated pts demonstrated numerically higher rates of endoscopic remission than UST-treated pts (ileal only, Δ22.5 [4.4, 40.6], P=0.017; colonic only, Δ18.3 [6.6, 30.0], P=0.003; ileal-colonic, Δ10.3 [-0.2, 20.9], P=0.057) (Figure). Endoscopic remission rates in the RZB-treated pts were generally similar between ileal only and colonic only CD. Conclusion In pts who have failed ≥1 anti-TNF therapy, RZB demonstrated greater rates of endoscopic remission compared to UST regardless of CD location, and greater rates of clinical remission in ileo-colonic and colonic CD.

P998 Phase 2 basket design study evaluating the efficacy and safety of an anti-TL1A antibody (TEV-48574) in moderate to severe ulcerative colitis or Crohn's Disease (RELIEVE UCCD)

Abstract Background TEV-48574 is a human antibody that targets tumor necrosis factor (TNF)-like ligand 1A, also known as TNF superfamily member 15 (TNFSF15). TEV-48574 is being evaluated in the first basket design trial in IBD. The basket design is uniquely suited for the efficient assessment of TEV-48574 as evidence suggests that TL1A signaling plays a key role in both ulcerative colitis (UC) and Crohn’s disease (CD). TL1A signaling is not a primary driver but an amplifier of inflammation; thus, targeting TL1A should mitigate excessive immune responses while leaving baseline immunity intact. Originating in oncology trials, the basket trial design has emerged as a new efficient approach for testing treatment efficacy in different disease indications with potentially common molecular mechanisms. The basket design approach allows the evaluation of multiple indications in a single study design that provides adequate support for initiation of confirmatory studies. Additionally, the basket design allows for shared sites and institutional review boards, data collection and analyses under consistent conditions. Herein, we describe the phase 2b basket trial evaluating TEV-48574 in UC and CD (clinicaltrials.gov NCT05499130), currently ongoing along with a long-term extension study (LTE)(NCT05668013). Methods In this double-blind placebo-controlled global study, TEV-48574 or placebo is administered subcutaneously to adults (n = 240) diagnosed with moderate-to-severe IBD (UC (n = 120) or CD (n = 120)). Patients who meet pre-specified inclusion/exclusion criteria are randomized to either one of two TEV-48574 dose regimens or placebo in a 1:1:1 ratio (stratified by diagnosis (UC or CD) and previous exposure to advanced IBD therapy(biologics and small molecules)) for 14 weeks. Patients who complete the 14-week induction period have the option to enter the LTE, consisting of a 44-week maintenance period for responders and a re-induction period for non-responders. Primary efficacy endpoints are induction of clinical remission (a modified Mayo Score of ≤2 points for UC), and endoscopic response (a reduction in Simple Endoscopic Score for Crohn's Disease (SES-CD) of ≥ 50% from baseline) for CD, at week 14. A Bayesian approach will be used to compute posterior probabilities for the response endpoints within each indication. Additional endpoints include safety assessments, measures of clinical response, biomarkers, pharmacokinetics, and immunogenicity. Results Conclusion TEV-48574 is a potential novel treatment option for patients with UC and CD that may have dual antifibrotic and anti-inflammatory effects. The phase 2 basket study design offers an efficient approach to advance TEV-45874to confirmatory phase 3 studies.

P314 Serum levels of Leucin-Rich α2 Glycoprotein predicts endoscopic mucosal healing of Crohn's disease

Abstract Background It has been suggested that serum levels of Leucin-Rich α2 Glycoprotein (LRG) correlate with disease activity of Crohn’s disease (CD). Small bowel capsule endoscopy (SBCE) can be performed together with ileo-colonoscopy (ICS) at the same day to assess mucosal healing in patients with clinically quiescent CD. The aim of this study was to determine the usefulness and a cut off value of LRG that indicate mucosal healing in patients with CD. Methods Clinically quiescent CD (CDAI<150) patients without perianal lesions received SBCE and ICS at the same day between July 2021 and August 2023 were included. Serum levels of CRP and LRG were measured in the time frame of median 23 days before or after the exam (IQR 14, 43). Endoscopic findings were evaluated by modified simple endoscopic score for CD (mSES-CD) composed of 3 variables (size of ulcers, proportion of ulcer surface and disease affected surface) of each 7 segments (jejunum, upper ileum, lower ileum, right colon, transvers colon, left colon and rectum). Mucosal healing was defined by the mSES-CD score of 0. Results Among 51 CD patients enrolled, 88.2% were male with the median age of 20 (IQR 22, 35) and the disease duration of 69 months (IQR 23, 35). History of small or large intestinal resection was found in 15 (29.4%) and 14 (27.4%) cases, respectively. The median CRP and LRG were 0.1 mg/dL (IQR 0.1, 0.4), and 12.3 μg/mL (IQR 8.8, 18.3), respectively. The median mSES-CD was 3 (0,6%), and 20 (39.2%) cases were score 0. There was a high correlation between LRG and CRP levels (p<0.0001, r=0.78), and the cut of value of LRG that indicates negative CRP (< 0.4 mg/dL) was 16.6 μg/mL; area under the curve (AUC) of ROC analysis 0.91, sensitivity 90.0%, specificity 84.8%. In addition, a significant correlation between LRG levels and mSES-CD was found (p< 0.0001, r= 0.65), while no correlation between CRP and mSES-CD (p=0.72, r= 0.27). The cut off value of LRG that indicates mucosal healing was 10.2 μg/mL (AUC 0.915, sensitivity 89.7%, specificity 85.7%) with positive predictive value of 92.9% and negative predictive value of 80.0%. Conclusion LRG can be a reasonable biomarker to monitor disease status of CD especially in clinically quiescent patients with small bowel CD. LRG values less than 10.2 μg/mL indicates endoscopic mucosal healing in patients with CD.

P391 A not so innocent bystander: The prevalence and burden of anaemia at IBD onset

Abstract Background Anaemia is the most common systemic complication of Inflammatory Bowel Disease (IBD). Contemporary studies linking its prevalence with symptom burden at disease onset are limited. We present the prevalence and disability associated with anaemia in a large new onset adult IBD cohort. Methods Demographic, clinical and biochemical indices were collected prospectively in patients referred with suspected IBD between January 2021 - April 2023. Anaemia was defined as haemoglobin (Hb) of <115g/L in women and <130g/L in men. Iron deficiency was defined as Ferritin <30ug/L (<100ug/L if active inflammation – CRP >5mg/L, Faecal Calprotectin [FCP] >200ug/g) or Iron saturations <15%. IBD disk scores were collected in a subgroup of patients. For two groups, non-parametric Mann-Whitney U tests were utilised, with a pairwise Dunn test and holm corrected p values for more than two. Results Hb results were available for 586 patients (182 CD, 170 UC, 234 non-IBD). Of these, an IBD disk score was available for 245 (84 CD, 71 UC, 90 non-IBD). Hb levels were significantly lower in CD than non-IBD (Table 1). Overall, a significantly larger proportion of patients with CD were anaemic than UC (X2 10.2 p=0.001, odds ratio 2.4 [95% CI 1.39-4.16]). Whilst most anaemic patients in both groups were iron deficient, many without anaemia also had demonstrable iron deficiency (Figure 1). In CD, Hb levels were significantly lower in ileocolonic disease than either isolated ileal (median Hb 125vs135.5g/L, p=0.002) or isolated colonic (125vs139g/L, p=0.002). Across IBD, Hb significantly correlated with Harvey Bradshaw Index (n=142, Spearman’s Rho [SR] -0.23 p=0.007), Partial Mayo (n=143, SR -0.23 p=0.006), Simple endoscopic score for CD (n=130, SR -0.29 p<0.001) and FCP (n=314, SR -0.23 p<0.001). Regarding overall disease burden, Hb correlated with overall disability as determined by the IBD disk (n=155, -0.23 p=0.004). Anaemic patients had higher overall disability (total disk score 62.5vs49 p=0.007). Using individual disk domains, those with anaemia had higher fatigue (median 9vs8, p=0.012), disruption of education or work (7vs4, p<0.001), impairment of body image (7vs4, p=0.019) and reduced sexual function (5.5vs1, p=0.004). When compared in a linear regression alongside age, body mass index, ethnicity, IBD type and baseline FCP, Hb was the second strongest predictor of overall disk score (Model fit R=0.515, BMI t=3.05 p=0.003, Hb t=-2.41 p=0.019). Conclusion Anaemia is frequently present at IBD onset, particularly in CD. Nearly half of those without anaemia have demonstrable iron deficiency. Severity of anaemia is associated with overall disease activity but influences symptom burden and disability beyond that which is attributable to mucosal inflammation alone.

P317 Diagnostic accuracy of plasma calprotectin and serum calprotectin in patients with suspected Crohn’s disease

Abstract Background Faecal calprotectin is a sensitive marker for chronic inflammatory bowel disease (IBD), and it correlates with the endoscopic disease activity. However, patient reluctance and handling in the laboratory are limitations for the clinical use, and there is a need for new reliable blood-based biomarkers. Prior studies indicate, that serum calprotectin (SCal) and plasma calprotectin (PCal) can be used as biomarkers for IBD, and SCal correlates better with disease activity in Crohn’s disease (CD) than in ulcerative colitis. The aim of this study was to investigate the diagnostic accuracy of SCal and PCal in patients examined for CD. Methods Patients with clinically suspected CD were enrolled in a prospective, blinded, multicentre study examining non-invasive modalities for diagnosing CD (ClinicalTrials.gov identifier NCT03134586). Patients had a standardized work-up including ileocolonoscopy, pan-enteric capsule endoscopy and blood samples within a 2-week period. EDTA plasma was prepared less than 2 hours of sampling by centrifugation at 3000 g for 15 minutes. Samples were stored in a biobank at − 80°C until further analysis. A routine C-reactive protein (CRP) was measured on the same day. SCal and PCal were analysed in batches using the calprotectin assay product nr.1201 from Gentian (Moss, Norway) on the Cobas platform (Roche, Basel, Switzerland). Analyses were performed in an ISO 15189 accredited laboratory. Results 126 patients were enrolled in the study: 69 % women and 31 % men with a median age of 27.5 years (Table 1). A total of 57 (45%) patients were diagnosed with CD based on the result of ileocolonoscopy and pan-enteric capsule endoscopy. Patients with CD had a mean PCal of 0.50 mg/L (95% confidence interval (CI) 0.38-0.62) compared to 0.35 mg/L (CI 0.27-0.44) in non-CD patients (P = 0.03). The mean SCal was 1.45 mg/L (CI 1.20-1.69) and 1.06 mg/L (CI 0.90-1.22) in patients with and without CD, respectively (P = 0.01). Receiver operating characteristics curves showed an AUC of 0.63 (CI 0.53-0.73) for SCal and 0.61 (CI 0.51-0.71) for PCal, which was inferior to CRP (0.76, CI 0.68-0.85, P < 0.02) (Figure 1). In patients diagnosed with CD, SCal and PCal had a moderate correlation with CRP (rs = 0.47 and 0.55, respectively, P < 0.001), and SCal had a weak correlation with the Simple Endoscopic Score for CD (rs = 0.29, P = 0.04) and the Crohn’s Disease Activity Index (rs = 0.36, P = 0.03). Conclusion Levels of PCal and SCal are increased in patients with CD reflecting the systemic inflammatory response in this disease. However, SCal and PCal are insufficient biomarkers in patients with clinically suspected CD, and they are both inferior to CRP.

P288 Fecal leukocyte esterase level can predict endoscopic activity for Inflammatory Bowel Disease patients

Abstract Background The urine leukocyte esterase (LE) strip is widely employed to detect leukocyte presence in human body fluids due to its simplicity, speed, and cost-effectiveness. Our previous study demonstrated that fecal LE (FLE) correlated with fecal calprotectin (FC) which serves as a surrogate marker reflecting disease activity in inflammatory bowel disease (IBD) patients. This study aims to assess the correlation between FLE and endoscopy severity. Methods This prospective study included IBD patients at National Taiwan University Hospital from December 2021 to November 2023. FLE and FC in the same stool sample, which was collected within one month of endoscopy, were analyzed. The correlation between FLC, FC, and endoscopic severity scores was assessed using the Pearson method. Active disease in ulcerative colitis (UC) and Crohn's disease (CD) patients was defined as Mayo endoscopic score (MES) ≥ 2 and simple Endoscopic Score for Crohn's Disease (SESCD) ≥ 8, respectively. Sensitivity, specificity, positive and negative predictive values (PPV and NPV, respectively), and the Area Under the Receiver Operating Characteristic curve (AUROC) were analyzed by using SPSS. Results A total of 177 IBD patients (93 with UC, 84 with CD) were included. The correlation between FLE and FC levels was moderately positive (r=0.305, p<0.001). The correlation between FLE and endoscopic severity in UC and CD patients was 0.442 (p<0.001) and 0.293 (p=0.007), respectively. Among UC patients, the area under the receiver operating characteristic curve (AUROC) for predicting MES ≥ 2 by FLE and FC was 0.717 and 0.787 (p=0.241), with an optimal cutoff of 2+ for FLE and 42.5 mg/kg for FC, respectively. At this cutoff point, FLE demonstrated a sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) for predicting MES ≥ 2 as 52.3%, 81.6%, 71.8%, and 65.6%, respectively. For CD patients, the AUROC for predicting SESCD ≥ 8 by FLE and FC was 0.761 and 0.869 (p=0.203), with an optimal cutoff of 2+ for FLE and 225 mg/kg for FC, respectively. FLE exhibited a sensitivity, specificity, PPV, and NPV of 81.8%, 64.4%, 74.3%, and 95.9% for predicting SESCD ≥8 respectively, at this cutoff. Conclusion Our results demonstrated that FLE can predict endoscopic activity, which is a cheaper and widely available monitoring tool, might be an alternative choice to FC for IBD monitoring.

Use of double-balloon endoscopy and an endoscopic scoring system to assess endoscopic remission in isolated small bowel Crohn's disease after treatment with infliximab.

It is unclear how clinical and endoscopic factors affect the attainment of endoscopic remission (ER) in patients with small bowel Crohn's disease (SB-CD) who are infliximab-naïve. We aimed to identify the effect of different factors on attaining ER using double-balloon endoscopy (DBE) evaluation. A single-center retrospective observational study was conducted from 1 January 2018 to 30 November 2022. Among 262 patients who were screened for isolated SB-CD by baseline DBE, 108 patients were assessed for effectiveness during maintenance infliximab therapy by a second DBE evaluation. DBE findings before and after infliximab therapy were compared. ER was defined as a simple endoscopic score for CD (SES-CD) below 3, and segmental ER as SES-CD activity of 0. Multivariate regression with calculations of odds ratios (OR) was used to determine the impact of different factors on attaining ER. In all, 41 patients (38.0%) achieved ER. An elevated C-reactive protein at week 6 was independently associated with a decreased probability of ER [OR: 0.86, 95% confidence interval (CI) = 0.75-0.98, p = 0.03]. Segmental ER of the terminal ileum, rather than the proximal ileum, was associated with a higher rate of ER (60.9% versus 38.2%, p = 0.01). High baseline SES-CD (⩾16) was unrelated to overall ER. For patients with disease in the terminal ileum, those with moderate/severe disease were less likely to attain segmental ER than those with mild disease [adjusted odds ratios (aOR): 0.27, 95% CI: 0.09-0.83, p = 0.02]. A large ulcer in the terminal ileum was associated with a lower rate of segmental ER (aOR: 0.18, 95% CI: 0.06-0.56, p = 0.01). For infliximab-naïve patients with SB-CD, the overall severity of the endoscopic score was unrelated to attainment of ER. Patients were less likely to attain segmental ER if they had greater endoscopic inflammation or larger ulcers in the terminal ileum.

The synergy of dual faecal immunochemical and faecal calprotectin testing for accurate assessment of endoscopic and histological activity in inflammatory bowel disease.

Faecal biomarkers are increasingly utilized for disease assessment in inflammatory bowel disease (IBD). To characterize the relative and combined accuracy of faecal calprotectin (FC) and faecal immunochemical testing (FIT) for detecting endoscopic and histologically active disease in Crohn's disease (CD) and ulcerative colitis (UC), subdivided by disease location. A prospective cohort study. Patients with confirmed IBD undergoing routine ileocolonoscopy for activity assessment were prospectively recruited and performed both FC and FIT ±30 days of ileocolonoscopy. Endoscopic activity was assessed via the simplified endoscopic score for CD, Mayo endoscopic score for UC and histological activity graded as nil/mild/moderate. Receiver-operator curve analyses were utilized to assess the performance of FC and FIT per disease subtype and location. In all, 137 (79 CD, 57 UC) patients were recruited. FC was more sensitive than FIT in detecting active endoscopic (CD: 91% versus 69%, UC: 94% versus 82%) and histological (CD: 86% versus 55%, UC 88% versus 56%) disease. However, FIT was more specific than FC in detecting active endoscopic (CD: 94% versus 56%, UC: 85% versus 69%) and histological (CD: 93% versus 55%, UC: 96% versus 70%) diseases. FIT was more sensitive and specific than FC in detecting active colonic CD (endoscopic activity: 94% versus 93%, histological activity: 92% versus 77%, respectively); however, it was poorly sensitive for active ileal CD (43% versus 89%). FC demonstrated higher sensitivity and FIT higher specificity for active IBD. Hence, dual testing was synergistic, displaying excellent performance characteristics across most IBD locations and subtypes, holding promise for future clinical application. Not applicable.

Determining the Accuracy of Intestinal Ultrasound Scores as a Prescreening Tool in Crohn's Disease Clinical Trials.

High rates of screen failure for the minimum Simple Endoscopic Score for Crohn's Disease (SES-CD) plague Crohn's disease (CD) clinical trials. We aimed to determine the accuracy of segmental intestinal ultrasound (IUS) parameters and scores to detect segmental SES-CD activity. A single-center, blinded, cross-sectional cohort study of children and young adult patients with CD undergoing IUS and ileocolonoscopy, comparing segmental IUS bowel wall thickness (BWT), hyperemia (modified Limberg score [MLS]), and scores to detect segmental SES-CD activity: (i) SES-CD ≤2, (ii) SES-CD ≥6, and (iii) SES-CD ≥4 in the terminal ileum (TI) only. Primary outcome was accuracy of BWT, MLS, and IUS scores to detect SES-CD ≤2 and SES-CD ≥6. Secondary outcomes were accuracy of TI BWT, MLS, and IUS scores to detect SES-CD ≥4 and correlation with the SES-CD. Eighty-two patients (median [interquartile range] age 16.5 [12.9-20.0] years) underwent IUS and ileocolonoscopy of 323 bowel segments. Segmental BWT ≤3.1 mm had a similar high accuracy to detect SES-CD ≤2 as IUS scores (area under the receiver operating curve [AUROC] 0.833 [95% confidence interval 0.76-0.91], 94% sensitivity, and 73% specificity). Segmental BWT ≥3.6 mm and ≥4.3 mm had similar high accuracy to detect SES-CD ≥6 (AUROC 0.950 [95% confidence interval 0.92-0.98], 89% sensitivity, 93% specificity) in the colon and an SES-CD ≥4 in the TI (AUROC 0.874 [0.79-0.96], 80% sensitivity, and 91% specificity) as IUS scores. Segmental IUS scores strongly correlated with the SES-CD. Segmental IUS BWT is highly accurate to detect moderate-to-severe endoscopic inflammation. IUS may be the ideal prescreening tool to reduce unnecessary trial screen failures.

Fecal miR-223 is a noninvasive biomarker for estimating Crohn's disease activity.

MicroRNA-223 (miR-223) has emerged as a promising noninvasive biomarker for Crohn's disease (CD). However, it is unclear which tissue derived miRNA-223 can more accurately estimate CD disease activity. To collect serum, terminal ileal mucosa biopsy and fecal samples from CD patients and healthy controls. The CD Activity Index (CDAI) score, Montreal classification, maintenance medicines, peripheral blood inflammatory markers, fecal calprotectin (FC) and the Simple Endoscopic Score for CD (SES-CD) were recorded. To compare the expression of miR-223 in the serum, intestinal tissue, and feces. MiR-223 expression levels in the serum, intestinal tissue and feces of CD patients were significantly higher than those of controls. The level of miR-223 in the serum, intestinal tissue and feces increased significantly in active CD patients compared with that in inactive CD patients. The levels of serum, intestinal tissue and fecal miR-223 were correlated with the CDAI. Serum miR-223 was also correlated with C-reactive protein (CRP) and IL-6, tissue miR-223 correlated with IL-6 and FC, and fecal miR-223 correlated with FC. In terms of the association with FC, fecal miR-223 had a higher Spearman r value than tissue miR-223. The area under the curve (AUC) values of serum, tissue and fecal miR-223 to diagnose CD were similar to those of CRP and FC (AUC > 0.8). The AUC values of tissue and fecal miR-223 to evaluate CD disease activity were 0.832 and 0.818, respectively, and were higher than serum miR-223, CRP and FC. Fecal miR-223 had a higher specificity of 92.3%. Fecal miR-223 might be a novel, noninvasive biomarker for estimating the disease activity of CD patients.

Intestinal ultrasound score predicts therapeutic outcomes of infliximab in pediatric patients with Crohn’s disease

Background and aims Objective evaluation of treatment response is critical in the management of Crohn’s disease (CD). Compared with endoscopy, intestinal ultrasound (IUS) is non-invasive and well-tolerated. This study is aimed to assess the predictive value of IUS score for treatment response in pediatric CD patients. Methods We conducted a retrospective study in pediatric CD patients who underwent endoscopy and IUS at start of infliximab treatment [T0] and after 22–38 weeks [T1] between February 2021 and January 2023. Pediatric Crohn’s Disease Activity Index (PCDAI), biochemical parameters, the Simple Endoscopic Score for Crohn’s disease (SES-CD) and IUS parameters were collected at two timepoints. IUS scores were assessed by International Bowel Ultrasound Segment Activity Score (IBUS-SAS). Results Thirty patients were included, with 53.3% reaching endoscopic response and 43.3% endoscopic remission. After infliximab treatment, IBUS-SAS (58.5 ± 24.2 vs 34.4 ± 21.6, p = .0001) was significantly decreased. At T1, change in IBUS-SAS (−38.2 ± 22.0 vs −7.9 ± 24.1, p = .0015) were pronounced in patients with endoscopic response compared with endoscopic non-response. Significant correlation were observed between IBUS-SAS and SES-CD, PCDAI, C-reaction protein, erythrocyte sedimentation rate, hemoglobin, albumin. The most accurate cutoff values for predicting endoscopic response were 57.4% decrease of IBUS-SAS (AUROC: 0.862, p < .001). The optimal cut-off of IBUS-SAS to correlate endoscopic remission was 26.0 (AUROC: 0.686, p = .017). Conclusions The validated ultrasound-base score, IBUS-SAS is an effective index for monitoring endoscopic response to infliximab therapy in CD. IUS evaluation could guide treatment decision for pediatric CD.

Vedolizumab, Adalimumab, and Methotrexate Combination Therapy in Crohn’s Disease (EXPLORER)

Although biologics have revolutionized the treatment of Crohn's disease (CD), an efficacy ceiling has been reached. Combining biologic therapies may improve remission rates. EXPLORER, a phase 4, single-arm, open-label study, evaluated triple combination therapy with vedolizumab (300 mg on day 1, weeks 2 and 6, and then every 8 weeks), adalimumab (160 mg on day 2, 80 mg at week 2, then 40 mg every 2 weeks), and methotrexate (15 mg weekly) in biologic-naïve patients with newly diagnosed, moderate- to high-risk CD. Endoscopic remission at week 26 (primary end point; Simple Endoscopic Score for CD ≤2), clinical remission at weeks 10 and 26 (secondary end point; Crohn's Disease Activity Index <150), and incidences of adverse events and serious adverse events were evaluated. Among 55 enrolled patients, the mean CD duration was 0.4 years, the mean baseline Simple Endoscopic Score for CD was 12.6, and the mean baseline Crohn's Disease Activity Index was 265.5. At week 26, 19 patients (34.5%) were in endoscopic remission. At weeks 10 and 26, 34 (61.8%) and 30 patients (54.5%), respectively, were in clinical remission. Post hoc Bayesian analysis showed that the probabilities that triple combination therapy produced a higher endoscopic remission rate (33.5%; 95% credible interval, 22.4-45.7) than placebo (14%), vedolizumab monotherapy (27%), or adalimumab monotherapy (30%) were 99.9% or higher, 86.3%, and 71.4%, respectively. Six patients had serious adverse events. Combination therapy resulted in endoscopic and clinical remission at week 26 in 34.5% and 54.5% of patients, respectively, with no safety signal related to the treatment regimen. This supports further evaluation of combination therapy in CD. gov number: NCT02764762.

Multiparametric MRI for Staging of Bowel Inflammatory Activity in Crohn's Disease with MUSE-IVIM and DCE-MRI: A Preliminary Study

To investigate if the combination of multishot diffusion imaging-based multiplexed sensitivity encoding intravoxel incoherent motion (MUSE-IVIM) and dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) is feasible for staging Crohn's disease (CD) activity. A total of 65 CD patients were enrolled and analyzed in this retrospective study. The simplified endoscopic score for Crohn's disease (SES-CD) and magnetic resonance index of activity (MaRIA) were used as the reference. The MUSE-IVIM and DCE-MRI data were acquired at 3.0-T MRI scanner and processed by two radiologists. Three MUSE-IVIM parameters: fast apparent diffusion coefficient (ADCfast), slow apparent diffusion coefficient (ADCslow), and the fractional perfusion (Fraction of ADCfast), as well as four DCE-MRI parameters: volume transfer constant (Ktrans), rate constant (Kep), extravascular extracellular volume fraction (Ve), and plasma volume fraction (Vp) were generated. Intraclass correlation coefficient (ICC), non-parametric test (Kruskal-Wallis H and Mann-Whitney U), logistic regression, receiver operating characteristic analysis, Delong test, and Spearman's correlation test were performed. According to SES-CD, 116 ileocolonic segments with CD lesions were identified as: inactive, mild, and moderate to severe. With multivariable logistic regression analysis, ADCfast (p<0.001), Fraction of ADCfast (p=0.005), Ktrans (p<0.001) and Kep (p=0.003) were identified as significant factors for differentiating among the three groups. Binary logistic analyses identified ADCfast (p=0.001), Ktrans (p=0.014), and Kep (p=0.029) as independent predictors for the active status. The combination of ADCfast, Ktrans, and Kep performed better than MaRIA score (p=0.028), for differentiating inactive and active status. MaRIA score was positively correlated with ADCfast (p<0.001), Ktrans (p<0.001), Kep (p<0.001), and Ve (p=0.001), however, negatively correlated with Fraction of ADCfast (p<0.001). The combination of MUSE-IVIM and DCE-MRI has been demonstrated to accurately stage inflammatory activity in CD.

Exploring the relationship between urinary phthalate metabolites and Crohn's disease via oxidative stress, and the potential moderating role of gut microbiota: A conditional mediation model

ObjectiveInteractions between phthalic acid esters (PAEs) exposure and Crohn's disease (CD) were unknown. This study aims to examine the association between exposure to PAEs and CD activity and to explore the roles of oxidative stress and microbiota. MethodsA cross-sectional study with 127 CD patients was conducted. The disease activity was evaluated based on symptoms (Harvey-Bradshaw index, HBI), endoscopy findings (Simple Endoscopic Score for CD, SES-CD), and computed tomography enterography (CTE-scores). Ten urinary PAEs metabolites (mPAEs), two urinary oxidative stress biomarkers, including 8-hydroxydeoxyguanosine (8-OHdG) and 8-iso-prostaglandin-F2α (8-iso-PGF2α), as well as 16S rRNA sequencing of stool samples were determined. Multiple linear regression models and Hayes's PROCESS macro for SPSS were used to evaluate the interplays between urinary PAEs metabolites, CD activities, oxidative stress, and microbiota diversity. ResultsThere were positive associations between most mPAEs and HBI. Oxidative stress mediated 20.69–89.29% of the indirect associations between low molecular weight (LMW) mPAEs and HBI, while the majority of the high molecular weight (HMW) mPAEs were directly associated with HBI. In addition, microbiota diversity moderated the indirect associations of LMW mPAEs on HBI. ConclusionsPAEs exposure was related to CD activity, and the association could be mediated by oxidative stress and reversed or alleviated by rich gut microbiota.

NAFLD Is Associated With Quiescent Rather Than Active Crohn's Disease.

Crohn's disease (CD) confers an increased risk of nonalcoholic fatty liver disease (NAFLD), but the pathogenesis remains poorly understood. We determined if active intestinal inflammation increases the risk of NAFLD in patients with CD. Two cohorts (2017/2018 and 2020) with CD and no known liver disease were enrolled consecutively during staging magnetic resonance enterography. We quantified proton density fat fraction, MaRIA (Magnetic Resonance Index of Activity), and visceral adipose tissue. NAFLD was diagnosed when proton density fat fraction ≥5.5%. Synchronous endoscopy was graded by the Simple Endoscopic Score for CD and Rutgeerts score, while clinical activity was graded by the Harvey-Bradshaw index. Cytokine profiling was performed for the 2020 cohort. Transient elastography and liver biopsy were requested by standard of care. NAFLD was diagnosed in 40% (n = 144 of 363), with higher prevalence during radiographically quiescent disease (odds ratio, 1.7; P = .01), independent of body mass index/visceral adipose tissue (adjusted odds ratio, 7.8; P = .03). These findings were corroborated by endoscopic disease activity, but not by aggregate clinical symptoms. Circulating interleukin-8 was independent of body mass index to predict NAFLD, but traditional proinflammatory cytokines were not. NAFLD subjects had similar liver stiffness estimates regardless of CD activity. Definitive or borderline steatohepatitis was present in most patients that underwent liver biopsy. Quiescent CD is associated with risk of NAFLD. These findings suggest potentially distinct pathogenic mechanisms of NAFLD in patients with CD compared with the prevailing leaky gut hypothesis proposed for individuals without inflammatory bowel disease. Future validation and mechanistic studies are needed to dissect these distinct disease modifying factors.

Standardizing Scoring Conventions for Crohn’s Disease Endoscopy: An International RAND/UCLA Appropriateness Study

Endoscopic assessment of disease activity is integral for evaluating treatment response in patients with Crohn's disease (CD). We aimed to define appropriate items for evaluating endoscopic activity and conventions for consistent endoscopic scoring rules in CD. A 2-round modified RAND/University of California at Los Angeles Appropriateness Method study was conducted. A panel of 15 gastroenterologists used a 9-point Likert scale to rate the appropriateness of statements pertaining to the Simple Endoscopic Score for CD, Crohn's Disease Endoscopic Index of Severity, and additional items relevant to endoscopy scoring in CD. Each statement was voted as appropriate, uncertain, or inappropriate based on the median panel rating and presence of disagreement. Panelists voted that it is appropriate for all ulcers to contribute to endoscopic scoring in CD, including aphthous ulcers, ulcerations at a surgical anastomosis, and anal canal ulcers (scored in the rectum). Endoscopic healing should reflect an absence of ulcers. Narrowing should be defined as a clear decrease in luminal diameter; stenosis should be defined by an impassable narrowing, and if occurring at the junction of 2 segments, scored in the distal segment. Scarring and inflammatory polyps were considered inappropriate for including in the affected area score. The optimal method for defining ulcer depth remains uncertain. We outlined scoring conventions for the Simple Endoscopic Score for CD and Crohn's Disease Endoscopic Index of Severity, noting that both scores have limitations. Therefore, we identified priorities for future research and steps for developing and validating a more representative endoscopic index in CD.