Crohn's Disease Activity Index Score Research Articles

Exposure–efficacy relationship of vedolizumab subcutaneous and intravenous formulations in Crohn’s disease and ulcerative colitis

ABSTRACT Background and aims This posthoc analysis of the GEMINI and VISIBLE studies in ulcerative colitis (UC) and Crohn's Disease (CD) assessed exposure−efficacy of vedolizumab intravenous (IV) and subcutaneous (SC). Methods A previously described population pharmacokinetic model was used to predict average serum and trough concentrations at steady state (Cav,ss, Ctrough,ss) and simulate the transition from vedolizumab IV to SC. Efficacy was defined as clinical remission at week 52: complete Mayo score ≤ 2 points and no individual subscore > 1 point (UC), and CD activity index score ≤ 150 points (CD). Results Data were from 1968 patients (GEMINI 1 [n = 334], VISIBLE 1 [n = 216], GEMINI 2 [n = 1009], VISIBLE 2 [n = 409]) who received maintenance treatment with vedolizumab IV-Q8W, IV-Q4W, SC-Q2W, or placebo. Model-predicted Cav,ss for IV-Q8W and SC-Q2W was similar in UC and CD. Cav,ss was higher for IV-Q4W than IV-Q8W and SC-Q2W. Ctrough,ss values from IV and SC aligned well with pooled observed Ctrough by treatment group in UC and CD. Cav,ss was equivalent for SC and IV. For UC and CD, efficacy rates were greater in patients in the highest quartiles of vedolizumab exposure for both formulations. Conclusion Exposure−efficacy relationships for IV and SC vedolizumab administration were comparable, confirming that both are equally effective during maintenance treatment.

A potential brain functional biomarker distinguishing patients with Crohn's disease with different disease stages: a resting-state fMRI study.

The previous studies have demonstrated that patients with Crohn's disease in remission (CD-R) have abnormal alterations in brain function. However, whether brain function changes in patients with Crohn's disease in activity (CD-A) and the relationship with CD-R are still unclear. In this study, we aimed to investigate whether the different levels of disease activity may differentially affect the brain function and to find the brain functional biomarker distinguishing patients with different disease stages by measuring the amplitude of low frequency fluctuations (ALFF). 121 patients with CD and 91 healthy controls (HCs) were recruited. The clinical and psychological assessment of participants were collected. The criteria for the disease activity were the Crohn's disease activity index (CDAI) scores. CD-R refers to CD patients in remission which the CDAI score is less than 150. Conversely, CD-A refers to CD patients in activity which the CDAI score is ≥150. The ALFF was compared among three groups by performing one-way analysis of variance, followed by a post hoc two-sample t-test. Differences among the groups were selected as seeds for functional connectivity analyses. We also investigated the correlation among clinical, psychological scores and ALFF. Binary logistic regression analysis was used to examine the unique contribution of the ALFF characteristics of the disease stages. There were widespread differences of ALFF values among the 3 groups, which included left frontal pole (FP_L), right supramarginal gyrus (SG_R), left angular gyrus (AG_L), right cingulate gyrus (CG_R), right intracalcarine cortex (IC_R), right parahippocampal gyrus (PG_R), right lingual gyrus (LG_R), right precuneous cortex (PC_R), left occipital fusiform gyrus (OFG_L). Significant brain regions showing the functional connections (FC) increased in FP_L, SG_R, PC_R and OFG_L between CD-A and HCs. The erythrocyte sedimentation rate had a negative correlation with the ALFF values in PC_R in the patients with CD. The phobic anxiety values had a negative correlation with the ALFF values in OFG_L. The psychoticism values had a negative correlation with ALFF values in the IC_R. And the hostility values had a positive correlation with the ALFF values in CG_R. Significant brain regions showing the FC increased in FP_L, SG_R, CG_R, PG_R, LG_R and OFG_L between CD-R and HCs. In binary logistic regression models, the LG_R (beta = 5.138, p = 0.031), PC_R (beta = 1.876, p = 0.002) and OFG_L (beta = 3.937, p = 0.044) was disease stages predictors. The results indicated the significance of the altered brain activity in the different disease stages of CD. Therefore, these findings present a potential identify neuroimaging-based brain functional biomarker in CD. Additionally, the study provides a better understanding of the pathophysiology of CD.

Effect of cannabinoids in mild-to-moderate cases of Crohn's disease as compared to placebo: a systematic review and meta-analysis of randomised controlled trials.

In view of limited treatment options (those too may fail) for Crohn's disease, cannabinoids have been tried as a therapeutic. However, their efficacy is not unequivocally established. This systematic review and meta-analysis was planned to pool data from randomised controlled trials (RCTs) evaluating effect of cannabinoids in Crohn's disease with an intention to take this uncertainty away. Following literature search in Medline, EMBASE, Scopus and Google Scholar databases, RCTs assessing the effect of cannabinoids on mild-to-moderate Crohn's disease in adults were included. Crohns' disease activity index (CDAI), QoL (Quality of life), number participants achieving full remission and serum CRP at eight weeks of treatment were the outcomes considered for meta-analysis. Quality of studies was assessed using Cochrane's RoB2 tool. Random effect model was applied for meta-analysis. Heterogeneity was assessed by Cochrane 'Q' statistics and I2 test. Sensitivity analysis was performed to identify the major contributor(s) to heterogeneity and assess robustness of the results. Risk of bias for the four included studies varied from 'low' to 'some concern'. Overall effect estimate (SMD-0.92; 95 % CI-1.80,-0.03) indicated a statistically significant effect of cannabinoids as compared to control (p<0.05) on CDAI score. Effect of cannabinoids on rest of the outcome parameters was comparable to that of placebo. Magnitude of heterogeneity for different outcome parameters ranged from 'low' to 'substantial'. Cannabinoids were superior to placebo for favourably affecting the disease severity in terms of CDAI score. However, no statistically significant difference was found between the two for improving QoL, causing full disease-remission and reducing inflammatory markers. The results must be interpreted with caution in view of relatively high heterogeneity among the studies.

IDENTIFICATION OF DISEASE SEVERITY DEFINITIONS FOR ULCERATIVE COLITIS AND CROHN’S DISEASE

Abstract BACKGROUND Evidence suggests that, in patients with ulcerative colitis (UC) or Crohn’s disease (CD), those with moderate disease may achieve better outcomes with vedolizumab than those with severe disease. However, no consensus definition of moderate disease exists for UC or CD, as confirmed by a comprehensive literature review published in 2016.1 We aimed to identify definitions of disease severity for UC and CD in studies published since the approval of vedolizumab. METHODS The first stage of the research comprised a systematic literature review (SLR) that complied with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020 statement and was registered prospectively with PROSPERO (CRD42023427948). Literature searches were conducted in Embase, MEDLINE, and the Cochrane Library databases on May 16, 2023 to identify publications from 2015 onwards. Title and abstract screening, followed by full-text review was undertaken by two blinded reviewers, with discrepancies resolved by a third reviewer. Data on disease severity indices and thresholds used to define mild, moderate, and/or severe disease were extracted from eligible primary publications. RESULTS Data were extracted from 119 eligible publications (Figure 1), of which 109 related to UC only, 7 to CD only, and 3 to both UC and CD. For UC, the most common disease severity index was Truelove and Witts’ criteria (N = 82), followed by Mayo score or one of its derivatives such as partial Mayo score or Mayo sub-score (N = 29), Lichtiger index (N = 9), Montreal classification (N = 4), Rachmilewitz score (N = 3), and Oxford criteria (N = 3). The definitions identified for mild and moderate disease were similar across studies; however, numerical thresholds used to define moderate and severe disease with Mayo score, partial Mayo score, and Lichtiger index overlapped (Figure 2). For CD, the Crohn’s Disease Activity Index (CDAI) (N = 6) was the most commonly used disease severity index, followed by the Harvey–Bradshaw index (HBI) (N = 2). Moderate disease was defined as a CDAI score of 200–450 or 220–450 or a HBI score of 8–16. CONCLUSION For UC, the thresholds used to define moderate disease were similar across studies but overlapped with those used for severe disease in some cases. Too few CD publications were identified to draw robust conclusions, likely due to the exclusion of those describing patients with mild-to-moderate or moderate-to-severe disease without further stratification in the title or abstract. A targeted literature review of publications reporting phase 3 clinical trials of drugs for UC or CD is ongoing; the thresholds of all measurements used to stratify the patient cohorts in these trials will be extracted to further understand the characteristics of patients with moderate disease. 1. Peyrin-Biroulet L, et al. Clin Gastroenterol Hepatol. 2016;14(3):348-354.e17. Figure 1 PRISMA flow diagram. Figure 2 Numerical ranges used to define mild, moderate, and severe disease for UC.

P1074 Impact of body mass index (BMI) on clinical outcomes and drug levels in patients with Crohn’s disease receiving maintenance treatment with subcutaneous infliximab: A post hoc analysis of the LIBERTY-CD study

Abstract Background Obesity and high levels of visceral adipose tissue are associated with lower response rates to intravenous (IV) infliximab (IFX).1 Subcutaneous (SC) IFX is a novel formulation that demonstrated superiority to placebo as maintenance therapy in patients (pts) with moderate-to-severe active Crohn’s disease (CD) in the Phase 3 LIBERTY-CD study. Assessing efficacy of SC IFX by BMI is important as, unlike the IV formulation, pts receive a fixed dose. This post hoc analysis aimed to assess the association between BMI and the efficacy of SC IFX therapy. Methods Data from LIBERTY-CD (NCT03945019) were analysed; 231 pts from the SC IFX arm were divided into four subsets by their BMI: underweight (BMI &amp;lt;18.5 kg/m2, n=27); normal (18.5–24.9 kg/m2, n=133); overweight (25–29.9 kg/m2, n=53); obese (≥30 kg/m2, n=18). Co-primary endpoints at Week (W) 54 (clinical remission [CD Activity Index (CDAI) score &amp;lt;150]; endoscopic response [≥50% decrease in Simple Endoscopic Score for CD (SES-CD) from baseline (BL)]) and W54 change from BL in CDAI score were assessed by BMI subset. Correlations between BMI and CDAI score, SES-CD or median trough level of infliximab (TLI), and the impact of BMI on W54 TLI, were evaluated. Analyses were conducted in a descriptive manner. Results At W54, there were no statistically significant differences in co-primary endpoints or change from BL in CDAI score across BMI subsets, despite descending trends in rates of achieving co-primary endpoints, change in CDAI score and TLI with increasing BMI (Table). From the underweight to obese subsets, clinical remission rates were 63.0%, 66.2%, 58.5% and 44.4% (p=0.125), endoscopic response rates were 55.6%, 36.1%, 41.5% and 27.8% (p=0.207) and median changes from BL in CDAI score were −227.3, −212.9, −196.2 and −204.5 (p=0.358). No significant correlations were observed between BMI and CDAI score (Pearson r=0.0972/p=0.141; Spearman rank r=0.0619/p=0.349) or BMI and SES-CD (Pearson r=0.0446/p=0.507; Spearman rank r=0.0375/p=0.577), while there was a weak, but significant, negative correlation between BMI and TLI (Pearson r=−0.2808/p&amp;lt;0.001; Spearman rank r=−0.2829/p&amp;lt;0.001) (Figure). Additionally, there was a significant difference in median W54 TLI across BMI subsets from underweight to obese (17.0, 13.6, 9.3 and 6.6 µg/mL; p=0.007) (Table). Conclusion While there was a significant difference in TLI across BMI subsets, there was no statistically significant impact of BMI on W54 clinical or endoscopic outcomes. These results could be explained by the relatively high TLI achieved with the SC formulation. Further larger and longer-term studies including pts with morbid obesity and utilising body composition assessment are warranted. 1Yarur A et al. Gastroenterology 2023;165:963–75.

P1013 Placebo rates in Crohn's disease: An individual patient data meta-analysis from multiple randomised controlled trials

Abstract Background Estimating placebo rates and their determinants is essential for designing efficient randomised clinical trials (RCTs) in inflammatory bowel disease. We conducted an individual patient data (IPD) meta-analysis of placebo data from RCTs in Crohn’s disease (CD). Methods MEDLINE, Embase, and CENTRAL were searched from 01/2010 to 01/2020 for contemporary phase 2 and 3 placebo-controlled RCTs of biologics in moderate-to-severe CD. De-identified IPD from eligible trials that were available through the Vivli and Yale University Open Data Access data-sharing platforms were obtained. Primary outcomes were placebo clinical response and remission. Pooled placebo rates and 95% CIs were estimated using a 2-stage meta-analytical approach. Significant patient-level factors (P&amp;lt;0.05) associated with placebo rates were identified using regression analyses. Results Placebo IPD were available from 8 induction (n=1147) and 4 maintenance trials (n=524). Pooled placebo clinical response and remission rates varied based on outcome definition and prior biologic exposure (Figure). In induction trials, overall placebo response and remission rates were 27% (95% CI 23-32%) and 10% (95% CI 8-14%), respectively. Among bio-exposed patients, placebo response and remission rates were 27% (95% CI 16-40%) and 9% (95% CI 6-15%), respectively, compared with 29% (95% CI 24-34%) and 11% (95% CI 8-15%) for bio-naïve patients. Overall placebo response and remission rates in maintenance trials were 32% (95% CI 23%-42%) and 22% (95% CI 14-33%), respectively. Corresponding placebo response and remission rates for bio-exposed patients were 21% (95% CI 8-46%) and 17% (95% CI 11-25%), and 36% (95% CI 28-44%) and 24% (95% CI 15-36%) for bio-naïve patients. Placebo rates were lowest when response was defined as a ≥100-point decrease from baseline in the Crohn's Disease Activity Index (CDAI) score, and when remission was defined using stool frequency (≤1.5) and abdominal pain (≤1) subscores. Higher baseline C-reactive protein concentrations were associated with lower odds of placebo response and remission, while higher baseline albumin levels increased the odds of these outcomes (Table). Increased baseline CDAI and 2-item patient-reported outcome (PRO2) scores predicted higher odds of placebo response in induction trials, yet this reduced the odds of remission in induction trials and of both outcomes in maintenance trials. Prior failure to tumour necrosis factor (TNF) antagonist therapy was more predictive than prior TNF antagonist/biologic exposure for reducing the odds of placebo response and remission. Conclusion Placebo rates and the patient-level factors influencing them vary according to study design, clinical outcome measure and outcome definitions.

P388 Eliakim score performance among patients with active Crohn’s disease

Abstract Background Pan-enteric capsule endoscopy [PEC] (PillCam Crohn’s, Medtronic, USA) is a useful tool for disease assessment and monitoring in Crohn’s disease (CD). We have previously demonstrated the reliability and accuracy of Eliakim score (ES) in the assessment of CD-activity among patients with quiescent disease. We aimed to examine the performance of ES among patients who experienced clinical flare, as well as its responsiveness and sensitivity to change during follow-up (≤52weeks). Methods Patients with CD who have been started on biologics were included. They were prospectively followed with clinical visits, biomarkers and PEC at baseline, and after 14 and 52 weeks. At each time-point Crohn’s disease activity index (CDAI), C-reactive protein (CRP) and fecal-calprotectin (FC) levels were collected, and Lewis score (LS) and ES were calculated (independently reviewed by two experienced readers). Inter-class classification (ICC) was used to asses for agreement between readers. Baseline correlations were obtained using the Spearman's correlation. Repeated-measures correlation (RMC) was calculated using the rmcorr package in R (version 3.3-1). William's test was used to assess difference between correlations. Results Seventy-four patients were included (median age of 31.0 [22.5-46.5] years, male–50%). 142 PEC procedures were performed (Baseline– 62, week 14– 58, week 52– 22). Inter-rater agreement between both readers was high for both the LS and ES (ICC of 0.872 [p&amp;lt;0.001] and 0.925 [&amp;lt;0.001], respectively). At baseline, the correlations between FC and ES (r=0.509 [p&amp;lt;0.001]) and FC and LS (r=0.467 [p&amp;lt;0.001]) were comparable (p=0.68). RMC between biomarkers and ES were higher than between biomarkers and LS (CRP: r=0.376 [p=0.005] vs. r=0.204 [p=0.138], FC: r=0.549 [p&amp;lt;0.001] vs. r=0.412 [p=0.003], for ES and LS, [p=0.034/0.021], respectively), while no difference was observed (p=0.77) with regard to CDAI score (r=0.381 [p=0.007] vs. r=0.346 [p=0.015]). Performing sub-group analysis restricted to procedures which were confined to the small bowel (n=88), RMC was numerically higher (p=0.12) between FC and ES (r=0.590 [p=0.001]) than between FC and LS (r=0.470 [p=0.010]). Conclusion ES is a reliable and accurate scoring system in assessing mucosal inflammation in patients with active CD, and might have a higher sensitivity to clinical/inflammatory biomarker changes over time compared to LS.

Azathioprine plus exclusive enteral nutrition versus azathioprine monotherapy for the prevention of postoperative recurrence in patients with Crohn's disease: an open-label, single-centre, randomised controlled trial.

Azathioprine (AZA) effectively prevents postoperative endoscopic recurrence (ER) in Crohn's disease (CD). However, the efficacy of AZA emerge needs 3 months. Exclusive enteral nutrition (EEN) can maintain remission for CD. The trial investigates whether AZA plus postoperative 3-month EEN is superior to AZA alone in preventing ER of CD. Totally, 84 high-risk CD patients undergoing intestinal resection received AZA alone or AZA plus a 3-month EEN (AZA+EEN) postoperatively. The primary endpoint was the rate of ER at month 12. Secondary endpoint included the rate of ER at month 3, clinical recurrence (CR), CD activity index (CDAI) scores, fecal calprotectin (FC) and CRP. Quality of life were assessed using Short Form-36 (SF-36) and the Inflammatory Bowel Disease Questionnaire (IBDQ). The patients in the AZA+EEN group exhibited significantly lower rates of ER compared to the AZA group at both months 12 (33.3% [13/39] vs 63.2% [24/38], P=0.009) and months 3 (8.6% [3/35] vs 28.1% [9/32], P=0.037) post-surgery. The rates of CR between the two groups at month-3 and month-12 were similar. The CDAI scores, FC, albumin level and CRP were all comparable between the 2 groups. The quality of life was significantly higher in the AZA group than that of the AZA+EEN group at month 3 but became comparable from month 5 to 12 postoperatively. 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.

Delayed Ustekinumab and Adalimumab Responders Have Similar Outcomes as Early Responders in Biologic-Naïve Crohn's Disease.

Differences in one-year outcomes among early and delayed responders have been demonstrated with some therapies in ulcerative colitis. However, it is unclear whether similar differences exist in patients with Crohn's disease (CD) treated with biologic therapies. This was a post-hoc analysis of patient-level data from the SEAVUE clinical trial program. Ustekinumab and adalimumab-treated patients with clinical response at week 8, defined as a reduction in CDAI score of at least 100 points from baseline or Crohn's Disease Activity Index (CDAI) score < 150, were deemed early responders and their outcomes were compared with delayed responders (week 8 non-responders who subsequently responded at week 16) and non-responders (no response at week 8 or 16). The primary outcome assessed was clinical remission (CR) at week 56, defined as CDAI < 150. There were 373 participants (187 treated with ustekinumab and 186 treated with adalimumab) included in this analysis. The overall rate of delayed clinical response was low in SEAVUE (13.1%). No differences were observed for week 56 CR among early vs. delayed responders to ustekinumab or adalimumab, nor were there significant differences for secondary outcomes assessed. Delayed responders to ustekinumab and adalimumab had a significant decline in CRP by week 8 as compared to non-responders. Among moderate-severe CD patients, early and delayed responders to adalimumab and ustekinumab have similar one-year clinical outcomes. Biomarker decline can be observed through the initial 8 weeks of therapy in patients who will eventually be delayed responders which may help differentiate from non-responders.

Efficacy of infliximab after loss of response of/intolerance to adalimumab in pediatric Crohn's disease: A retrospective multicenter cohort study of the "GETAID pédiatrique".

Infliximab (IFX) and adalimumab (ADA) are recommended for induction and maintenance of remission in pediatric Crohn's disease (CD). ADA is now often used in first line due to its efficacy and tolerability, but a loss of response (LOR) can occur over time. The aim was to assess the efficacy of IFX as second line therapy after LOR or intolerance to ADA in pediatric CD patients at 1 year. We conducted a retrospective and multicenter study in France among the "GETAID pédiatrique" centers between April 2019 and April 2022. CD patients under 18 years old and treated with IFX after ADA failure or intolerance were included. We collected anthropometric, clinical, and biological data at baseline (start of IFX), at 6 and 12 months. Clinical remission was defined by a Weighted Pediatric CD Activity Index (wPCDAI) score less than 12.5 points. Of the 32 patients included in our study, 27 (84.4%) were still on IFX at 12 months of the switch. Among them, 13 had discontinued ADA because of a LOR, 12 for insufficient response and 2 due to primary nonresponse. At M12, 22 patients were in corticosteroid free clinical remission (68.7%). Under IFX, the wPCDAI decreased over time (47.5 ± 24.1, 16.6 ± 21.2 and 9.7 ± 19.0 at M0, M6 and M12 respectively). The only factor associated with clinical remission at 12 months was absence of perianal disease at the end of the IFX induction. IFX is effective in maintaining remission at 1 year in pediatric CD patients experiencing a LOR or intolerance with ADA, and IFX could be an interesting therapeutic choice instead of other biologics in this situation.

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.

Correlation between Treatment Outcomes and Serum Vitamin D Levels As Well As Infliximab Trough Concentration among Chinese Patients with Crohn's Disease.

The relationship between vitamin D (vit-D) levels and the effectiveness of infliximab (IFX) in patients with Crohn's disease (CD) remains controversial. To evaluate the interaction between vit-D levels and the response to IFX therapy in patients with CD. This was a retrospective cohort study. Serum vit-D and IFX trough concentrations (TC) were measured in 84 patients, and statistical analyses were performed. The total vit-D deficiency rate at enrollment, at week 14 and week 38, was 64.3%, 41.67%, and 37.5%, respectively (P < 0.001). CD activity index (CDAI) (120, range, 93-142.75) and simplified endoscopic activity score for CD (SES-CD) (2, range, 0-4) at week 14 were lower than that of enrollment (CDAI, 136.5, range, 101.25-196; SES-CD 13, range, 5-23) (P < 0.001). The biochemical remission (BR), clinical remission (CR), endoscopic remission (ER), and response (ERe) rates of week 38 were 76.1%, 88.5%, 22.4%, and 67.2%, respectively. vit-D levels at enrollment were positively correlated with CDAI at week 38 (P = 0.024). IFX serum TC was related to BR (P = 0.036), CR (P = 0.032) at week 14, and ERe (P = 0.009) at week 38. Among Chinese patients with CD, vit-D levels prior to IFX therapy are related to CDAI scores, and IFX serum TC is associated with BR, CR, and ERe.

Short-Term Clinical Response and Changes in the Fecal Microbiota and Metabolite Levels in Patients with Crohn's Disease After Stem Cell Infusions.

Recent studies have shown a close relationship between the gut microbiota and Crohn's disease (CD). This study aimed to determine whether mesenchymal stem cell (MSC) treatment alters the gut microbiota and fecal metabolite pathways and to establish the relationship between the gut microbiota and fecal metabolites. Patients with refractory CD were enrolled and received 8 intravenous infusions of MSCs at a dose of 1.0 × 106 cells/kg. The MSC efficacy and safety were evaluated. Fecal samples were collected, and their microbiomes were analyzed by 16S rDNA sequencing. The fecal metabolites at baseline and after 4 and 8 MSC infusions were identified by liquid chromatography-mass spectrometry (LC--MS). A bioinformatics analysis was conducted using the sequencing data. No serious adverse effects were observed. The clinical symptoms and signs of patients with CD were substantially relieved after 8 MSC infusions, as revealed by changes in weight, the CD activity index (CDAI) score, C-reactive protein (CRP) level, and erythrocyte sedimentation rate (ESR). Endoscopic improvement was observed in 2 patients. A comparison of the gut microbiome after 8 MSC treatments with that at baseline showed that the genus Cetobacterium was significantly enriched. Linoleic acid was depleted after 8 MSC treatments. A possible link between the altered Cetobacterium abundance and linoleic acid metabolite levels was observed in patients with CD who received MSCs. This study enabled an understanding of both the gut microbiota response and bacterial metabolites to obtain more information about host-gut microbiota metabolic interactions in the short-term response to MSC treatment.

Evolution of Symptoms After Ustekinumab Induction Therapy in Patients With Crohn’s Disease

Ustekinumab is an effective treatment of Crohn's disease (CD). Of interest to patients is knowing how soon symptoms may improve. We analyzed ustekinumab response dynamics from the ustekinumab CD trials. Patients with CD received intravenous induction with ustekinumab ∼6 mg/kg (n= 458) or placebo (n= 457). Week 8 ustekinumab responders received subcutaneous ustekinumab 90 mg as the first maintenance dose or as an extended induction dose for nonresponders. Patient-reported symptom changes (stool frequency, abdominal pain, general well-being) within the first 14 days and clinical outcomes through week 44 were evaluated using the CD Activity Index. After ustekinumab infusion, stool frequency improvement was significantly (P < .05) greater than placebo on day 1 and for all patient-reported symptoms by day 10. In patients with no history of biologic failure or intolerance, cumulative clinical remission rates increased from 23.0% at week 3 to 55.5% at week 16 after the subcutaneous dose at week 8. Corresponding cumulative rates for patients with a history of biologic failure or intolerance increased from 12.9% to 24.1%. Neither change from baseline in CD Activity Index score nor week 8 ustekinumab pharmacokinetics were associated with week 16 response. Among all patients who received subcutaneous ustekinumab 90 mg q8w, up to 66.7% were in clinical response at week44. Ustekinumab induction provided symptom relief by day 1 post-infusion. Following ustekinumab infusion and a subcutaneous 90 mg injection, clinical outcomes continued to increase through week 16 and up to week 44. Regardless of week 8 clinical status or ustekinumab pharmacokinetics, patients should receive additional treatment at week8. gov numbers, NCT01369329, NCT01369342, and NCT01369355.

Comparison of Clinical Outcomes in Pediatric Patients with Ileocolonic Crohn Disease Treated with Infliximab Versus Adalimumab.

Infliximab is considered superior to adalimumab in patients with ulcerative colitis, especially in severe cases. Whether this is true for Crohn disease (CD) patients with colonic involvement is unclear. Our aim was to compare the clinical effectiveness of infliximab versus adalimumab in pediatric ileocolonic (L3) CD. This retrospective study included patients <18 years with ileocolonic CD treated with infliximab or adalimumab between 2014 and 2021. Primary outcome was steroid-free clinical remission by week 52. Secondary outcomes were treatment modifications, drug discontinuation, inflammatory bowel disease (IBD)-associated hospitalizations, and surgery during the first year of treatment. We identified 74 patients treated with adalimumab and 41 with infliximab, with comparable demographic features. Concomitant immunomodulator therapy at biologic initiation was significantly lower in the adalimumab group (28% vs 85%, P < 0.001). Rates of drug intensification were higher in the infliximab group at end of induction (EOI) and at 52 weeks (55% vs 32% and 88% vs 46%, P < 0.001). Given significant differences between initial median Pediatric Crohn Disease Activity Index scores (20.0 [interquartile range, IQR 15.0-27.5] vs 11.0 [IQR 7.5-20.0] for infliximab and adalimumab groups, respectively, P < 0.001), propensity score matching was performed. Following matching, the rate of patients in steroid-free clinical remission by EOI was significantly higher in the adalimumab group (93.8% vs 46.9%, P < 0.001), but comparable by 1 year. Moreover, inflammatory markers and fecal calprotectin values were also similar at these time points. Rates of drug discontinuation, IBD-associated admissions, and surgery were similar between groups. In a retrospective study of patients with ileocolonic CD, adalimumab and infliximab had comparable outcomes by 52 weeks.

Dietetic advocacy for long-term use of exclusive enteral nutrition resulted in high-risk surgical avoidance for complicated fibrotic Crohn's disease – A case report

Surgery is often the only therapeutic option for the management of fibrotic Crohn's disease (FCD). Exclusive Enteral Nutrition (EEN), a nutritionally complete liquid formula, is an effective, safe, short-term treatment for Crohn's Disease. No cases were found internationally of adults with FCD on long-term EEN. We report on clinical outcomes and self-reported quality of life (QoL) after longer-term EEN provision in a patient with complex FCD. "Billie", a 54-year-old female, was admitted with ileal FCD diagnosed in 1985. Previous treatments were unsuccessful, including multiple bowel resections. Billie was chronically bedbound with pain and depression. CDAI (Crohn's disease activity index) score was 640 (<150) with ∼3-20 liquid stools/day, and recurrent partial bowel obstructions. Radiological findings were so severe surgeons reluctantly considered surgery but "one more resection will result in short bowel syndrome". Billie trialled EEN given her QoL was "non-existent". Unable to tolerate the taste, EEN was administered via nasogastric tube. After two months, EEN was administered ongoing via percutaneous endoscopic gastrostomy given patient preference and dietetic advocacy. After eight weeks on EEN, Billie's pain predominantly resolved, with bowel motions of ∼1-2/day, and nil bowel obstructions. Twelve months after EEN commencement, Billie's CDAI was 52, with 'no indication for surgical intervention' and was self-reporting that "life is good". After 18 months, Billie remains asymptomatic, and in clinical remission. This unique case is a wonderful example of dietetic advocacy and showcases the positive impact long-term EEN may have on surgical avoidance, clinical outcomes and self-reported QoL.

Application of multi-spectral CT imaging in Crohn's disease: a systematic review.

No quantitative computed tomography (CT) biomarker is actually sufficiently accurate to assess Crohn's disease (CD) lesion activity, with adequate precision to guide clinical decisions. To assess the available literature on the use of iodine concentration (IC), from multi-spectral CT acquisition, as a quantitative parameter able to distinguish healthy from affected bowel and assess CD bowel activity and heterogeneity of activity along the involved segments. A literature search was conducted to identify original research studies published up to February 2022. The inclusion criteria were original research papers (>10 human participants), English language publications, focus on dual-energy CT (DECT) of CD with iodine quantification (IQ) as an outcome measure. The exclusion criteria were animal-only studies, languages other than English, review articles, case reports, correspondence, and study populations <10 patients. Nine studies were included in this review; all of which showed a strong correlation between IC measurements and CD activity markers, such as CD activity index (CDAI), endoscopy findings and simple endoscopic score for Crohn's disease (SES-CD), and routine CT enterography (CTE) signs and histopathologic score. Statistically significant differences in IC were reported between affected bowel segments and healthy ones (higher P value was P < 0.001), normal segments and those with active inflammation (P < 0.0001) as well as between patients with active disease and those in remission (P < 0.001). The mean normalized IC at DECTE could be a reliable tool in assisting radiologists in the diagnosis, classification and grading of CD activity.

P795 Impact of anxiety and depression on inflammatory bowel disease patients

Abstract Background IBD patients may complain of stress and emotional disorders (anxiety and depression), impacting their quality of life. Anxiety and depression has been reported to be more common in IBD than in the general population. The aim of study was to estimate the prevalence and severity of anxiety and depression among IBD patients and to identify their impact on IBD related features. Methods Consecutive IBD patients presented from January 2021 to February 2022 at our outpatient IBD clinic, were included in this study. Demographic data, disease activity scores, endoscopic scores, disease duration, localization, hospitalization, laboratory data, were collected for each patient. Based on Hospital Anxiety and Depression Scale (HADS) patients were divided in 2 groups: those with symptoms of anxiety and depression and those without. Total Mayo Score (TMS) was used to evaluate UC disease activity while Crohn’s disease activity index (CDAI) for CD patients. CD was considered active when CDAI score &amp;gt; 150; UC was considered active when TMS &amp;gt;2. Results A total of 48 IBD patients (30F: 18M), mean age 41.2±15.6 years were included. 43 (89.6%) patients were diagnosed with UC, and 5 (10.4%) with CD. Mean disease duration was 5.1±4.6 years.37.2% of UC patients were in remission, 20.9% had mild disease, 32.6% moderate, and 9.3% severe disease.40% of CD patients were in remission while 60% had active disease.27.1% of patients were anti TNF-α naïve,43.8% on cortisone, 45.8% were on adalimumab and 27.1% on infliximab treatment. Anxiety and depression symptoms were present in 45.8% and 27.1% of patients, respectively.These symptoms were found combinedin 27%of the patients. No statistically significant difference was observed on the presence and scores of anxiety and depression between UC and CD patients.Presence of anxiety was significantly associated with female gender (p=0.052), UC disease extent (p=0.078), cortisone use (p=0.077), and previous hospitalizations (p=0.01.8). A significant correlation was observed between anxiety score and CDAI score (p=0.006, r=0.971); UC Mayo score (p=0.013, r=0.376) and CRP level (p=0.053, r=0.281). Presence of depression was associated with female gender (p=0.052) and UC disease activity (p=0.097).Depression score was only associated with UC Mayo score (p=0.062). On multiple linear regression,only TMS was correlated to anxiety and depression score (p=0.022, p=0.048, respectively). Conclusion Anxiety and depression are disorders frequently encountered in IBD patients, especially among females. When anxiety and/or depression were present, IBD patients demonstrated a more active disease. Addressing these psychological problems would be helpful achieving a better treatment and quality of life.

P814 Clinical trial design in Crohn’s disease: interpreting future endpoints based on post hoc analyses of the vedolizumab phase 3 trials GEMINI 2 and VISIBLE 2

Abstract Background Crohn’s disease (CD) is a chronic, relapsing–remitting disease characterized by inflammation of the gastrointestinal tract. Historically, the Crohn’s Disease Activity Index (CDAI) has been used to assess outcomes in clinical trials involving patients with CD. However, in contrast to the alignment of regulatory standards for trials in ulcerative colitis, the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) differ regarding the most appropriate endpoint definitions for trials in CD. We examined how clinical remission endpoints in CD trials have evolved and conducted post hoc analyses of two vedolizumab trials, GEMINI 2 and VISIBLE 2, to understand how endpoint definitions influence clinical trial outcome measures of treatment efficacy. Methods Endpoint definitions of clinical remission in completed and ongoing phase 3 trials of advanced therapies in CD were extracted from published literature and ClinicalTrials.gov. Post hoc analyses of data from GEMINI 2 and VISIBLE 2 were conducted by measuring the difference (%Δ) between the proportions of patients achieving clinical remission with vedolizumab versus placebo at week 52 as assessed by six endpoint definitions (A: stool frequency score [SFS] ≤ 2.8 and not worse than baseline score; B: SFS ≤ 3 and not worse than baseline score; C: abdominal pain score (APS) ≤ 1 and not worse than baseline score; D: SFS ≤ 2.8 and APS ≤ 1; E: SFS ≤ 3 and APS ≤ 1; F: CDAI ≤ 150) (Figure 1). Results Most phase 3 trials of advanced therapies in CD included a clinical remission endpoint that was defined by CDAI score: typically, CDAI &amp;lt; 150 or ≤ 150. However, several recent trials have also included a primary or secondary clinical remission endpoint defined using components of the CDAI score such as SFS and APS (Table 1). Post hoc analyses of GEMINI 2 and VISIBLE 2 revealed minimal change in %Δ for each of the new endpoint definitions tested compared with the primary analysis for each trial (Figure 1). Conclusion Objective measures, including patient-reported outcomes and components of the CDAI score such as SFS and APS, have been used to define clinical remission in recent CD trials. Despite differences in regulatory guidance for defining clinical remission, our post hoc analyses of GEMINI 2 and VISIBLE 2 reveal that the efficacy of vedolizumab, measured using a variety of endpoint definitions from recent CD trials, was similar to that previously reported using CDAI ≤ 150.

P354 Application of the clinical decision support tool to predict treatment outcomes in Crohn’s Disease patients treated with vedolizumab subcutaneous formulation

Abstract Background There is a need to identify Crohn’s Disease (CD) patients who will obtain most clinical benefit from treatment with vedolizumab (VDZ), an anti-α4β7 integrin inhibitor for the treatment of ulcerative colitis and Crohn’s Disease (CD). Previously, a clinical decision support tool (CDST) has been developed and validated to guide treatment decisions in CD patients (pts) treated with intravenous VDZ.1 In this study, we aimed to test the ability of the CDST to predict clinical outcomes in CD pts receiving maintenance treatment with the subcutaneous (SC) formulation of VDZ. Methods Pts with moderate to severe CD receiving maintenance treatment with VDZ SC in the VISIBLE 2 study were categorized using the CDST into low (≤13 points), intermediate (&amp;gt;13 and ≤19 points) and high response probability groups (&amp;gt;19 points) based on the scoring system detailed in Table 1. Clinical outcomes evaluated included clinical remission: CD Activity Index (CDAI) ≤ 150 at Week 6, 14, 30, and 52, and enhanced clinical response: decrease from baseline in CDAI score ≥ 100 points at Week 52. All outcomes were evaluated as observed. Results There were 275 pts who completed induction treatment with VDZ 300 mg IV and continued into maintenance treatment with VDZ 108 mg SC until Week 52. Using the CDST, at baseline, 14 pts (5.1%) had a low, 98 (35.6%) had an intermediate, and 163 (59.3%) had a high probability of treatment response with VDZ. Due to the low number of pts in the low probability group, the low and intermediate groups were combined. At Week 6, 99 pts (61.1%) in the high probability group had achieved clinical remission vs 38 pts (33.9%) in the low/intermediate probability group (Fig 1). Rates of clinical remission in the high probability group continued to exceed those of the low/intermediate group through until Week 52 when 89 pts (86.4%) in the high probability group were in clinical remission vs 43 pts (79.6%) in the low/intermediate probability group (Fig 1). In the high probability group, 97 pts (94.2%) had an enhanced clinical response at Week 52 compared with 46 pts (85.2%) in the low/intermediate group. Conclusion Compared with the low/intermediate group, pts categorized by the CDST as having the highest probability of treatment response to VDZ achieved clinical remission sooner, as early as Week 6. These findings provide further confirmation of the CDST as a means of identifying pts with CD likely to benefit from treatment with VDZ in either IV or SC formulations.