Inflammatory Bowel Disease Clinical

Defining Endpoints and Biomarkers in Inflammatory Bowel Disease: Moving the Needle Through Clinical Trial Design

Background Acute Severe Ulcerative Colitis (ASUC) is a medical emergency, with limited therapeutic options available for medical management. Tofacitinib and Upadacitinib are novel Janus Kinase inhibitors (JAKi), with proven efficacy for ulcerative colitis (UC). This study aimed to examine the outcomes of patients treated with JAKi for ASUC in a real-world population. Methods A retrospective multi-centre study was conducted including patients (≥18 years) with ASUC commenced on Tofacitinib or Upadacitinib from April 2021 to April 2024. ASUC was defined according to Truelove and Witt’s criteria. Demographic and clinical data were recorded at admission, JAK induction, discharge, week 8, week 16 and 1 year post-induction. The primary outcome was need for colectomy. We further evaluated adverse events and drug-specific response. Results A total of 124 patients were included from 11 Australian Inflammatory Bowel Disease (IBD) centers. Tofacitinib was used in 49%, while Upadacitnib was used in the remainder. 58% of patients received JAKi as first line salvage therapy, while the remainder received JAKi sequentially after failure of first line infliximab therapy. The rate of colectomy during admission was 17% and 40% by 1 year. There was no significant difference between rate of colectomy during index admission (p=0.38), or 1 year post induction (p=0.24) between Tofacitinib and Upadacitinib. There was a significantly increased risk of inpatient colectomy for those receiving sequential salvage compared to initial JAKi salvage (p=<0.01). However, there was no significant difference in the rate of colectomy in either cohort up to 1 year post induction (p=0.19). Clinical response was observed in 45% of patients by day 3 of induction and 65% by day 7. Clinical remission rates were 40% by week 8 and 65% by week 16. Biochemical remission was achieved in 51% by week 16. Mucosal healing was achieved in 47% of patients who underwent repeat endoscopy within 16 weeks of induction. Adverse events occurred in 16% of patients, all of which were minor and did not require hospitalisation. The most common events noted were acne (7%) and nasopharyngitis (6%). Conclusion Jaki demonstrate effectiveness and safety for the management of ASUC. There was no significant difference in the inpatient colectomy rate between Tofacitinib and Upadacitinib. There was a significantly higher rate of inpatient colectomy for patients requiring sequential salvage therapy, but no significance when patients were followed up to 1 year. There is variability in prescribing practice between dosage of Tofacitinib and Upadacitinib, duration and dosage of corticosteroid wean, and the use of prophylactic PJP and VTE prophylaxis.

Mucosal healing (MH) is associated with improved clinical outcomes in patients with Crohn's disease (CD) and ulcerative colitis (UC). MH as a target for treatment has been suggested, although there is little pediatric data. The goal of this study was to evaluate MH in clinical practice in pediatric patients with inflammatory bowel disease in clinical remission. A retrospective review of electronic health record data was performed on all patients with CD or UC who underwent at least 2 colonoscopies from 2010 through 2016. Only patients in clinical remission undergoing a scope for MH were included in our study. The incidence of MH and histologic healing (HH) was analyzed, along with cumulative rates of MH in each group. MH was defined by both physician assessment of MH and an endoscopic score of zero for CD and UC. A total of 76 patients with CD and 28 patients with UC underwent at least one MH scope while in clinical remission. Of the 76 patients with CD, 51 patients (67%) demonstrated MH by physician assessment, 34 patients (45%) demonstrated MH by a simple endoscopic score for CD of zero, and 35 patients (46%) demonstrated HH. Of the 28 patients with UC, 20 patients (71%) demonstrated MH by physician assessment, 10 patients (36%) demonstrated MH by a Mayo score of zero, and 10 patients (36%) demonstrated HH. Nineteen patients underwent a second MH scope and 11 (58%) demonstrated MH by physician assessment, 7 patients (37%) demonstrated MH by simple endoscopic score for CD or Mayo scores of zero, and 5 patients (26%) demonstrated HH. Of those patients with active disease, 21 of 25 patients with CD underwent escalation of therapy, whereas 8 of 8 patients with UC underwent escalation of therapy. Cumulative rates of MH when defined by physician assessment were 79% (60 of 76 patients) in CD and 79% (22 of 28 patients) in UC. MH is feasible in pediatric CD and UC, and rates of cumulative MH in pediatric patients are similar to previously published adult data. In children with inflammatory bowel disease in clinical remission, approximately one-third demonstrate active disease at endoscopy.

Background Transabdominal bowel ultrasound (TABUS) is an ideal tool to assess the bowel wall thickness (BWT) of children with Crohn’s disease (CD) due to its minimal invasiveness. Recently the Simple Ultrasound Activity Score for CD (SUS-CD) was developed and validated in adults using the Simple Endoscopic Score for CD (SES-CD). Our aim was to determine how the SUS-CD performed in children at diagnosis in comparison to endoscopy. Methods Pediatric patients (0–18 years old) with suspected inflammatory bowel disease (IBD) were prospectively enrolled through the Edmonton Pediatric IBD Clinic in Alberta, Canada. Patients underwent a baseline TABUS to visualize the intestine (excluding rectum, which is difficult to see with TABUS), blood work and endoscopy. The weighted pediatric CD activity index (wPCDAI) assessed disease activity, and SES-CD assessed endoscopic disease. Modified SUS-CD (excluding rectal sub score) was calculated using BWT scores (0=<3mm, 1=3–4.9mm, 2=5–7.9mm, 3=>8mm) and colour doppler scores (0=no or 1 vessel, 1=2–5 vessels, 2=>5 vessels per cm2) for each segment (terminal ileum, right colon, transverse colon, left colon) and compared to SES-CD. Modified SUS-CD was correlated to wPCDAI score, C-reactive protein (CRP) and fecal calprotectin (FCP). Using SPSS, anova and Chi square were used to assess for an association between TABUS parameters and wPCDAI. Spearman’s rank (rho) and Pearson’s correlation (r) were used to assess for a correlation between modified SUS-CD with SES-CD, wPCDAI, CRP and FCP. Results 40 patients recruited, 35 had CD (mean age 12.6(2.85)) and 5 were normal and scanned for suspected IBD (mean age 12.2(3.75)). Median wPCDAI and SES-CD scores for CD patients were 61(IQR 35.6–77.5) and 15(IQR 7.5–21) respectively. Fat proliferation was associated with severe CD based on wPCDAI (p<0.05). The modified SUS-CD score correlated well with the modified SES-CD score (rho=0.79,r=0.76,p<0.001,R2 linear=0.465). When the BWT threshold was lowered by 0.5mm for each BWT category, correlation improved (rho=0.80,r=0.82,p<0.001,R2 Linear=0.541). Using a similar lower threshold for BWT, a receiver operating characteristic curve analysis revealed an area under the curve of 0.87 and 0.90 for detecting mild endoscopic activity and moderate endoscopic activity, respectively. There was a significant correlation between SUS-CD and wPCDAI score (r=0.56,p<0.01), CRP (r=0.55,p<0.01) and FCP (r=0.56,p<0.01). Conclusion Fat proliferation was associated with more severe CD. The modified SUS-CD correlated well with modified SES-CD score, wPCDAI, CRP and FCP. Correlation improved when BWT threshold in each category was dropped by 0.5mm. These data support the use of TABUS as an effective adjunct to the assessment of pediatric CD.

Background Infliximab remains a cornerstone in managing inflammatory bowel disease (IBD) patients. The recent introduction of subcutaneous (SC) infliximab offers a potential alternative to intravenous (IV) administration. However, the optimal timing of the switch is still unclear. We aimed to investigate the difference in mucosal healing rates and therapy persistence in patients switched to SC infliximab at week 6 as opposed to those maintained on IV therapy. Methods All patients starting infliximab treatment from January 2023 to April 2024 were included. Patients with primary non-response to IV infliximab and those starting treatment for prophylaxis of postoperative disease recurrence were excluded from the analysis. At week 6, patients were stratified into two groups: SC (n = 48) and IV (n = 77). The primary outcomes included mucosal healing and persistence on therapy. Mucosal healing was defined as a Mayo endoscopic score of 0 or 1 for ulcerative colitis patients, a simple endoscopic score for Crohn’s disease (SES-CD) ≤ 3, or a modified Rutgeerts score ≤ i2a. Drug concentrations were measured, and odds ratios were calculated for comparative efficacy. Statistical analyses were performed using R version 4.3.1 Results A total of 125 IBD patients starting infliximab for active disease with were included (71 with Crohn’s disease, 54 with ulcerative colitis). No significant differences in gender, age at diagnosis, age at infliximab initiation and concomitant immunomodulator use were found between the IV and SC treatment groups. Patients in the IV group had a significantly shorter disease duration compared to SC group (median 2, interquartile range (IQR) [1-11] years vs median 7, IQR [3-14] years; p=0.009). In 86% of the cohort, infliximab was the first-line biologic. No significant difference in mucosal healing rates was found between the IV and SC treatment groups (p = 0.06). Therapy discontinuation rates were similar between groups: 24% (18/77) for IV versus 22% (11/48) for SC. Median infliximab concentrations measured at week 14 were significantly higher in the SC group (median 12.0, IQR [10,9-12] µg/mL) compared to the IV group (median 6.2, IQR [4,1-9,3] µg/mL; p = 0.004). No therapy optimization was observed in the SC group, whereas 32% (n = 23) of patients in the IV group required dose optimization. Conclusion Switching to subcutaneous infliximab at week 6 is equally effective, with similar treatment persistence compared to IV maintenance therapy. Furthermore, SC application is preferred by patients and is cost-effective, with significant proportion of patients on iv maintenance therapy requiring treatment optimization during follow-up. These findings support SC infliximab as a viable alternative in IBD management.

Fecal calprotectin is a marker of inflammation in inflammatory bowel disease (IBD). Since mucosal healing has become a goal of treatment in IBD we examined how reliably calprotectin levels reflect mucosal disease activity. In all, 126 IBD patients and 32 irritable bowel syndrome (IBS) patients needing colonoscopy delivered a sample of feces prior to the start of bowel cleansing. Besides collection of symptom scores and blood tests, experienced endoscopists recorded the Simple Endoscopic Score for Crohn's Disease (SES-CD) and the Crohn's Disease Endoscopic Index of Severity (CDEIS) in Crohn's disease (CD) patients and the Mayo endoscopic score in ulcerative colitis (UC) patients. Stool samples were shipped for central calprotectin PhiCal Assay (enzyme-linked immunosorbent assay [ELISA]). Correlation analysis was done with Pearson statistics. The median (interquartile range [IQR]) fecal calprotectin levels were 175 (44-938) μg/g in CD, 465 (61-1128) μg/g in UC, and 54 (16-139) μg/g in IBS. Correlations were significant with endoscopic disease scores in both CD and in UC. Using ROC statistics, a cutoff value of 250 μg/g indicated the presence of large ulcers with a sensitivity of 60.4% and a specificity of 79.5% (positive predictive value [PPV] 78.4%, negative predictive value [NPV] 62.0%) in CD. Levels ≤ 250 μg/g predicted endoscopic remission (CDEIS ≤ 3) with 94.1% sensitivity and 62.2% specificity (PPV 48.5%, NPV 96.6%). In UC, a fecal calprotectin >250 μg/g gave a sensitivity of 71.0% and a specificity of 100.0% (PPV 100.0%, NPV 47.1%) for active mucosal disease activity (Mayo >0). Calprotectin levels significantly correlated with symptom scores in UC (r = 0.561, P < 0.001), but not in CD. Fecal calprotectin levels correlate significantly with endoscopic disease activity in IBD. The test appears useful in clinical practice for assessment of endoscopic activity and remission.

Data on acute severe ulcerative colitis (ASUC) management in patients with prior anti-TNF exposure are limited. We compared medical management, colectomy risk and mortality between anti-TNF-exposed and bio-naive patients. This retrospective, multicenter GETECCU study included two ASUC cohorts (2010-2020): anti-TNF-exposed (cohort 1) and bio-naive (cohort 2). Patients previously treated with other advanced therapies were excluded. Steroid response was defined by reduced bowel movements and C-reactive protein. Rescue therapies were used for steroid failure. Maintenance therapy was initiated post-ASUC. Clinical effectiveness was assessed using the partial Mayo score (remission ≤2). Colectomy rates were analyzed through survival analysis and Cox regression. Mortality at 12 months were also evaluated. A total of 461 patients were included: 149 in cohort 1 and 312 in cohort 2. Steroid use was lower in cohort 1 (82% vs 97%, p < 0.001), but clinical response rates were similar. Rescue therapy rates were comparable (52% vs 57%, p = 0.88); infliximab use was lower in cohort 1 (25% vs 54%, p < 0.01). At 12 months, cohort 1 showed lower remission (44% vs 59%, p = 0.03) and higher colectomy (17% vs 8.7%, p = 0.01). Overall colectomy was higher in cohort 1 (34% vs 17%; HR 2.46, p = 0.001). One-year mortality was 1.52% (no significant differences between cohorts). ASUC management in anti-TNF-exposed patients is heterogeneous and differs from that of bio-naive patients, with increased risk of treatment failure and colectomy.

accurate endoscopic assessment is crucial for treatment decisions in Crohn's disease (CD), but endoscopic scores are complex and not easily applicable in routine practice. This study aimed to assess interobserver reproducibility of Crohn's Disease Endoscopic Index of Severity (CDEIS), Simple Endoscopic Score for Crohn's Disease (SES-CD) and their subsections, in inflammatory bowel disease (IBD) experts and non-experts, to improve endoscopic assessment. an observational, prospective study was performed including 22 CD patients who underwent routine colonoscopy at an IBD unit, after excluding patients with inadequate bowel preparation (Boston Bowel Preparation score < 6). Seven endoscopists from four centers, four specialized in IBD, independently scored the videos using CDEIS and SES-CD. Interobserver variability was assessed, comparing IBD experts and non-experts, and correlating endoscopic scores with clinical activity and biomarkers. overall intra-class correlation coefficient (ICC) was 0.83 for CDEIS and 0.77 for SES-CD, indicating substantial agreement. The lowest correlations were found with deep ulcers in the ileum, descending colon, and rectum (CDEIS), and ulcer size in the ileum and stricture detection in the descending colon (SES-CD). Non-IBD experts showed higher interobserver agreement (ICC: 0.91 CDEIS, 0.88 SES-CD) compared to IBD experts (ICC: 0.79 for both). No correlation was found between endoscopic scores and Harvey-Bradshaw index or C-reactive protein (CRP). SES-CD showed a significant correlation with fecal calprotectin (0.58, p = 0.01) and CDEIS trended towards significance (r = 0.44, p = 0.064). Regarding endoscopic remission, 22 % patients were inconsistently classified. although CDEIS and SES-CD are highly reproducible without specialized training, they have limitations to detect mild inflammatory activity. An ideal score should emphasize ileal activity and simplify the assessment of ulceration severity and stenosis to improve clinical utility.

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Background:While mucosal healing (MH) and transmural healing (TH) predict relevant clinical outcomes in Crohn’s disease (CD), little is known about the real significance and clinical impact of deep remission (DR).Objectives:To better explore the concept of DR, toward a direct correlation between MH, TH, and biomarkers.Design:Real-world observational longitudinal study to evaluate the rate of clinical remission (CR), MH and TH, and the fecal calprotectin (FC)/C-reactive protein (CRP) levels in all consecutive CD patients on biologics.Methods:A receiver operating characteristic (ROC) curve was constructed to define the best FC and CRP cut-offs associated with MH and TH. Finally, patients achieving CR, MH, and TH, in association with the target FC/CRP values, were considered in DR.Results:Among 118 CD patients, CR, MH, and TH were achieved in 62.7, 44.1, and 32.2%, respectively. After 2 years, the mean FC levels decreased from 494 ± 15.4 μg/g to 260 ± 354.9 μg/g (p < 0.01). Using the ROC curve analysis, an FC cut-off value of 94 μg/g was associated with both MH [sensitivity: 94.2%, specificity: 84.8%, positive predictive value (PPV): 83.05%, negative predictive value (NPV): 94.92%, area under the curve (AUC): 0.95] and TH (sensitivity: 92.1%, specificity: 70%, PPV: 64.4%, NPV: 94.9%, AUC: 0.88). CRP < 5 mg/L was associated with both MH (sensitivity: 96.1%, specificity: 62.1%, PPV: 66.7%, NPV: 95.35%, AUC: 0.85) and TH (sensitivity: 97.4%, specificity: 52.5%, PPV: 52%, NPV: 95.35%, AUC: 0.78). When considering CD patients with concomitant CR, MH, and TH associated with an FC < 94 μg/g and CRP < 5 mg/L, this association was found identified in 33 patients (27.9%).Conclusion:An FC < 94 μg/g and a normal CRP are associated with CR, MH, and TH and could be included in the definition of DR in association. So by definition, DR could be achieved in approximately 30% of CD patients during maintenance treatment with biologics.

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Objective: To determine the correlation between inflammatory markers (fecal calprotectin and CRP) and Simple Endoscopic Score for Crohn's Disease (SES-CD) in patients with Crohn's disease. Study Design: Cross-sectional study. Setting: Department of Medicine, Liaquat University of Medical and Health Sciences. Period: 24th August 2024 to 24th February 2025. Methods: Thirty-three patients with endoscopically diagnosed Crohn's disease were enrolled. Blood samples for CRP and first-morning stool samples for fecal calprotectin were collected. SES-CD was calculated during endoscopic evaluation. Demographic and clinical data were recorded using standardized proformas. Spearman's correlation coefficient was used to assess relationships between variables. Results: The study included 33 patients with a median age of 44.00 years (IQR: 34.00-52.50) and mean BMI of 25.86 ± 2.30. The median SES-CD score was 8.00 (IQR: 6.00-13.00), and mean CRP level was 14.00 ± 6.48 mg/L. Spearman correlation analysis revealed strong positive correlations between SES-CD and both fecal calprotectin (ρ = 0.994, p &lt; 0.001) and CRP levels (ρ = 0.993, p &lt; 0.001). A significant correlation was also found between SES-CD and BMI (ρ = 0.882, p &lt; 0.001). No significant correlations were observed between SES-CD and age (ρ = 0.048, p = 0.791), gender (ρ = -0.102, p = 0.571), or disease duration (ρ = -0.017, p = 0.925). Conclusion: Both fecal calprotectin and CRP demonstrated strong correlations with endoscopic disease activity in Crohn's disease, suggesting their potential utility as reliable non-invasive biomarkers for monitoring disease severity and guiding treatment decisions.

Background. Vedolizumab is a gut-selective monoclonal anti-α4β7-integrin antibody approved for the treatment of adults with moderately to severely active Crohn’s disease (CD). Aim. To conduct a systematic literature review and meta-analysis of published real-world studies examining mucosal healing (MH) rates in patients with CD treated with vedolizumab in routine clinical practice. Methods. MEDLINE-, Cochrane-, and EMBASE-indexed publications from January 2014 to January 2020 and 2018-2019 conference abstracts were searched for real-world studies reporting MH-related outcomes in vedolizumab-treated adults with CD. A meta-analysis was conducted in R to generate pooled estimates of MH. The primary analysis included studies reporting point estimates of MH/endoscopic remission as absence of ulcers/erosions and/or Simple Endoscopic Score for CD (SES-CD) cut − points &lt; 4 , at 6 and 12 months. Results. The systematic literature review included 36 studies, predominantly of antitumour necrosis factor-experienced patients. MH and endoscopic remission were the most frequently reported endpoints. MH rates were 10.1%-46.0% at 6 months (ten studies) and 21.2%-62.5% at 12 months (eight studies). Fifteen studies defining MH as absence of ulcers/erosions and/or SES-CD cut − points &lt; 4 were included for meta-analysis. Pooled MH rates for the primary analysis were 31.8% at 6 months (95% confidence interval (CI): 25.6-38.3; five studies, N = 223 ) and 33.4% at 12 months (95% CI: 25.9-41.4; three studies, N = 151 ). Conclusion. Approximately one-third of vedolizumab-treated patients with CD achieved MH at both 6 and 12 months in real-world clinical settings, despite utilisation in largely biologic-refractory patients. These findings confirm the effectiveness of vedolizumab for achieving MH in patients with CD.

An Accelerated Infliximab Induction Regimen Reduces the Need for Early Colectomy in Patients With Acute Severe Ulcerative Colitis

Introduction: Infliximab (IFX) has been efficacious in reducing colectomy rates among patients with moderate-to severe ulcerative colitis, but predictors of colectomy within 30 days of IFX among patients with acute severe ulcerative colitis (ASUC) are less established. Methods: We performed a single-center retrospective analysis of patients who received at least one dose of IFX while admitted between 2011-2022. We assessed demographic, clinical and laboratory predictors of colectomy within 30 days of first IFX dose. Multivariable and time-to-event analysis using Kaplan-Meier with log-rank statistics were used to assess risk factors for colectomy within 30 days. Results: A majority of the 172 patients hospitalized with ASUC who received IFX received 10 mg/kg (87.79%). Overall, 22/172 patients (12.79%) underwent colectomy within 30 days of first IFX dose. On univariable analysis, age, sex, race, ethnicity, BMI and smoking status were not associated with risk of colectomy. Higher initial CRP was significantly associated with 30-day risk of colectomy (106.17 vs. 65.10 mg/dL among patients who did not undergo colectomy; p< 0.01), as was a decrease of CRP ≤50% prior to discharge (p< 0.01). Lower initial albumin [< 3 (36.36%), 3.0-3.5 (40.91%), >3.5 g/dL (22.73%)] was associated with our primary outcome (p=0.046), as was a higher number of bowel movements in a 24-hour period prior to discharge (5.6 vs. 3.9 among patients who did not undergo colectomy; p=0.0256). On multivariable analysis, higher initial CRP (aOR 1.01, 95% CI 1.00 – 1.02), ≤50% change in CRP after first dose of IFX (aOR 9.00, 95% CI 2.43 – 33.29) and higher number of bowel movements in a 24-hour period prior to discharge (aOR 1.24, 95% CI 1.01– 1.52) remained significantly associated with risk of colectomy when adjusting for relevant covariables (Table). On Kaplan-Meier analysis, initial CRP >100 mg/dL, albumin < 3 g/dL and change in CRP ≤50% prior to discharge were significantly associated with decreased time to colectomy (Figure). Conclusion: Among patients with ASUC, higher CRP, decrease of CRP ≤50% and higher number of bowel movements prior to discharge were associated with increased risk of colectomy within 30-days of receiving IFX. Initial CRP >100 mg/dL, albumin < 3 g/dL and decrease of ≤50% in CRP prior to discharge were associated with decreased time to colectomy. These results can identify patients at highest risk and impact clinical decision-making regarding need for and timing of colectomy in patients with ASUC receiving IFX.Figure 1.: Kaplan–Meier curve showing estimates of proportion of patients requiring colectomy within 30 days of first infliximab dose (A) comparing patients with albumin on admission < 3 g/dL and albumin on admission ≥ 3 g/dL (p=0.0488) and (B) comparing patients with CRP on admission > 100 mg/dL and CRP on admission ≤ 100 mg/dL (p<0.01). Table 1. - Multivariable Analysis Examining Predictors of Colectomy within 30 Days Among Patients Hospitalized with Acute Severe Ulcerative Colitis Receiving Infliximab. *p=0.015; **p<0.01; ***p=0.036 Variable adjOdds Ratio (95% Confidence Interval) Disease Duration (years) 0.95 (0.86 – 1.04) Family history of IBD No Reference Yes 0.53 (0.10 – 2.79) Extent of disease on admission Proctitis/Left sided colitis Reference Not documented 0.13 (0.01 – 2.04) Pancolitis 1.30 (0.35 – 4.85) GI infection No Reference Yes 2.13 (0.51 – 8.91) CRP on admission (mg/dL)* 1.01 (1.00 – 1.02) Serum albumin on admission >3.5 g/dL Reference 3-3.5 g/dL 1.83 (0.47 – 7.12) < 3 g/dL 3.77 (0.79 – 18.07) Percent change in CRP after first infliximab dose** >50% decrease Reference ≤50% decrease 9.00 (2.43 – 33.29) Number of bowel movements in 24-hour period prior to discharge*** 1.24 (1.01– 1.52)