Endoscopic Outcomes of Risankizumab in Crohn’s Disease: A Real-World Analysis of Terminal Ileal Lesions

Background: Ustekinumab is a biologic that targets and blocks the IL-12 and IL-23 receptors and effectively reduces clinical and endoscopic activity of Crohn’s Disease (CD) (1-3). Despite advances in CD treatment, including novel biologic therapies, surgical intervention is still common (4). Preventing postoperative recurrence of disease is critical to avoid subsequent procedures as these operations are expensive and invasive with risk for complications. Studies have previously evaluated for the association of postoperative drug levels, specifically of tumor necrosis factor inhibitors in relation to endoscopic disease recurrence (5-6). However, no study has been conducted to explore the association between postoperative ustekinumab levels and both endoscopic and clinical CD activity. Methods: This was a retrospective study of CD patients from a tertiary referral center that had an ustekinumab level taken postoperatively. Thirty-two total patients were identified. Ustekinumab drug levels were taken within 2 years postoperatively. Harvey-bradshaw index (HBI) was used to evaluate clinical disease activity and a combination of Rutgeerts’ and simple endoscopic score (SES) for Crohn’s Disease was used for endoscopic activity. Values for labs, clinical scores, and endoscopic scores were taken closest to surgery preoperatively with at least a one-month delay after surgery for postoperative values. Delta was the numeric difference between pre and postoperative measurements. Surgical procedures included small or large bowel resection, proctectomy, and fistulectomy. Patients were separated into groups depending on if their ustekinumab level was adequate, defined as greater than or equal to 4 μg/mL, or suboptimal, defined as below 4 μg/mL. All statistics were completed using built-in Excel functions for linear regression, linear correlation, and one-tailed t-test for unequal variance. P values of <0.05 and correlations above 0.8 were considered significant. Results: Average time drug levels taken postoperatively was 257 days. Postoperative hemoglobin levels were significantly higher in the adequate level group, 13.3 g/dL compared to 12.0 g/dL (P = 0.028). Hematocrit levels were also higher in the adequate ustekinumab level group, 40.5 versus 37.1 (P = 0.027). Clinically, patients with adequate ustekinumab levels had a greater change of their HBI score compared to preoperatively, delta HBI of -3 compared to 0.4 (P = 0.046). Only the suboptimal group showed a significant average decrease in endoscopic disease activity preoperatively to postoperatively, 85.7% to 37.5% (P = 0.029). No significant linear correlations were observed when comparing ustekinumab level to postoperative lab values, clinical scores, and endoscopic scores or their deltas. Conclusion(s): Adequate levels of ustekinumab yielded higher postoperative hemoglobin and hematocrit levels in addition to a greater reduction in HBI score. Only the suboptimal ustekinumab level group showed a significant reduction in average endoscopic disease activity compared to preoperative scores, which is consistent with findings that HBI does not necessarily correlate to endoscopic disease activity. The data suggests that adequate ustekinumab levels following CD surgery reduces the risk of anemia postoperatively and results in better clinical CD remission (HBI < 5) and response (delta HBI >=3). Future studies are needed to find the optimal ustekinumab levels both pre and postoperatively in order to maintain CD remission.

Background and objective Leucine-rich alpha-2 glycoprotein (LRG) is a novel biomarker for Crohn’s disease (CD). The utility of combination use of LRG and C-reactive protein (CRP) has not been reported. This study aimed to investigate the diagnostic performance of LRG in combination with CRP to predict endoscopic activity. Methods A single-centre, retrospective, cross-sectional study was conducted. Patients with CD who had serum LRG concentrations measured at least once between June 2020 and May 2021 were enrolled. Clinical activity was evaluated with the Harvey–Bradshaw Index (HBI). Spearman’s rank correlation coefficient (rs ) was used to analyse the correlations between the HBI, LRG concentrations and CRP concentrations. In patients undergoing ileocolonoscopy or balloon-assisted enteroscopy within 60 days before or after LRG measurement, endoscopic activity was evaluated with the simple endoscopic score for Crohn’s disease (SES-CD). The diagnostic performance of LRG and CRP for endoscopic activity was evaluated using receiver operating characteristic (ROC) analysis. Results Four hundred and eighty-nine measurements in 343 patients were analysed. Although a strong correlation was found between LRG and CRP concentrations (rs = 0.75), the HBI did not well correlate with LRG or CRP concentrations. Endoscopic activity was analysed in 56 patients. In diagnosing endoscopically moderate to severe activity (SES-CD > 6), the area under the ROC curve of LRG was greater than that of CRP (0.74 vs. 0.63; p = .037). The optimal cut-off value estimated by Youden’s index was 15.5 µg/mL for LRG, and 0.13 mg/dL for CRP. LRG and CRP concentrations were considered positive when they were above these cut-off values, and the sensitivity and specificity for an SES-CD > 6 were 58.3% and 93.8%, respectively. Dual positivity of LRG and CRP showed the highest specificity. Conclusions Combination use of dual positive LRG and CRP is useful for diagnosing endoscopically moderate to severe disease.

To identify a correlation between diagnostic markers of Crohn's disease and endoscopic data using the Capsule Endoscopy Crohn's Disease Activity Index for isolated small intestine lesions. We studied 127 patients over previous 19 years. All patients were divided into 2 groups: isolated Crohn's disease of small intestine (group 1) and lesion of small and large intestine or large intestine only (group 2). All patients underwent capsule enteroscopy (MiroCam system, South Korea). Clinical activity of Crohn's disease was determined using the Best's scale, endoscopic activity - using the the Capsule Endoscopy Crohn's Disease Activity Index. We also analyzed fecal calprotectin and other laboratory markers. We found moderate correlation between fecal calprotectin and clinical activity of Crohn's disease, as well as endoscopic activity, C-reactive protein and leukocytes in overall sample of patients. There was moderate correlation between endoscopic activity and clinical activity in overall sample of patients. We found no correlation between fecal calprotectin and endoscopic activity, endoscopic activity and clinical activity, endoscopic activity and C-reactive protein and leukocytes in patients with isolated small bowel disease. Isolated small intestine lesion is accompanied by significantly lower level of fecal calprotectin compared to lesion of small and large intestine. In isolated small intestine lesion, endoscopic data do not correlate with clinical symptoms and fecal calprotectin level. Thus, analysis of severity of disease using the Crohn's Disease Clinical Activity Scale alone and fecal calprotectin may not always be effective for isolated small bowel lesion.

To assess the association of microribonucleic acid (miRNA) gene polymorphisms with the risk and clinicopathological characteristics of Crohn's disease (CD) and the influence of miRNA gene variants on the response to ustekinumab (UST) treatment among CD patients. From January 2018 to February 2025, 312 patients diagnosed with CD and 527 gender- and age-matched normal controls were selected as the study subjects at the Department of Gastroenterology of the Second Affiliated Hospital of Wenzhou Medical University. Genotypes of miR-155 (rs767649), miR-21 (rs13137), miR-124 (rs531564) and miR-146a (rs57095329, rs2431697) were determined with multiplex polymerase chain reaction-ligase detection reaction (PCR-LDR) technique. The patients were divided into different subgroups according to the Montreal Classification Criteria for CD. Harvey-Bradshaw index (HBI) and simplified endoscopic score for CD were respectively applied to assess the clinical and endoscopic disease activity of CD. Unconditional logistic regression model was employed to analyze the distribution of miRNA gene polymorphisms between the two groups, as well as their influence on the clinicopathological characteristics of CD patients. Among them, 185 CD patients received first-line UST treatment, with the first sufficient dose of UST (6 mg/kg) administered intravenously. Based on the changes in HBI at week 8, the response of patients to UST treatment was evaluated. Unconditional logistic regression model was employed to analyze the distribution of miRNA gene polymorphisms between clinically responsive group (the decline of HBI ≥ 3 scores compared to week 0) and non-responsive group. All of the P values were adjusted by Bonferroni correction. This study has been approved by the Medical Ethics Committee of the Second Affiliated Hospital of Wenzhou Medical University (Ethics No.: 2025-K-12-01). No significant difference was found in the distribution of miRNA gene polymorphisms between the two groups (all P > 0.05). The variant genotype (TC+CC) of rs2431697 was more common among patients with terminal ileal-type and ileocolic-type CD than those with the colonic-type CD (OR = 4.98, 95%CI: 1.49~16.68, P = 0.009, adjusted P = 0.045). However, the opposite conclusion was drawn for the homozygous variant genotype (TT) of rs13137 and variant genotype (GC+CC) of rs531564 (OR = 0.37, 95%CI: 0.18~0.76, P = 0.007, adjusted P = 0.035; OR = 0.36, 95%CI: 0.18~0.73, P = 0.004, adjusted P = 0.020). Compared to patients with non-stricturing and penetrating CD, the variant genotype (AG+GG) and variant allele (G) of rs57095329 were more common in those with stricturing and penetrating CD (OR = 4.06, 95%CI: 2.46~6.71, P < 0.001, adjusted P < 0.005; OR = 3.12, 95%CI: 2.06~4.73, P < 0.001, adjusted P < 0.005). However, the frequencies of variant genotype (AT+TT) and variant allele (T) of rs13137 were lower among patients with stricturing and penetrating CD than in those without (OR = 0.25, 95%CI: 0.15~0.41, P < 0.001, adjusted P < 0.005; OR = 0.45, 95%CI: 0.33~0.63, P < 0.001, adjusted P < 0.005). Additionally, the variant genotype (AG+GG) and variant allele (G) of rs57095329 were more common among those with moderately to severely endoscopic activity than those with mildly endoscopic activity (OR = 2.01, 95%CI: 1.19~3.42, P = 0.009, adjusted P = 0.045; OR = 2.04, 95%CI: 1.28~3.25, P = 0.003, adjusted P = 0.015). In total 117 cases had shown clinical response by week 8, while 68 cases showed no response. Compared with t he clinically non-responsive group, the variant genotype (TC+CC) and variant allele (C) of rs2431697 were more common in the clinically responsive group (OR = 3.86, 95%CI: 1.80~8.32, P = 0.001, adjusted P = 0.005; OR = 2.60, 95%CI: 1.34~5.06, P = 0.005, adjusted P = 0.025). However, the variant genotype (TA+AA) of rs767649 was less frequent in the clinically responsive group than the non-responsive group (OR = 0.40, 95%CI: 0.21~0.74, P = 0.004, adjusted P = 0.020). The same conclusion was drawn for the variant genotype (AT+TT) and variant allele (T) of rs13137 when the clinically responsive group was compared with the non-responsive group (OR = 0.30, 95%CI: 0.14~0.63, P = 0.002, adjusted P = 0.010; OR = 0.54, 95%CI: 0.35~0.82, P = 0.005, adjusted P = 0.025). Genetic polymorphisms of miRNAs are not associated with the risk of developing CD. The miR-146a (rs57095329) variant may increase the endoscopic activity of CD and the risk for stenosis or penetration. However, the miR-146a (rs2431697) variant may increase the risk of ileal involvement. The miR-21 (rs13137) variant may reduce the risk of ileal involvement and the risk of stenosis or penetration. The miR-124 (rs531564) variant may reduce the risk of ileal involvement. Among patients receiving UST treatment, the miR-146a (rs2431697) variant may increase the clinical response by week 8. However, both the miR-155 (rs767649) and miR-21 (rs13137) variants may decrease the clinical response by week 8.

BACKGROUND: Contrast-enhanced ultrasonography (CEUS) is an imaging technique that has been used to monitor patients with Crohn's Disease (CD). Our aim was to determine the performance of conventional US and CEUS and other non-invasive parameters such as clinical activity and analytical biomarkers to detect ileal CD inflammatory activity assessed by ileocolonoscopy. METHODS: Thirty patients with known ileal CD were evaluated. All patients underwent a conventional US followed by a CEUS using a microbubble contrast agent (SonoVue®). US examinations was performed using a Hitachi HI VISION Avius®, employing a linear abdominal transducer. Qualitative and quantitative parameters from the sonographic analysis included maximum bowel wall thickness, vascularity pattern by Doppler US and quantitative measurements of contrast bowel wall enhancement using CEUS (peak intensity and time to peak). Disease small bowel activity was assessed by ileocolonoscopy (reference) and patients were graded as inactive (normal or mild disease) or active (moderate or severe inflammation). Clinical disease activity was assessed by the Harvey–Bradshaw Index (HBI). Fecal calprotectin (FC) and C reactive protein (CRP) were performed within 1 week from CEUS and correlated with ileal inflammatory activity assessed by ileocolonoscopy. RESULTS: Endoscopic disease severity was as follow: normal or mild in 14 patients (46.7%), moderate or severe in 16 patients (53.3%). Sixteen patients (53.3%) had significant clinical activity (HBI≥5 points). No association was found between clinical activity by HBI and endoscopic disease activity (P=0.77). In patients with moderate and severe endoscopic activity, mean FC tended to be higher than in patients with inactive disease, but the difference was not statistically significant (878.6 μg/L vs 809.6 μg/L, P=0.78). No association was found between mean CRP and endoscopic activity (23.1 vs 23.9, P=0.95). In patients with active endoscopic disease, wall bowel thickness of the terminal ileum was higher than in patients with inactive disease, but this result was not statistically significant (6.5 mm vs 5.7 mm, P=0.33). No association was found between the presence of moderate to severe vascularity by Doppler (P=0.15), loss of normal stratification of the bowel wall (P= 0.596), mesentery hypertrophy (P= 0.69), mesenteric lymph nodes (P= 0.34) and disease activity. For CEUS, the peak intensity was related with disease severity (19.2 vs 8.7, P=0, 01) with a good capability to predict endoscopic activity in ileoscopy (area under the ROC curve 0.8, 95% CI 0.63-0.96). The time to peak could not predict endoscopic activity in ileoscopy (21.4 sec vs 20.9 sec, P=0.78). CONCLUSION(S): Clinical and analytical parameters are not sufficient to predict endoscopic activity in the terminal ileum. Conventional US is also not capable to predict endoscopic activity, being contrast-enhanced US an excellent non-invasive method for this purpose. CEUS peak intensity is a non-invasive and valuable parameter for an accurate detection of ileal inflammatory activity in CD leaving open, in the future, the possibility to monitor the therapeutic response.

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

BackgroundWhether the disease activity of ulcerative colitis (UC) and Crohn’s disease (CD) is correlated with the severity of coronavirus disease 2019 (COVID-19) remains poorly investigated with only few selected cohort studies having addressed this in the past.MethodsWe conducted a population-based study investigating the outcomes of COVID-19 among patients with UC and CD in Denmark. The Danish COVID-19 IBD Database is an extensive population-based database which prospectively monitors the disease course of laboratory-confirmed COVID-19 among patients with UC and CD. Severe COVID-19 was defined as COVID-19 necessitating intensive care unit admission, ventilator use, or death, while adverse COVID-19 was defined as requirement of COVID-19 related hospitalization. Clinical disease activity was measured by simple clinical colitis index and Harvey-Bradshaw Index in UC and CD, respectively. The biochemical activity was defined as C-reactive protein higher than 5 mg/L or fecal calprotectin higher than 250 μg/g. The endoscopic activity was defined as Mayo Endoscopic Subscore of at least 2 in UC, or Simple Endoscopic Score Crohn’s Disease of at least 3 for CD. Sequelae following COVID-19 were defined as symptoms that (i) developed during or after an infection consistent with COVID-19, (ii) and were present for more than 12 weeks, (iii) and were not attributable to alternative diagnoses.ResultsDuring the inclusion period between January 28th, 2020, to April 1st, 2021, the study included 319 patients with UC and 197 patients with CD who developed laboratory confirmed COVID-19. Of these, data on clinical, biochemical, and endoscopic activity were available among 265/319 (83.1%), 319/319 (100.0%), and 66/319 (20.7%) of patients with UC, respectively, and 140/197 (71.1%), 131/197 (66.5%), and 42/197 (21.3%) of patients with CD. Figures 1–2 outlines the outcomes of COVID-19 according to the degree of clinical, biochemical and endoscopic disease activity. In both UC and CD, clinical, biochemical, and endoscopic activity were not associated with adverse or severe COVID-19, nor long-term outcomes, in unadjusted nor adjusted analysis (Table 1). ConclusionIn this population-based study, we found no association between disease activity of UC or CD and severity of COVID-19. These findings have implications for the risk stratification of patients with IBD acquiring COVID-19.

To explore the ability of gastrointestinal ultrasound (GIUS) to separate patients in endoscopic remission from patients with active disease in a heterogeneous hospital cohort with Crohn's disease (CD). 145 CD patients scheduled for ileocolonoscopy were prospectively included. The endoscopic disease activity was quantified using the Simple Endoscopic Score for Crohn's disease (SES-CD), and mucosal healing was strictly defined as SES-CD = 0. Ultrasound remission was defined as wall thickness < 3 mm (< 4 mm in the rectum). Additionally, SES-CD was compared to color Doppler, Harvey Bradshaw's index (HBI), C-reactive protein (CRP) and calprotectin. 23 patients were examined by two investigators for interobserver assessment. 102 had active disease and 43 patients were in remission. GIUS yielded a sensitivity of 92.2 % and a specificity of86 % for wall thickness and a sensitivity of 66.7 % and a specificity of 97.7 % for color Doppler. The sensitivity and specificity were 34.3 % and 88.4 %, respectively, for HBI, 35.7 % and 82.9 %, respectively, for CRP and 55.9 % and 82.1 %, respectively, for calprotectin. The interobserver analysis revealed excellent agreement for wall thickness (k = 0.90) and color Doppler (k = 0.91) measurements. GIUS has a high sensitivity for detecting endoscopic activity. Accordingly, bowel ultrasound has the potential to reduce the number of routine ileocolonoscopies in patients with CD.

Background Vedolizumab (VDZ) is an effective treatment for Crohn’s disease (CD); however, inadequate and loss of response is common. Pivotal VDZ trials evaluated alternative dosing intervals, demonstrating numeric but not statistical superiority in efficacy as compared to FDA-approved dosing. The safety and effectiveness of FDA-approved and modified-dosing schedules in a real-world population are unknown. We aimed to evaluate clinical and endoscopic effectiveness &amp; safety of standard and modified maintenance VDZ dosing in a real world cohort. Methods We retrospectively reviewed CD patients (pts) treated with &amp;gt;3 months VDZ, assessing Harvey Bradshaw Index (HBI), Simple Endoscopic Score for Crohn’s disease (SESCD), Short Inflammatory Bowel Disease Questionnaire (SIBDQ), C-reactive protein (CRP), albumin and hematocrit prior to and following standard VDZ dosing, and prior to and following modified VDZ maintenance dosing. We measured duration on therapy and adverse events. Results We identified 226 eligible pts, mean age 41.5 years, 55.3% female, median disease duration 10 years, 88.9% with prior biologic exposure. Mean duration on VDZ was 28.3 months. Standard VDZ dosing: 61.5% of pts with active clinical disease and adequate follow up data achieved clinical response after 3–12 months; 41.0% had clinical remission. 51.9% of pts with active endoscopic disease and adequate follow up data achieved mucosal improvement; 42.3% had endoscopic remission; 26.0% had mucosal healing after 3–24 months. 50.0% of pts with elevated CRP and adequate follow up data normalized CRP after 3–12 months. Modified maintenance dosing: 72 non-remitters to standard VDZ dosing received modified VDZ maintenance dosing. 51.5% of pts with active clinical disease prior to starting dose modification and adequate follow up data achieved clinical response after 3–12 months of modified maintenance dosing; 42.4% had clinical remission. 22.2% of pts with SESCD ≥3 prior to starting dose modification achieved mucosal improvement after 3–24 months; 22.2% had mucosal healing. 26.7% of pts with SESCD ≥4 prior to starting modified dosing had endoscopic remission after 3–24 months. 50.0% of pts with elevated CRP and adequate follow up data normalized their CRP after 3–12 months. Safety: 82.7% of pts reported ≥1 adverse events, most commonly infection and worsening CD symptoms. Discussion Standard VDZ dosing resulted in clinical and endoscopic improvement in pts with moderate-severe CD, with prior exposure to multiple advanced therapies. For non-remitters to standard dosing, modified VDZ maintenance dosing improved clinical disease activity in ∼50% of pts and improved endoscopic disease activity in ∼20% of pts, suggesting that for pts who did not achieve remission with standard VDZ dosing, modified VDZ dosing may result in clinical and endoscopic improvement.

Background Upadacitinib (UPA) and risankizumab (RSK) are alternatives for Crohn’s disease (CD) patients refractory to conventional therapies or biologics, although their optimal positioning is unclear. Aims to compare the durability and effectiveness of UPA and RSK after biologic failure in CD; to identify risk factors for relapse and for therapy discontinuation; and to explore safety profile of UPA and RSK in this scenario. Methods Adult patients from the prospectively-maintained ENEIDA registry of GETECCU who received UPA or RSK as second- (after 1 anti-TNF) or third-line (after 2 anti-TNFs, after 1 anti-TNF+vedolizumab, or after 1 anti-TNF+ustekinumab) with ≥12 weeks of follow-up, were included. Clinical remission was defined as Harvey-Bradshaw Index (HBI) ≤ 4, and clinical response as a decrease in HBI &amp;gt; 3 points. Biologic remission was considered as faecal calprotectin (FC) ≤ 250 µg/g, and biologic response as a reduction of ≥ 50% in FC levels. Endoscopic activity was graded as quiescent (remission), mild, moderate or severe (as endoscopist’s criteria); and radiologic activity as absence/presence according to radiologist. Outcomes were evaluated at 12, 24, and 48 weeks. Treatment durability was analysed using Kaplan-Meier curves, and factors for therapy discontinuation and relapse were identified by Cox regression. All adverse events (AEs) were recorded. Results A total of 562 patients from 39 centers were included [UPA: n = 242 (43%), RSK: n = 320 (57%)] (Table 1). In second-line, 12 and 24-week durability was 70%/59% for UPA and 72%/72% for RSK; in third-line, 61%/40% for UPA, and 80%/76% for RSK (p &amp;lt; 0.05). Outcomes were included in Table 2. In second-line, predictive factors for therapy discontinuation were stricturing-fistulising behaviour (Hazard Ratio [HR]=1.9, 95% confidence interval [CI]=1.1-3.3), and UPA vs. RSK treatment (HR = 1.8, 95%CI=1.1-3.1). In third-line, UPA treatment was associated with treatment discontinuation (HR = 2.4, 95%CI=1.5-4). The severity of CD at baseline was associated with relapse in second- (HR = 7.1, 95%CI=3.9-12.7) and in third-line (HR = 5.4, 95%CI=3.4-8.7). AEs were reported in 64 (28%) UPA- and 28 (10%) RSK- treated patients (p &amp;lt; 0.05), most commonly acne for UPA, while infections predominated with RSK. Treatment was maintained in 81% of UPA and 91% of RSK patients with AEs (p &amp;lt; 0.05). Conclusion UPA and RSK are effective options after biologic failure in CD patients. Both agents showed high treatment durability with greater persistence observed for RSK in third-line. CD behaviour and UPA treatment (vs. RSK) were predictive factors for therapy discontinuation, while severity of CD at baseline predicted relapse. AEs occurred more frequently with UPA, leading to a higher rate of treatment discontinuation compared with RSK.

Background:Crohn’s disease (CD) is a chronic inflammatory bowel disease. Monitoring the disease activity and providing appropriate treatment are essential for improving long-term prognosis. Endoscopy remains the gold standard for assessing disease activity; however, it is invasive and costly. Recently, we identified gelsolin as a promising serum biomarker for endoscopic disease activity in ulcerative colitis.Objective:To investigate serum gelsolin levels as a potential biomarker for mucosal activity in the small bowel and colon of patients with CD. Furthermore, we aimed to compare the performance of gelsolin with that of C-reactive protein (CRP) in detecting mucosal activity.Design:A retrospective observational study at a single tertiary care center.Methods:Serum gelsolin and CRP were measured in 82 patients with CD and 16 healthy controls. Endoscopic disease activity was assessed using the Applied Simple Endoscopic Score for CD (aSES-CD). We conducted receiver operating characteristic curves and correlation analyses. In addition, subgroup analyses were performed to evaluate differences in the biomarker performance between ileal and ileocolonic types of CD.Results:Serum gelsolin levels were significantly lower in patients with CD than in healthy controls (p < 0.001). Gelsolin levels were negatively correlated with aSES-CD, particularly in patients with the ileocolonic-type CD, and showed a stronger correlation with endoscopic activity than CRP. The area under the curve for gelsolin was 0.8377, with a cutoff of 13 µg/mL, yielding 75% and 83% sensitivity and specificity, respectively.Conclusion:Serum gelsolin is a prospective noninvasive biomarker that outperforms CRP in detecting endoscopic disease activity in patients with ileocolonic-type CD.

Background and AimMonitoring mucosal inflammation in inflammatory bowel disease (IBD) is of major importance to prevent complications and improve long-term disease outcome. The correlation of clinical activity indices with endoscopic disease activity is, however, moderate. Fecal calprotectin (FC) is a better predictor of mucosal inflammation, but values between 100 and 250 µg/g are difficult to interpret in clinical practice. We aimed to evaluate the occurrence of indefinite FC levels in a real-life IBD cohort and study the additional value of a combination of biochemical markers and clinical activity indices.MethodsIn total, 148 Crohn’s disease (CD) and 80 ulcerative colitis (UC) patients visiting the outpatient clinic were enrolled. FC, clinical disease activity scored by the Harvey–Bradshaw index or Simple Clinical Colitis Activity Index, and C-reactive protein (CRP) were assessed. In a subset of patients, endoscopic activity was scored by the simple endoscopic score-Crohn’s disease and Mayo endoscopic subscore. Clinical activity index, CRP, and FC were integrated in a combination score and compared with endoscopy.ResultsIndefinite FC values were present in 24% of CD and 15% of UC. In the cohort of patients with endoscopy scores available, the combination score predicted endoscopic disease activity in CD with a sensitivity of 83% and specificity of 69% [positive predictive value (PPV) 58%, negative predictive value (NPV) 89%]. In UC, this was 88 and 75% (PPV 93%, NPV 60%).ConclusionsA combination of FC with clinical activity indices or CRP may aid in classifying patients with indefinite disease activity according to FC alone.

Leucine-rich alpha-2 glycoprotein (LRG) is a novel serum biomarker for inflammation in inflammatory bowel disease (IBD). This prospective study aimed to compare the value of LRG with C-reactive protein (CRP) and fecal calprotectin for evaluating clinical and endoscopic disease activity in patients with IBD. At entry, clinical and endoscopic disease activity was assessed in 267 patients with IBD (ulcerative colitis [UC] 203; Crohn's disease [CD] 64), and the levels of LRG, CRP and fecal calprotectin were measured. The accuracy of the biomarkers for the detection of clinical and endoscopic disease activity was determined by the area under the receiver operating characteristic curve. Leucine-rich alpha-2 glycoprotein showed a significant relationship with the clinical and endoscopic severity in both UC and CD (both diseases, P < .0001). In the clinical assessment of UC, the accuracy of LRG was significantly higher than that of CRP (0.73 vs 0.63; P < .001). In the endoscopic assessment of UC, the accuracy of LRG was significantly higher than that of CRP (P = .01), but it was significantly lower than that of fecal calprotectin (P = .009; LRG, 0.80; CRP, 0.72; fecal calprotectin, 0.91). In the clinical and endoscopic assessment of CD, the accuracy was not significantly different between the biomarkers (clinical activity: LRG, 0.71; CRP, 0.64; fecal calprotectin, 0.66; in endoscopic activity: LRG, 0.79; CRP, 0.78; fecal calprotectin, 0.81). Leucine-rich alpha-2 glycoprotein is a reliable serum biomarker for the assessment of clinical and endoscopic disease activity in patients with IBD. It can be an alternative to CRP for the assessment of UC.

The goal of treatment for Crohn's disease (CD) is to achieve mucosal or transmural healing, and biomarker measurements are useful in monitoring disease activity and guiding treatment. This study aimed to investigate the utility of a new urinary biomarker, prostaglandin E-major urinary metabolite (PGE-MUM), in assessing CD activity. The study involved 87 patients with CD who underwent endoscopic examination and measurements of 4 biomarkers: Prostaglandin E-major urinary metabolite, fecal calprotectin (FC), leucine-rich α2 glycoprotein (LRG), and C-reactive protein (CRP). Endoscopic activity was assessed by the Simple Endoscopic Score for Crohn's Disease (SES-CD). Correlations between the CD activity index (CDAI) and SES-CD with the 4 biomarkers were analyzed, and receiver-operating characteristic (ROC) analyses were performed to predict SES-CD ≧ 3. All 4 biomarkers showed significant correlations with both CDAI and SES-CD. The cutoff (area under the curve [AUC]) values for predicting SES-CD ≥ 3 were as follows: PGE-MUM, 25.2 µg/g Cr (0.800); FC, 257mg/kg (0.816); LRG, 11.8 µg/mL (0.748); and CRP, 0.22mg/dL (0.656). Subgroup analysis revealed significant correlations between PGE-MUM and SES-CD in both the L1 (small intestine only) and L2 + L3 (including large intestine) groups, with correlation coefficients of 0.654 and 0.586, respectively. In the L1 group, ROC analysis revealed that, among the 4 biomarkers, PGE-MUM had the highest AUC for predicting SES-CD ≥ 3, with a cutoff (AUC) of 33.1 µg/g Cr (0.861). PGE-MUM is a biomarker that can reflect endoscopic activity in patients with CD and may be particularly useful in small intestinal lesions.

Background Receptor-interacting protein kinase-3 (RIPK3) is a key mediator of necroptosis, a regulated form of cell death implicated in the pathogenesis of Crohn’s disease (CD). Increased tissue expression of RIPK3 in inflamed areas of the intestinal mucosa has been found both in experimental models and in patients with active disease, but the prognostic role of the marker remains unclear. This study focuses on the prognostic potential of tissue expression of RIPK3 in patients with Crohn’s disease for the development of severe disease and complications. Methods Tissue expression of RIPK3 was determined immunohistochemically from biopsy samples of 85 patients with Crohn’s disease. Histological activity, clinical activity using the Crohn’s Disease Activity Index (CDAI), disease location and behaviour according to the Montreal classification, and endoscopic activity using the Simple Endoscopic Score for Crohn’s Disease (SES-CD) were also evaluated. The Rutgeerts score was applied in patients who had undergone surgical intervention. Results High expression of the marker was associated with an increased risk of intestinal complications in patients with Crohn’s disease (HR = 3.83; 95% CI 2.34–6.29; p &amp;lt; 0.001), future surgical interventions (HR = 2.16; p = 0.001), comorbidities (HR = 2.35; p = 0.001) and frequent hospitalisations (p = 0.046). The strongest association was observed in cases with intestinal complications. Increased RIPK3 expression was found in patients with frequent relapses (≥2 times per year) compared with those with infrequent relapses (≤1 per year) (181.36 vs 162.50; p = 0.021). A weak positive correlation was observed between relapse frequency and RIPK3 expression (r = 0.250; p = 0.021), indicating that higher relapse rates are associated with increased marker expression. RIPK3 expression was elevated and showed positive correlations with clinical (r = 0.64, p &amp;lt; 0.01), endoscopic (r = 0.59, p &amp;lt; 0.05) and histological (r = 0.68, p &amp;lt; 0.01) activity (Fig. 1). The highest expression was observed in patients with extensive disease involving the upper gastrointestinal tract - L1 + L4 (225.50, p = 0.045) and L2 + L4 (218.00), in those with combined stricturing and penetrating behaviour - B2 + B3 (180.38) and in cases with concomitant perianal disease (181.85; p &amp;lt; 0.05). Conclusion Increased RIPK3 expression in Crohn’s disease is strongly associated with severe clinical, endoscopic and histological activity, intestinal complications, frequent relapses and severe course. Increased RIPK3 expression is an independent predictor of disease progression, further confirming its potential as a novel prognostic marker in Crohn’s disease. Conflict of interest: Dr. Panayotova, Elena: No conflict of interest