Leucine-Rich Alpha-2 Glycoprotein Is an Accurate Serum Marker for Endoscopic and Histological Remission in Ulcerative Colitis

Shining a Light on Barrier Function

Treating ulcerative colitis (UC) requires mucosal healing (MH); however, clinical remission does not always involve MH. Fecal calprotectin (FC) is a useful marker to determine MH. Leucine-rich alpha-2 glycoprotein (LRG) and prostaglandin E-major urinary metabolite (PGE-MUM) have similar performance to FC and may also predict MH. No previous studies have provided a detailed comparative analysis of LRG, PGE-MUM, and FC. Herein, we investigated their associations with endoscopic activity and their potentials as predictors of MH. This single-center, prospective, observational study included patients with ulcerative colitis in clinical remission for >3 months (partial Mayo score ≤ 2) who were to undergo colonoscopy between July 2023 and June 2024. Endoscopic remission (ER) was defined as Mayo endoscopic score of 0, while histological remission (HR) was based on the Geboes score. Overall, 46 patients were enrolled, and all underwent colonoscopy; 20 (43%) had ER, and 9 (20%) had HR. The median LRG, PGE-MUM, and FC levels were significantly higher in patients without ER than in those who achieved ER (P < .05). The areas under the receiver operating characteristic curves of LRG, PGE-MUM, and FC for determining ER were 0.686 (95% confidence interval [CI]: 0.530–0.845), 0.695 (95% CI: 0.552–0.872), and 0.788 (95% CI: 0.658–0.919), respectively. The optimal cutoff value obtained from the receiver operating characteristic curve, LRG, PGE-MUM, and FC values for determining ER were 14.2 µg/mL, 30.6 μg/gCr, and 143 mg/kg, respectively. The areas under the receiver operating characteristic curves for LRG + FC and PGE-MUM + FC to determine ER were 0.800 (95% CI: 0.672–0.928) and 0.865 (95% CI: 0.764–0.966), respectively. LRG and PGE-MUM are potential biomarkers for determining ER in clinical remission. Combining LRG and PGE-MUM assessments with FC may improve the accuracy of confirming ER in ulcerative colitis, even during the remission phase.

Real-time use of artificial intelligence at colonoscopy predicts relapse in ulcerative colitis: predicting with “intelligence”

Background Current expert-based recommendations suggest that clinical and endoscopic remission should be pursued as treatment targets in ulcerative colitis (UC). However, combined endoscopic and histologic remission may be associated with improved outcomes. Methods Retrospective single-center cohort study including consecutive patients with UC under advanced therapy (biologics and small molecules) with endoscopic and histologic evaluation. We evaluated the rates of hospitalization, surgery, steroid-free remission, and treatment discontinuation after 1-year of follow-up according to the type of remission. Endoscopic remission was defined as a Mayo endoscopic subscore of 0. Histologic remission was defined as the absence of ulcers, erosions and neutrophils in the lamina propria. Results One hundred and six patients were included. Thirty-five patients (33.0%) achieved combined endoscopic and histologic remission, 21 patients (19.8%) endoscopic but not histologic remission and 50 patients (47.2%) did not achieve endoscopic remission. At the end of 1-year, 85 patients (79.4%) achieved steroid-free remission, 14 (13.0%) required hospitalization, 4 (3.7%) surgery, 15 (14.1%) discontinued treatment. A compound outcome was reached by 31 (29.2%) patients. In multivariate analysis including age at diagnosis, age at biologic, type of advanced treatment, disease duration, immunomodulation, previous biologic exposure and type of remission, only the type of remission was associated with a lower chance of reaching any unfavourable outcome (reference no remission) - combined endoscopic and histologic remission (OR 0.162 95%CI 0.05-0.528, P=0.003) and isolated endoscopic remission (OR 0.286 95%CI 0.084-0.971, P=0.045). Kaplan-Meier analysis showed longer outcome-free survival in patients with combined endoscopic and histologic remission. Conclusion Achieving combined endoscopic and histologic remission is associated with better clinical outcomes after 1 year of advanced treatment compared to no remission. However, we could not confirm a significant advantage of combined endoscopic and histologic remission over endoscopic remission alone.

Incremental Benefit of Achieving Endoscopic and Histologic Remission in Patients With Ulcerative Colitis: A Systematic Review and Meta-Analysis

Computer-Aided Diagnosis With Monochromatic Light Endoscopy for Scoring Histologic Remission in Ulcerative Colitis

Introduction: Leucine-rich alpha-2-glycoprotein (LRG) is a potential biomarker for disease activity and reflects mucosal healing in patients with ulcerative colitis (UC). However, only a few studies have described a detailed sensitivity analysis of LRG in predicting mucosal healing in patients. This study aimed to evaluate the association between LRG and the endoscopic activity of UC and its predictability for mucosal healing and explore the utility and clinical application of LRG. Methods: The diagnostic accuracy of biomarkers, including LRG, in predicting the endoscopic activity of UC was evaluated. All consecutive patients who underwent total colonoscopy between April 2021 and September 2022 were included. The Mayo endoscopic subscore (MES) was used for assessing endoscopic activity. Furthermore, endoscopic remission was defined as an MES of ≤1. Clinical activity was evaluated based on stool frequency and bloody stool. Receiver operating characteristic curve analysis and binary logistic regression were performed to assess the diagnostic accuracy of the biomarkers. We evaluated LRG trends and treatment response in patients with MES ≥2 who underwent induction therapy. Results: This study comprised 214 patients. The proportions of endoscopically and clinically active patients were 33.6% and 49.1%, respectively. LRG had an area under the curve (AUC) of 0.856, with a higher diagnostic accuracy than other biomarkers, such as C-reactive protein, leukocyte, neutrophil, platelet, and albumin. The cutoff value for LRG was 15.6 μg/mL (sensitivity, 72.2%; specificity, 86.6%). Using the MES, patients with higher scores had higher LRG levels than those with lower scores. The cutoff value, AUC, sensitivity, and specificity varied with a higher AUC for left-sided colitis and pancolitis than for proctitis. Logistic regression analysis showed that LRG was an independent predictor of endoscopic remission using multivariate analysis, even with the factor of clinical activity. The change ratio of LRG pre- and post-treatment was statistically significant in the higher LRG group. Conclusion: LRG reflected endoscopic activity independently, regardless of clinical symptoms. An LRG below the cutoff value could indicate a significantly low probability of endoscopic activity in asymptomatic patients, and follow-up endoscopy (not for cancer screening) may be unnecessary. Furthermore, a higher LRG level might be more useful as an indicator of treatment efficacy.

Vedolizumab Induces Endoscopic and Histologic Remission in Patients With Crohn’s Disease

Persistent active endoscopic and histological inflammation is associated with poorer outcomes in ulcerative colitis (UC). Fecal calprotectin is a surrogate marker of endoscopic and histological remission. To confirm the correlation between fecal calprotectin and endoscopic or histological disease activity and to define the optimal cutoff value to detect endoscopic and histological remission. From a prospectively maintained database, we analyzed 61 UC patients who had fecal calprotectin measurement and endoscopy performed within 1month. Endoscopic activity was graded using the Mayo endoscopic subscore (MES). Histological remission was defined as normal histology or quiescent histological activity. Eighteen patients (29.5%) and five patients (8.1%) had endoscopic remission defined as MES≤1 or MES=0, respectively. We observed a significantly lower median level of fecal calprotectin in patients with endoscopic remission than those with endoscopic activity for both definition of endoscopic remission, i.e., MES≤1 (158 vs 490µg/g, p=0.0005) or MES=0 (94 vs 414µg/g, p=0.013). Seven patients (11.5%) were in histological remission. They had a lower median level of fecal calprotectin than those with active histological inflammation (107 vs 416µg/g, p=0.016). Using a ROC curve, fecal calprotectin<250µg/g predicted endoscopic remission (MES≤1) with a sensitivity of 67% and specificity of 77%, while fecal calprotectin <200µg/g predicted histological remission with a sensitivity of 71% and specificity of 76%. Fecal calprotectin level correlated with both endoscopic activity and histological activity and is a reliable biomarker in assessing mucosal healing in UC.

Endoscopic remission in ulcerative colitis (UC) is associated with improved clinical outcomes. We assessed whether histological remission predicts clinical outcomes, estimated the magnitude of effect, and determined whether histological remission provides additional prognostic utility beyond clinical or endoscopic remission. Bibliographic databases were searched for studies in inflammatory bowel disease providing baseline histological status and relation to an outcome of clinical relapse or exacerbation. Our primary analysis compared the proportion of patients with study-defined histological remission vs. the proportion with histological activity who developed clinical relapse/exacerbation. Additional analyses compared the proportion with relapse/exacerbation for the presence vs. absence of different histological features and for histological remission vs. endoscopic remission and clinical remission. A fixed-effect model was used for meta-analysis, with a random-effects model if statistical heterogeneity was present. Fifteen studies met inclusion criteria. The major methodological shortcoming was lack of blinding of the assessor of clinical relapse/exacerbation to baseline histological status in 13 of the 15 studies. Relapse/exacerbation was less frequent with baseline histological remission vs. histological activity (relative risk (RR)=0.48, 95% confidence interval (CI) 0.39-0.60) and vs. baseline clinical and endoscopic remission (RR=0.81, 95% CI 0.70-0.94). Relapse/exacerbation was also less common in the absence vs. presence of specific histological features: neutrophils in epithelium (RR=0.32, 95% CI 0.23-0.45), neutrophils in lamina propria (RR=0.43, 95% CI 0.32-0.59), crypt abscesses (RR=0.38, 95% CI 0.27-0.54), eosinophils in the lamina propria (RR=0.43, 95% CI 0.21-0.91), and chronic inflammatory cell infiltrate (RR=0.28, 95% CI 0.10-0.75). Histological remission was present in 964 (71%) of the 1360 patients with combined endoscopic and clinical remission at baseline. UC patients with histological remission have a significant 52% RR reduction in clinical relapse/exacerbation compared with those with histological activity. Histological remission is also superior to endoscopic and clinical remission in predicting clinical outcomes. As ~30% of patients with endoscopic and clinical remission still have histological activity, addition of histological status as an end point in clinical trials or practice has the potential to improve clinical outcomes.

Studies on serum leucine-rich alpha-2 glycoprotein (LRG) in inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn's disease (CD), are scarce; the methods for estimating disease activity are less established, particularly for CD. This study is aimed at evaluating the utility of serum LRG as a potential inflammatory marker for IBD and to investigate the LRG gene expression in peripheral blood mononuclear cells (PBMCs) as a possible source of serum LRG. Overall, 98 patients with UC and 96 patients with CD were prospectively enrolled and clinically evaluated; 92 age-matched individuals served as the healthy controls. The blood samples were analyzed for serum LRG levels and routine laboratory parameters. Disease activity was assessed clinically and endoscopically. Finally, LRG gene expression in the PBMCs from a different cohort (41 patients with UC, 34 patients with CD, and 30 healthy controls) was examined. The serum LRG levels were higher during active disease than during inactive disease; additionally, serum LRG levels were positively correlated with clinical disease activity, C-reactive protein (CRP) levels, and other laboratory parameters in patients with UC and CD and with endoscopic disease activity in UC. UC and CD showed comparable areas under the curve (AUC) values for determining clinical remission and differentiating between endoscopic remission associated with LRG and CRP. The levels of LRG mRNA were also increased in PBMCs from patients with UC and CD and reflected disease activity. These data suggest that serum LRG, originated partially from PBMCs, is an inflammatory marker in UC and CD. A large-scale well-designed study should be conducted in the future to more accurately reveal the clinical significance of LRG in patients with IBD.

The Use of Intestinal Ultrasound in Ulcerative Colitis—More Than a Mucosal Disease?

Background Clinical remission, defined by the Mayo Clinic Score (MCS) or modified MCS, is the accepted regulatory endpoint in drug development for ulcerative colitis (UC). Whilst histologic remission is a more stringent outcome, recent trials have reported numerically higher rates compared to endoscopic or clinical remission rates at the same timepoint, suggesting that histologic remission may be a more sensitive endpoint for detecting treatment response Methods A systematic review was performed from inception to December 2020, including all placebo-controlled drug trials for adults with UC. Clinical, endoscopic, and histologic induction remission rates for active treatment and placebo arms were pooled on the logit scale using a random-effects model to account for both between- and within-study variability. Risk ratios (RR) and risk differences comparing the rate of remission in active treatment arms to the rate of remission in placebo arms were also pooled using a random-effects model. Results For induction trials, 15/84 reported clinical, endoscopic, and histologic remission rates at the same timepoint. Clinical remission was mostly defined as a MCS≤2 with no individual subscore&amp;gt;1 (10/15;66.6%), and endoscopic remission as MES=0 (6/15; 40%) or MES≤1 (9/15; 60%). Histologic remission was defined using Geboes score in 10/15(66.7%) trials, with a score≤1.0 in 4/10(40%), score=0 in 3/10(30%), and score&amp;lt;3.0 in 3/10(30%) trials. For placebo/active treatment arms, the pooled clinical, endoscopic, and histologic remission rates were 11.3%(95% CI 7.4–16.9%) /17.8%(95% CI 13.7–22.8%), 13.4%(95% CI 8.5–20.5%) /18.7% (95% CI 12.2–27.5%), and 18.2%(95% CI 13.8–23.6%) /27%(95% CI 20.6–34.7%), respectively(Figure 1). The differences in pooled clinical, endoscopic, and histologic remission rates between active treatment and placebo were 7.2%(95% CI 4.3%–10.1%), 6.6% (95% CI 2.5%–10.7%), and 8.4% (95% CI 4.3%–12.4%), respectively(Figure 2A), and the pooled RR comparing clinical, endoscopic, and histologic remission rates in the active treatment and placebo arms were 1.59 (95%CI 1.19–2.13), 1.49 (95%CI 1.16–1.90), and 1.47 (95%CI 1.20–1.81), respectively(Figure 2B) Conclusion Histologic remission has been proposed as a treatment target for patients with UC, given an association between this outcome and lower rates of clinical relapse.1 Although we found numerically higher pooled histologic remission rates for active treatment and placebo arms, compared to pooled clinical and endoscopic remission rates, we found no difference in the pooled RR for clinical, endoscopic, and histologic remission rates in the active treatment and placebo arms. Whilst histology has the potential to serve as a more efficient endpoint for drug development, more studies are needed.

Background and Aims: Recent advances in Ulcerative Colitis (UC) treatment have the potential to improve clinical outcomes if inflammation is controlled. The emerging concept of "disease clearance" (DC) aims to achieve combined clinical, endoscopic, and histological remission. However, whether DC is associated with better outcomes remains unclear. This study aimed to evaluate the impact of DC on UC patients. Methods: Consecutive UC patients who underwent colonoscopy and had clinical follow-up of at least 18 months were included between September 2012 and December 2017. Clinical condition (Patient-Reported Outcome, PRO), Mayo endoscopic score (MES), and histopathology (Geboes score, GS) were assessed at baseline and every 6 months. Disease clearance (DC) was defined as simultaneous clinical remission (PRO2 = 0), endoscopic remission (MES = 0), and histological remission (GS ≤ 2). Results: A total of 101 UC patients with a median time since diagnosis of 103 ± 102 months were included. At baseline colonoscopy, 52 patients (51.5%) achieved DC. These subjects had a lower rate of negative outcomes than those without DC (21.2% vs. 59.2%, p < 0.001). Kaplan-Meier curves confirmed a lower risk of clinical relapse in DC patients (log-rank, p = 0.001). Among patients with endoscopic remission, only those with DC had a lower risk of negative outcomes (21.2% vs. 75%, p < 0.01). Achieving DC reduced the risk of flare-ups even in patients with clinical remission or histological remission. Conclusions: Achieving DC in UC patients reduces the risk of negative outcomes during follow-up, supporting its inclusion as a key composite treatment goal in UC management.

Background Treating beyond endoscopic remission, aiming for histological remission, has shown to reduce relapse and hospitalization rates in patients with ulcerative colitis (UC). However, very little is known on how histological remission associates with patient reported outcomes (PROMs). Methods PROMs (Simple clinical colitis activity index [SCCAI], IBD disk and Visual Analogue Scales [VAS]) were prospectively collected through a digital questionnaire in all patients with UC undergoing colonoscopy between July 21st 2020-Jan 21st 2021. Mayo endoscopic sub score and UCEIS were determined, as well as the Nancy histologic index (NHI) of the most affected area. Endoscopic remission was defined as Mayo endoscopic sub score 0 and UCEIS 0; histologic remission as NHI 0, absence of active inflammation as NHI ≤ 1. PRO2 remission was defined as stool frequency ≤ 1 (absolute stool frequency ≤ 3 OR 1–2 stools more than usual) and rectal bleeding score of 0. Results Fifty-six paired assessments were collected in 48 unique patients (Table 1), with a histologic, endoscopic and PRO-2 remission rate of 23.2%, 28.6% and 38.2% respectively. Patients with histologic remission or absence of histologic inflammation had a significantly lower overall IBD disability (p=0.007, p=0.003) and disease activity score (p=0.003, p&amp;lt;0.001), as compared to patients without. In line, NHI correlated with the overall IBD disk (r=0.40, p=0.002) and SCCAI score (r=0.50, p&amp;lt;0.001). Many individual components of both scores (abdominal pain, arthralgia, impact on education and work/interpersonal interactions/sexual function, regulation of defecation, blood loss, general wellbeing, joint pain, numbers of stools during night/day, urgency) differed significantly between patients with and without histologic remission. VAS scores assessing general wellbeing (r=0.33, p=0.01), impact on daily activities (r=0.41, p=0.002), UC-related symptoms (r=0.42, p=0.001) and worries (r=0.40, p=0.002) correlated with histology. Quartile analysis of the overall IBD disk and SCCAI scores confirmed the highest likelihood for histologic remission in patients with the lowest scores (Q1-Q2 vs Q3-Q4 39.3% vs 7.1%, p=0.01; 40.0% vs 9.7%, p=0.01) (Figure 1). Nevertheless, the overall accuracy of the IBD disk (0.75) or SCCAI score (0.76) for histologic remission is lower (p&amp;lt;0.05) than the accuracy of the Mayo endoscopic (0.90) or UCEIS (0.90) score. Table 1: Baseline features Abstract OP09 – Figure 1: Quartile analysis Conclusion In patients with UC, PROMs for disability and clinical disease activity reflect histologic disease activity and should therefore be further explored in (trial) endpoint discussions. However, they cannot fully replace endoscopic and histologic findings, and should be considered complementary.