Y-ECCO Literature Review: Giulia D’Arcangelo
Giulia D’Arcangelo
Intestinal barrier healing is superior to endoscopic and histologic remission for predicting major adverse outcomes in Inflammatory Bowel Disease: The Prospective ERIca Trial
Timo Rath, Raja Atreya, Julia Bodenschatz, et al.
Gastroenterology 2023;164:241–55
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Introduction
Mucosal healing (MH) in both Crohn's Disease (CD) and Ulcerative Colitis (UC) has been recognised as an important treatment target for many years. Indeed, the 2021 update of the Selecting Therapeutic Targets (STRIDE) consensus reaffirmed MH as the top priority among long-term treatment objectives [1]. Nonetheless, it is important to note that endoscopic inflammation may not always mirror the histological picture. Histological healing is an emerging endpoint in IBD. This is particularly true in UC, in which it represents a deeper level of recovery with some early evidence for correlation with better long-term outcomes; for CD, however, findings have been more controversial [2, 3]. Despite the increasing focus on histology, histological scoring systems are complex, with only two validated ones, both in the setting of UC, i.e. there is no validated scoring system in the context of CD.
To address these limitations, in vivo assessment of the mucosa by means of confocal laser microscopy (CLE) has gained substantial interest. CLE provides high-resolution, real-time mucosal imaging during endoscopy, accurately grading inflammatory activity and allowing assessment of intestinal barrier integrity [4, 5]. Recent research has demonstrated a significant correlation between impaired barrier function and the severity of bowel symptoms in IBD patients not achieving MH, suggesting the potential to enhance patient outcomes by addressing intestinal permeability issues [6].
Given the current "treat-to-target" approach for successful IBD treatment, a deeper evaluation of disease activity, including the assessment of epithelial barrier function (potentially guiding treatment adjustments), might provide added benefits for patients – based on the premise that “the deeper the better”. The present trial by Rath and colleagues, the “Endoscopic Remission, Histologic Remission, and Barrier Healing for Predicting Disease Behavior in IBD (ERIca)” trial, compared the value of endoscopic remission, histological remission and barrier healing for the prediction of long-term disease outcome.
Methods and key findings
This prospective observational study included 181 IBD patients (n=100 CD and n=81 UC) in clinical remission, as per established clinical activity scores. Ileocolonoscopy and histology with assessment of intestinal barrier function by CLE were performed and graded through established scores at baseline. The primary aim of this study was to compare the predictive value of barrier healing, endoscopic remission and histological remission with regard to major adverse outcomes (MAOs), defined as (1) disease relapse, (2) IBD-related hospitalisation, (3) IBD-related surgery and (4) treatment escalation.
Ulcerative Colitis
Out of the 81 patients diagnosed with UC, 43 (53.1%) showed endoscopic remission (Mayo Endoscopic Score ≤1), while 44 (54.3%) and (42) 51.9% showed histological healing as assessed by the Robarts histopathology index (RHI) and the Nancy histological index (NHI), respectively. Twenty-one patients (25.9%) presented intact barrier function, as defined by lack of fluorescein leakage into the crypt lumen. Of these 21, eight (38.1%) exhibited a Mayo Endoscopic Score of 0 (endoscopic healing). Overall MAO rate was 48.8% and 35.3% in patients with endoscopic remission and endoscopic healing, respectively, and 52.3% and 50% in patients with histological remission according to the RHI and the NHI, respectively. On Kaplan-Meier analysis, patients with endoscopic remission and endoscopic healing, as well as patients with histological remission, had a significantly higher likelihood of remaining without MAOs during follow-up compared to those with endoscopically or histologically active disease. Patients with colonic barrier healing showed the lowest MAO rate of 19.1% and had a significantly higher probability of remaining without a MAO during follow-up compared to those with no barrier healing.
Crohn’s Disease
Of the 100 CD patients, 66% and 50% had endoscopic remission defined as absence of ulceration (IO-IBD definition) and SES-CD<3, respectively. Histological remission (modified Riley score 0–4) was detected in 58% of children. At baseline, only 25% of CD patients had an intact barrier on endomicroscopy without fluorescein leakage in the terminal ileum, while 27% showed colonic barrier healing. Time-to-event analysis using Kaplan-Meier estimates showed a significantly higher probability of remaining free of MAOs in patients with endoscopic remission (the rate of MAOs was 56.1% in those with endoscopic healing, defined as absence of ulceration, and 50% in those with SES-CD<3). No significant difference in the probability of remaining without MAOs during follow-up was observed in patients with CD with and without histological remission (p=0.089), the MAO rate being 55.2% in patients with histological remission. No MAOs were observed during follow-up in the 25 patients with CD who had barrier healing in the terminal ileum, resulting in a 0% MAO rate. Of the 27 patients with colonic barrier healing, eight experienced MAOs (29.6%). Patients with CD showing barrier healing in either the terminal ileum or the colon had a significantly higher likelihood of a disease course free from MAOs compared to those without barrier healing (p<0.0001 and p=0.00017, respectively).
The analysis of the diagnostic performance of endoscopic healing, histological healing and barrier healing in predicting the disease course showed that, in both UC and CD, barrier healing outperformed endoscopic and histological remission in predicting the occurrence of MAOs. In UC, barrier healing in the colon had an 85% accuracy. In CD, barrier healing in the terminal ileum had an accuracy of 88.7%, and a perfect specificity and positive predictive value (100%), while colonic barrier healing showed an accuracy of 72.7%.
Conclusions
This study from Rath and colleagues suggests that assessing the intestinal barrier with CLE can significantly improve the prediction of future disease behaviour. The study provides welcome data indicating that dynamic monitoring of the intestinal barrier could be a valuable clinical tool for risk stratifying IBD patients and predicting more complex disease outcomes. Indeed, the study offers hope that predictive tools may be emerging which can finally deliver on the aspiration of precision medicine in IBD. One thing that has become clear about predictive tools is that they need to strike the right balance between risks and benefits for individuals with IBD. The future application of such tools might allow tailored treatment plans to be devised and agreed with those patients predicted to face a more complex disease course [7]. Importantly, in the treat-to-target era, the findings of this study suggest that assessing and enhancing barrier function might be a target in future clinical trials (and potentially clinical practice). This work will also hopefully stimulate further research to understand the molecular mechanisms driving barrier integrity in different parts of the intestines and to elucidate the biological implications of these mechanisms for disease prognosis.
References
- Turner D, Ricciuto A, Lewis A, et al. International Organization for the Study of IBD. STRIDE-II: An Update on the Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE) Initiative of the International Organization for the Study of IBD (IOIBD): Determining Therapeutic Goals for Treat-to-Target strategies in IBD. Gastroenterology 2021;160:1570–83.
- Gupta A, Yu A, Peyrin-Biroulet L, et al. Treat to target: the role of histologic healing in inflammatory bowel diseases: a systematic review and meta-analysis. Clin Gastroenterol Hepatol 2021;19:1800–13.e4.
- Yoon H, Jangi S, Dulai PS, et al. Incremental benefit of achieving endoscopic and histologic remission in patients with ulcerative colitis: a systematic review and meta-analysis. Gastroenterology 2020;159:1262–75.e7.
- Hundorfean G, Chiriac MT, Mihai S, et al. Development and validation of a confocal laser endomicroscopy-based score for in vivo assessment of mucosal healing in ulcerative colitis patients. Inflamm Bowel Dis 2017;24:35–44. Erratum in: Inflamm Bowel Dis 2018;24:2655.
- Karstensen JG, Saftoiu A, Brynskov J, et al. Confocal laser endomicroscopy: a novel method for prediction of relapse in Crohn’s disease. Endoscopy 2016;48:364–72.
- Chang J, Leong RW, Wasinger VC, et al. Impaired intestinal permeability contributes to ongoing bowel symptoms in patients with inflammatory bowel disease and mucosal healing. Gastroenterology 2017;153:723–31.e1.
- Lamb CA, Saifuddin A, Powell N, Rieder F. The future of precision medicine to predict outcomes and control tissue remodelling in inflammatory bowel disease. Gastroenterology 2022;162:1525–1542.
Giulia D’Arcangelo - Short Biography
Giulia D’Arcangelo is a Paediatric Gastroenterologist at Umberto I Hospital in Rome and a PhD candidate in Biotechnology in Clinical Medicine at Sapienza University of Rome. She is currently working on exploring new biomarkers for Inflammatory Bowel Disease and is conducting the project "New Non-Invasive Techniques in the Management of Paediatric Inflammatory Bowel Diseases: Improving Quality of Care and Reducing National Health System Costs", which has been awarded a grant from the national Italian Ministry of Health.