Introduction

Several histopathological features have been identified as risk factors for postoperative recurrence (POR) in Crohn’s disease (CD) including active inflammation, submucosal plexitis and transmural inflammation. Furthermore, granulomas and myenteric plexitis have been included as risk factor for POR in the current international guidelines. However, these factors have been identified in predominantly retrospective and older studies without adjustment for clinical risk factors.

Aims & Methods

This study aimed to assess the association between these histopathological features and early postoperative endoscopic recurrence in a large prospective, multicenter cohort study.
CD patients (≥16 years) scheduled for ileocolic (re-)resection (ICR) and those who underwent an ileocolonoscopy at 6 months following ICR were included. Primary outcome of the study was early postoperative endoscopic recurrence (ePOR)(modified Rutgeerts’ score ≥ i2b at 6 months). Proposed histopathological risk factors for postoperative recurrence were assessed in the ileal and colonic resection margins by expert pathologists blinded for clinical risk factors and outcome. Uni- and multivariable logistic regression was performed to explore the association of the histopathological features.

Results

In total, 293 patients (60% female; median age 33.3 years; primary resection 79%) underwent an ICR after a median disease duration of 5.2 (IQR 0.9–12.4). ePOR was observed in 37% of patients. At ICR, active smoking at surgery was reported in 22%. Isolated ileal location (64%) and stricturing disease (53%) were the most common disease location and behaviour at surgery. Postoperative prophylactic medication was initiated in 30% of patients (immunomodulator [IMM] 25%, anti-TNF agent with or without IMM 56%, vedolizumab 5% and ustekinumab 15%). Active inflammation, transmural inflammation, myenteric plexitis, submucosal plexitis and granulomas were reported at the ileal resection margin in 29%, 9%, 14%, 16% and 4%. At the colonic resection margin, the above mentioned parameters were reported in 9%, 2%, 7%, 8% and 3%. Univariate analyses identified associations for moderate to severe inflammation at the ileal (OR 2.3; 95%CI 1.3-4.0) and colonic resection margin (OR 3.7; 95%CI 1.3-10.3), submucosal plexitis at the ileal resection margin (OR 1.9; 95%CI 1.0-3.5) and transmural inflammation at the colonic resection margin (OR 10.7; 95%CI 1.3-90.5)(Table 1). In multivariable analysis, moderate to severe inflammation (aOR 4.6; 95%CI 1.1-19.5) at the colonic resection margin was associated with ePOR. No other histopathological features were significantly associated with ePOR in multivariable analysis. Active smoking was identified as risk factor (aOR 2.8; 95%CI 1.4-5.6), whereas postoperative prophylactic medication (aOR 0.3; 95%CI 0.2-0.7) and ileocolic disease at time of surgery (aOR 0.3; 95%CI 0.2-0.7) were identified as protective factors.

Conclusion

In this study, a predictive value of histopathological features in ICR specimens of CD patients for early POR has not been confirmed, with the exception of moderate to severe inflammation at the colonic resection margin. Therefore, there is a strong need for new biomarkers to adequately predict POR in patients with Crohn's disease.

Introduction

Side effects, patient preference, and high costs may prompt cessation of anti-TNF therapy in ulcerative colitis (UC) patients in sustained remission. Given the risk of relapse, careful patient selection is essential. This study aimed to assess relapse rates and identify predictors of relapse following anti-TNF cessation in UC patients in remission.

Aims & Methods

A systematic search on cohort studies reporting relapse rates after cessation of anti-TNF therapy in ≥30 UC patients in clinical remission was performed 6 September 2024. Individual patient data was requested. We excluded patients with steroid use, ≤6 months anti-TNF therapy, ≤16 years, previous colectomy (n=4), golimumab as anti-TNF therapy (n=3) or without follow-up. Continuation of treatment with immunomodulators or mesalamine at cessation of anti-TNF was allowed. Relapse was defined as the need to (re)start treatment with steroids, anti-TNF or other advanced therapies, or the need for surgical treatment, as applied by the original author. Pooled relapse rates were computed using a random-effects model. A prediction model was built with a Cox proportional hazards model, performance assessed by iteratively leaving one study out (internal-external cross-validation, IECV). Missing covariate data were multiply imputed 100 times using the MICE algorithm. Variable selection was guided by three criteria: ≤20% missing data, a univariate p-value ≤ 0.2, and input from clinical experts.

Results

In total, 654 patients from 8 studies were included in the individual participant data meta-analysis. At anti-TNF cessation, median age was 40 years (IQR 31-51) with a median anti-TNF treatment of 18 months (IQR 18-36). The majority of patients were treated with infliximab (n = 610, 93%). Only 42 patients (9%) received a second-line anti-TNF therapy. The pooled relapse rate were 24% [95% CI 19-29%, I² = 44%] and 34% [95% CI 29-40%, I² = 39] at 1 and 2 years after cessation, respectively. Upon cessation, 211 patients (33%) continued mesalamine, 239 (39%) thiopurines, and 136 (22%) a combination of both. In our model, thiopurine therapy and older age at cessation were associated with a reduced risk of relapse, whereas immunomodulator refractoriness as an indication for starting anti-TNF therapy was associated with an increased risk. Other factors included in the prediction model were disease extent, type of anti-TNF therapy, history of anti-TNF therapy, fecal calprotectin level and endoscopic activity, leading to a c statistic of 0.55 [95% CI 0.51-0.59] (Table 1).

Table 1: Predictors of relapse in a pooled Cox regression analysis

Conclusion

Approximately 1 in 4 patients experience a relapse of UC within 1 year after anti-TNF cessation, increasing to 1 in 3 within 2 years. Continuation of thiopurines is associated with a reduced risk. A prediction model for relapse was developed in this large IPD meta-analysis cohort and may aid in shared decision-making on anti-TNF cessation. However, its limited discriminative ability underscores the need for further refinement, incorporating data on microscopic remission and molecular and immunological markers to better capture deeper disease control.

Introduction

Histological assessment in Inflammatory Bowel Disease (IBD) is often required with endoscopic diagnoses to establish disease activity. This is evident in patients where histological healing is a major therapeutic goal and when endoscopic healing can also exhibit microscopic disease. IBD can manifest in numerous landmark features which are structural and inflammatory related. Histological activity is determined through erosion/ulceration, architectural changes in tissue morphology, mucin depletion and presence of varied inflammatory cells the colonic crypts, Muscularis Mucosae (MM) and Lamina Propria (LP). Histological scoring systems vary in complexity and methodology and subject to discrepancies in inter-rater consensus. Our model aims to provide accurate measurements of key histological features in Ulcerative Colitis (UC) used in scoring systems as both a decision support tool for improving pathologist scoring alignment and sensitive quantitative metrics of inflammatory cells to evaluate disease activity.

Aims & Methods

We developed an ensemble of convolutional neural networks to identify cell types, tissue foreground, crypts, MM, and haemorrhage in H&E images of IBD biopsy data. Models were trained with expert-labelled annotations comprising 34,289 image-annotation pairs (80% training, 20% validation) from in-house and publicly available data. Model accuracy was assessed with 6,464 held-out image-annotation pairs from 26 Whole Slide Images (WSIs) from all sites of the large intestine commonly sampled during endoscopic investigation, while ground truth annotations were reviewed by GI-trained pathologists to certify accuracy. We used geospatial methods to derive boundaries of the LP from other predicted domains, associate cells to delineated regions, measure architectural changes and derive spatially differentiated metrics of inflammatory burden in 66 patients with confirmed UC.

Results

The AI model spatially differentiates and segments cell types and tissue compartments. This produces metrics for inflammatory cell counts in regions of interest such as crypts, LP, and MM. Goblet cell segmentation within crypts allows for measurement of mucin depletion. This can be visualized for pathologists where each inflammatory cell type across the WSI is represented as density metrics. Automated quantification of inflammatory cells across AI-identified tissue domains throughout the bowels of UC patients revealed large intra- and inter-patient variability.

Conclusion

Our AI model can measure histological healing by detecting architectural change, inflammatory cell number, goblet cell reduction and erosions and ulceration. This allows for metrics and visual overlays to assist with pathologist reading and quantifying changes in mucosal biopsies in a clinical trial setting which requires extremely sensitive tools only AI can provide.

Disclosure

DW/AM/RL/PA/PW and CL are employees at Perspectum Ltd. EF and RG are consultants for Perspectum Ltd. All other co-authors have no conflicts of interest to declare relevant to this work.