Immune checkpoint inhibitor-associated gastrointestinal and hepatic adverse events and their management

BACKGROUND: Drug-induced colitis is a known complication of therapies that alter the immune balance, damage the intestinal barrier or disturb intestinal microbiota. Immune checkpoint inhibitors (ICI) directed against cancer cells may result in activated T lymphocyte-induced immune-related adverse events (AEs), including immune-related colitis and hepatitis. The aim of this review article is to summarize the incidence of gastrointestinal (GI) and hepatic AEs related to ICI therapy. We have also looked at the pathogenesis of immune-mediated AEs and propose management strategies based on current available evidence. METHODS: A literature search using PubMed and Medline databases was undertaken using relevant search terms pertaining to names of individual drugs, mechanism of action, related AEs and their management. RESULTS: ICI-related GI AEs are common, and colitis appears to be the most common side effect, with some studies reporting incidence as high as 30%. The incidence of both all-grade colitis and hepatitis were highest with combination therapy with anti-CTLA-4/PD-1; severity of colitis was dose-dependent (anti-CTLA-4). Early intervention is associated with better outcomes. CONCLUSION: ICI-related GI and hepatic AEs are common and clinicians need to be aware. Patients with GI AEs benefit from early diagnosis using endoscopy and computed tomography. Early intervention with oral steroids is effective in the majority of patients, and in steroid-refractory colitis infliximab and vedolizumab have been reported to be useful; mycophenolate has been used for steroid-refractory hepatitis

High-definition-iSCAN virtual chromoendoscopy has high sensitivity and specificity for the diagnosis of eosinophilic esophagitis

Abstract Background and study aims A major challenge in eosinophilic esophagitis (EoE) is disease recognition during endoscopy as there are no pathognomonic findings. We aimed to determine the utility of high-definition (HD) iSCAN virtual chromoendoscopy (VC) in diagnosis of EoE. Patients and methods One hundred eighty-nine consecutive patients presenting with dysphagia or food bolus impaction were assessed using HD-iSCAN VC (Pentax, Japan) with biopsies from distal, mid, upper esophagus and from furrows where visible. Results Of 189 patients, 45 (23.8 %, male = 29, median age 40y) had a histological diagnosis of EoE; 73.3 % of the patients were newly diagnosed. iSCAN endoscopic features of EoE were linear furrows (91 %), edema (77.8 %), rings or tracheal appearance (73.3 %), whitish exudates (26.6 %) and narrowing or stricture (5 %). One patient (2.2 %) had all 5 endoscopic features. Ten patients (22.2 %) had linear furrows, edema,rings or tracheal appearance and whitish exudates on iSCAN, with a positive predictive value (PPV) 100 % (95 % CI 69.1 %-100 %) and negative predictive value (NPV) 80.4 % (95 % CI 73.9 %-86 %). Thirteen patients (29 %) presented with linear furrows, edema and rings or tracheal appearance on iSCAN, with a PPV 100 % (95 % CI 75.3 %-100 %) and NPV 81.8 % (95 % CI 75.3 %-87.2 %). Six patients (13.3 %) had furrows and edema and 6 patients (13.3 %) had furrows and rings or tracheal appearance on iSCAN, with a PPV 100 % (95 % CI 54.1 %-100 %) and NPV 78.69 % (95 % CI 72 %-84.4 %), respectively. The sensitivity and specificity of HD-iSCAN endoscopy were 97.62 % (95 % CI 87.43 %-99.94 %) and 89.58 % (95 % CI 83.40 %-94.05 %). The accuracy of HD-iSCAN endoscopy was 92.47 % (95 % CI 87.67 %-95.56 %). Conclusion HD-iSCAN endoscopy is sensitive and specific with good accuracy for EoE diagnosis. Linear furrows, edema and tracheal appearance were the most common findings and these 3 endoscopic features had a high predictive value for diagnosis of EoE. </jats:p

Beyond white light:optical enhancement in conjunction with magnification colonoscopy for the assessment of mucosal healing in ulcerative colitis

Abstract Background and study aim The I-SCAN optical enhancement (OE) system with magnification is a recently introduced combination of optical and digital electronic virtual chromoendoscopy, which enhances mucosal and vascular details. The aim of this pilot study was to investigate the use of I-SCAN OE in the assessment of inflammatory changes in ulcerative colitis (UC). Patients and methods A total of 41 consecutive patients with UC and 9 control patients were examined by I-SCAN OE (Pentax Medical, Tokyo, Japan). Targeted biopsies of the imaged areas were obtained. A new optical enhancement score focusing on mucosal and vascular changes was developed. The diagnostic accuracy of I-SCAN OE was calculated against histology using two UC histological scores – Robarts Histopathology Index (RHI) and ECAP (Extent, Chronicity, Activity, Plus additional findings). Results The overall I-SCAN OE score correlated with ECAP (r = 0.70; P &lt; 0.001). The accuracy of the overall I-SCAN OE score to detect abnormalities by ECAP was 80 % (sensitivity 78 %, specificity 100 %). I-SCAN OE vascular and mucosal scores correlated with ECAP (r = 0.65 and 0.71, respectively; P &lt; 0.001). The correlation between overall I-SCAN OE score and RHI was r = 0.61 (P &lt; 0.01), and the accuracy to detect abnormalities by RHI was 68 % (sensitivity 78 %, specificity 50 %). The majority of patients with Mayo 0 had abnormalities on I-SCAN OE. Conclusion In UC, the new I-SCAN OE technology accurately identified mucosal inflammation, and correlated well with histological scores of chronic and acute changes.</jats:p

PICaSSO Histologic Remission Index (PHRI) in ulcerative colitis: development of a novel simplified histological score for monitoring mucosal healing and predicting clinical outcomes and its applicability in an artificial intelligence system

[EN] Histological remission is evolving as an important treatment target in UC. We aimed to develop a simple histological index, aligned to endoscopy, correlated with clinical outcomes, and suited to apply to an artificial intelligence (AI) system to evaluate inflammatory activity. Methods Using a set of 614 biopsies from 307 patients with UC enrolled into a prospective multicentre study, we developed the Paddington International virtual ChromoendoScopy ScOre (PICaSSO) Histologic Remission Index (PHRI). Agreement with multiple other histological indices and validation for inter-reader reproducibility were assessed. Finally, to implement PHRI into a computer-aided diagnosis system, we trained and tested a novel deep learning strategy based on a CNN architecture to detect neutrophils, calculate PHRI and identify active from quiescent UC using a subset of 138 biopsies. Results PHRI is strongly correlated with endoscopic scores (Mayo Endoscopic Score and UC Endoscopic Index of Severity and PICaSSO) and with clinical outcomes (hospitalisation, colectomy and initiation or changes in medical therapy due to UC flare-up). A PHRI score of 1 could accurately stratify patients' risk of adverse outcomes (hospitalisation, colectomy and treatment optimisation due to flare-up) within 12 months. Our inter-reader agreement was high (intraclass correlation 0.84). Our preliminary AI algorithm differentiated active from quiescent UC with 78% sensitivity, 91.7% specificity and 86% accuracy. Conclusions PHRI is a simple histological index in UC, and it exhibits the highest correlation with endoscopic activity and clinical outcomes. A PHRI-based AI system was accurate in predicting histological remission.MI and SG are funded by the NIHR Birmingham Biomedical Research Centre at the University Hospitals Birmingham NHS Foundation Trust and the University of Birmingham.Gui, X.; Alina Bazarova; Del Amor, R.; Vieth, M.; De Hertogh, G.; Villanacci, V.; Zardo, D.... (2022). PICaSSO Histologic Remission Index (PHRI) in ulcerative colitis: development of a novel simplified histological score for monitoring mucosal healing and predicting clinical outcomes and its applicability in an artificial intelligence system. Gut. 71:889-898. https://doi.org/10.1136/gutjnl-2021-3263768898987

Involvement of mast cells in basal and neurotensin-induced intestinal absorption of taurocholate in rats

Neurotensin (NT), a hormone released from intestine by ingested fat, facilitates lipid digestion by stimulating pancreatic secretion and slowing the movement of chyme. In addition, NT can contract the gall bladder and enhance the enterohepatic circulation (EHC) of bile acids to promote micelle formation. Our recent finding that NT enhanced and an NT antagonist inhibited [(3)H]taurocholate ([(3)H]TC) absorption from proximal rat small intestine indicated a role for endogenous NT in the regulation of EHC. Here, we postulate the involvement of intestinal mast cells in the TC uptake process and in the stimulatory effect of NT. In anesthetized rats with the bile duct cannulated for bile collection, infusion of NT (10 pmol.kg(-1).min(-1)) enhanced the [(3)H]TC recovery rate from duodenojejunum by 2.2-fold. This response was abolished by pretreatment with mast cell stabilizers (cromoglycate, doxantrazole) and inhibitors of mast cell mediators (diphenhydramine, metergoline, zileuton). In contrast, mast cell degranulators (compound 48/80, substance P) and mast cell mediators (histamine, leukotriene C(4)) reproduced the effect of NT. N(G)-nitro-l-arginine methyl ester enhanced and l-arginine inhibited basal and NT-induced TC uptake, consistent with the known inhibitory effect of nitric oxide (NO) on mast cell reactivity. These results argue that basal and NT-stimulated TC uptake in rat jejunum are similarly dependent on mast cells, are largely mediated by release of mast cell mediators, and are subject to regulation by NO