Endoscopic characterization of neoplastic and non-neoplastic lesions in inflammatory bowel disease: systematic review in the era of advanced endoscopic imaging.

Background: Current guidelines strongly recommend the use of validated classifications to support optical diagnosis of lesions with advanced endoscopic imaging in the lower gastrointestinal tract. However, the optimal strategy in inflammatory bowel disease (IBD) is still a matter of debate. Objectives: To analyze the accuracy of endoscopic classifications or single predictors for in vivo lesion characterization during endoscopic surveillance of IBD with advanced endoscopic imaging. Design: Systematic review. Data sources and methods: Medline and PubMed were used to extract all studies which focused on lesion characterization of neoplastic and non-neoplastic lesions in IBD. The diagnostic accuracy of endoscopic classifications and single endoscopic predictors for lesion characterization were analyzed according to type of patients, lesions, and technology used. When available, the rates of true and false positives or negatives for neoplasia were pooled and the sensitivity (SE), specificity (SP), positive predictive value, and negative predictive value (NPV) were calculated. Results: We included 35 studies (2789 patients; 5925 lesions - 1149 neoplastic). Advanced endoscopic imaging included dye-based chromoendoscopy, virtual chromoendoscopy (VCE), magnification and high-definition endoscopy, confocal laser endomicroscopy (CLE), endocytoscopy, and autofluorescence imaging. The Kudo classification of pit patterns was most frequently used, with pooled SE 83%, SP 83%, and NPV 95%. The endoscopic criteria with the highest accuracy, with minimum SE ⩾ 90%, SP ⩾ 80%, and NPV ⩾ 90% were: the Kudo-IBD classification used with VCE (Fuji Intelligent Color Enhancement and i-SCAN); combined irregular surface and vascular patterns used with narrow band imaging; the Mainz classification used with CLE. Multiple clinical and technical factors were found to influence the accuracy of optical diagnosis in IBD. Conclusion: No single endoscopic factor has yet shown sufficient accuracy for lesion characterization in IBD surveillance. Conventional classifications developed in the non-IBD setting have lower accuracy in IBD. The use of new classifications adapted for IBD (Kudo-IBD), and new technologies based on in vivo microscopic analysis show promise.

Development of the Escalation of Therapy or Intervention (ETI) Calculator for Patients with Ulcerative Colitis Using ePROMs.

BACKGROUND AND AIMS: Digital collection of patient-reported outcome measures [PROMs] is largely unexplored as a basis for follow-up for patients with ulcerative colitis [UC]. Our aim was to develop a model to predict the likelihood of escalation of therapy or intervention at an outpatient appointment that may be used to rationalize follow-up. METHODS: TrueColours-IBD is a web-based, real-time, remote monitoring software that allows longitudinal collection of ePROMs. Data for prediction modelling were derived from a Development Cohort, guided by the TRIPOD statement. Logistic regression modelling used ten candidate items to predict escalation of therapy or intervention. An Escalation of Therapy or Intervention [ETI] calculator was developed, and applied in a Validation Cohort at the same centre. RESULTS: The Development Cohort [n = 66] was recruited in 2016 and followed for 6 months [208 appointments]. From ten items, four significant predictors of ETI were identified: SCCAI, IBD Control-8, faecal calprotectin, and platelets. For practicality, a model with only SCCAI and IBD Control-8, both entered remotely by the patient, without the need for faecal calprotectin or blood tests was selected. Between 2018 and 2020, a Validation Cohort of 538 patients [1188 appointments] was examined. A 5% threshold on the ETI calculator correctly identified 343/388 [88%] escalations and 274/484 [57%] non-escalations. CONCLUSIONS: A calculator based on digital, patient-entered data on symptoms and quality of life can predict whether a patient with UC requires escalation of therapy or intervention at an outpatient appointment. This may be used to streamline outpatient appointments for patients with UC.

Early management of acute severe UC in the biologics era: development and international validation of a prognostic clinical index to predict steroid response.

OBJECTIVES: We aimed to determine whether changes in acute severe colitis (ASC) management have translated to improved outcomes and to develop a simple model predicting steroid non-response on admission. DESIGN: Outcomes of 131 adult ASC admissions (117 patients) in Oxford, UK between 2015 and 2019 were compared with data from 1992 to 1993. All patients received standard treatment with intravenous corticosteroids and endoscopic disease activity scoring (Ulcerative Colitis Endoscopic Index of Severity (UCEIS)). Steroid non-response was defined as receiving medical rescue therapy or surgery. A predictive model developed in the Oxford cohort was validated in Australia and India (Gold Coast University Hospital 2015-2020, n=110; All India Institute of Medical Sciences, New Delhi 2018-2020, n=62). RESULTS: In the 2015-2019 Oxford cohort, 15% required colectomy during admission vs 29% in 1992-1993 (p=0.033), while 71 (54%) patients received medical rescue therapy (27% ciclosporin, 27% anti-tumour necrosis factor, compared with 27% ciclosporin in 1992-1993 (p=0.0015). Admission C reactive protein (CRP) (false discovery rate, p=0.00066), albumin (0.0066) and UCEIS scores (0.015) predicted steroid non-response. A four-point model was developed involving CRP of ≥100 mg/L (one point), albumin of ≤25 g/L (one point), and UCEIS score of ≥4 (1 point) or ≥7 (2 points). Patients scoring 0, 1, 2, 3 and 4 in the validation cohorts had steroid response rates of 100, 75.0%, 54.9%, 18.2% and 0%, respectively. Scoring of ≥3 was 84% (95% CI 0.70 to 0.98) predictive of steroid failure (OR 11.9, 95% CI 10.8 to 13.0). Colectomy rates in the validation cohorts were were 8%-11%. CONCLUSIONS: Emergency colectomy rates for ASC have halved in 25 years to 8%-15% worldwide. Patients who will not respond to corticosteroids are readily identified on admission and may be prioritised for early intensification of therapy.

Broad external validation of a multivariable risk prediction model for gastrointestinal malignancy in iron deficiency anaemia.

BACKGROUND: Using two large datasets from Dorset, we previously reported an internally validated multivariable risk model for predicting the risk of GI malignancy in IDA-the IDIOM score. The aim of this retrospective observational study was to validate the IDIOM model using two independent external datasets. METHODS: The external validation datasets were collected, in a secondary care setting, by different investigators from cohorts in Oxford and Sheffield derived under different circumstances, comprising 1117 and 474 patients with confirmed IDA respectively. The data were anonymised prior to analysis. The predictive performance of the original model was evaluated by estimating measures of calibration, discrimination and clinical utility using the validation datasets. RESULTS: The discrimination of the original model using the external validation data was 70% (95% CI 65, 75) for the Oxford dataset and 70% (95% CI 61, 79) for the Sheffield dataset. The analysis of mean, weak, flexible and across the risk groups' calibration showed no tendency for under or over-estimated risks in the combined validation data. Decision curve analysis demonstrated the clinical value of the IDIOM model with a net benefit that is higher than 'investigate all' and 'investigate no-one' strategies up to a threshold of 18% in the combined validation data, using a risk cut-off of around 1.2% to categorise patients into the very low risk group showed that none of the patients stratified in this risk group proved to have GI cancer on investigation in the validation datasets. CONCLUSION: This external validation exercise has shown promising results for the IDIOM model in predicting the risk of underlying GI malignancy in independent IDA datasets collected in different clinical settings.

Predicting Outcome in Acute Severe Colitis-Controversies in Clinical Practice in 2021.

Acute severe ulcerative colitis [ASUC] remains a common medical emergency, with 25% of patients with ulcerative colitis experiencing at least one event in their disease course. Despite advances in medical therapy, ASUC continues to be associated with considerable morbidity and mortality, with up to 30% of patients requiring colectomy during initial admission. Our aim was to review the current controversies and recent progress in risk stratification, prediction of outcome, and personalisation of care in ASUC. We re-assess the use of Truelove and Witts' criteria, serum biomarkers, and the use of composite clinical indices in current clinical practice. We explore the potential for endoscopic prediction using defined validated indices for accurate and early prognostication, and the need to define outcome. We also consider the impact of the current COVID-19 pandemic. Finally, we discuss the current research agenda, including the application of new and emerging biomarkers coupled with multi-omics and the implications in management and optimisation of outcome. Research priorities for the prediction of outcome in acute severe colitis include the following. 1. Development of an accurate admission score to guide early medical rescue therapy or colectomy. 2. Utility of point-of-care faecal calprotectin, with determination of optimal cut-off values. 3. Role of serum and faecal infliximab levels to both predict outcome and guide accelerated infliximab dosing. 4. Role of novel biomarkers, including serum calprotectin, in predicting response to corticosteroids or rescue therapy. 5. Specific predictors of response to ciclosporin and infliximab to allow rationalisation of drug use. 6. Utility of validated endoscopic scores. 7. Utility of radiological assessment beyond use of plain abdominal X-ray. 8. The use of multiomics and machine learning to predict risk of Acute Severe Colitis in patients with Ulcerative Colitis.

Targeted versus universal tuberculosis chemoprophylaxis in 1968 patients with inflammatory bowel disease receiving anti-TNF therapy in a tuberculosis endemic region.

BACKGROUND: Anti-tumour necrosis factor (anti-TNF) therapy increases the risk of tuberculosis (TB). Given limitations of screening techniques, it remains uncertain if patients receiving anti-TNF in TB endemic regions should be screened for latent infection with chemoprophylaxis restricted to those with proven infection, or if all patients should receive chemoprophylaxis. AIMS: To compare the incidence of active TB with infliximab (IFX) following targeted and universal TB chemoprophylaxis, and to determine the rates of adverse events (AE) related to TB chemoprophylaxis METHODS: A multi-centre retrospective cohort study was performed at 18 hospitals in China of 1968 adult patients with IBD receiving IFX from 2009 to 2017. TB screening prior to IFX was performed with chest X-ray and/or computed tomography [CT] and immune reactivity testing (interferon-γ release assay and/or tuberculin skin test). Patients were followed-up for a minimum of 3 months after IFX discontinuation, or until last hospital visit if IFX therapy was ongoing. Targeted strategy was defined as TB chemoprophylaxis only for patients with a positive latent TB screen, with universal strategy defined as TB chemoprophylaxis for all patients. RESULTS: Mean follow-up was 1.07 ± 0.87 years with a total follow-up of 2102 patient-years. There were 1433 patients in the targeted and 483 patients in the universal TB chemoprophylaxis groups, with no significant difference in the incidence rates of active TB between groups (673.3 per 100 000 population per year vs 891.5 per 100 000 population per year, P = 0.60). In the targeted group, 55/1433 patients received TB chemoprophylaxis compared with 483/483 in the universal group, with significantly fewer AEs related to TB chemoprophylaxis in the targeted compared to the universal group (0.35% (5/1433) vs 6.8% (33/483), P < 0.05). CONCLUSIONS: In this study of patients receiving IFX in a TB endemic area, universal chemoprophylaxis was not associated with a reduced risk of active TB when compared to a targeted chemoprophylaxis strategy, and AEs were more common. This supports the use of targeted TB chemoprophylaxis when anti-TNF therapy is initiated in TB endemic regions.

De-escalation of medical therapy in inflammatory bowel disease.

Treatment strategies for inflammatory bowel disease (IBD) now increasingly target deep remission, yet the resultant more aggressive use of medical therapy is associated with potentially serious adverse events and significant costs. It is, therefore, of vital importance to consider when, how and in whom medical therapy may be safely de-escalated. This issue is of great potential relevance in the current SARS-Cov-2 pandemic. In this review, we first discuss the rationale for drug withdrawal in IBD, before considering the available data on withdrawal of 5-aminosalicylates (5-ASA), immunomodulators (IM) and biological therapy in both ulcerative colitis (UC) and Crohn's Disease (CD). We consider how to identify patients most appropriate for drug withdrawal and outline a potential monitoring strategy for the early detection of relapse following drug withdrawal. We conclude with important future perspectives in this challenging field, and highlight ongoing trials that are likely to shape practice in the years to come.

Review article: withdrawal of 5-aminosalicylates in inflammatory bowel disease.

BACKGROUND: 5-aminosalicylates (5-ASA) are widely used in inflammatory bowel disease (IBD), but emerging evidence suggests that they may be safely withdrawn in significant subsets of patients. This is important to address: 5-ASA therapy accounts for up to 25% of total healthcare costs in ulcerative colitis (UC), while almost a third of patients with Crohn's disease (CD) receive long-term 5-ASA despite no clear evidence of benefit. Further, rationalising medication burden may improve overall adherence and outcome. AIMS: To summarise the rationale for 5-ASA withdrawal, review the current evidence in both UC and CD and consider the data surrounding colorectal cancer (CRC) prevention, guiding an evidence-based withdrawal strategy. METHODS: PubMed was searched to identify relevant studies. Only papers published in English were reviewed, with priority given to randomised clinical trials and meta-analyses. RESULTS: For patients with UC, consideration of 5-ASA withdrawal should be made on a case-by-case basis, but it appears safest for those in deep remission without any of the following risk factors: younger age (<40 years), remission for less than 2 years, a history of multiple flares, extensive disease. 5-ASA withdrawal should also be considered in patients with UC escalated to biologic therapy who have achieved remission and in all patients with CD. Although 5-ASA therapy may have chemopreventive benefits for CRC, the cost-benefit ratio appears significant, and this indication is not justified by evidence in those who have achieved remission and are continuing therapy with other agents, or in those in sustained remission without a history of extensive disease. CONCLUSIONS: Although the majority of patients with IBD receive 5-ASA during their disease course, safe withdrawal appears possible in many, with important implications for both health economics and patient experience. A number of unanswered questions, however, remain.

Real-world Effectiveness of Tofacitinib for Moderate to Severe Ulcerative Colitis: A Multicentre UK Experience.

BACKGROUND: Tofacitinib is a partially selective Janus kinase inhibitor approved for the treatment of refractory moderate to severe ulcerative colitis [UC]. We sought to define the effectiveness and adverse effects of tofacitinib in a real-world cohort. METHODS: We conducted a retrospective observational cohort study of 134 patients with UC [64% male; median age 37 years [range 16-81]; 83% of patients had previously received at least one biologic] treated with tofacitinib from October 2018 to October 2019 in four UK centres. Disease activity was assessed using the Simple Clinical Colitis Activity Index [SCCAI] or partial Mayo score [PMS], depending on study site. Response and remission were defined as a reduction in SCCAI or PMS of ≥3and SCCAI ≤2 or a PMS ≤1, respectively. RESULTS: Overall, 74% (88/119; 95 confidence interval [CI] 65-81%] patients responded to tofacitinib at Week 8 and steroid-free remission was observed in 44% [47/108; 95% CI 3453%] patients at Week 26. Primary non-response was independently associated with younger age [p = 0.014] and higher C-reactive protein [CRP] levels at baseline [p = 0.004]. Only 23% [3/13] of patients who continued tofacitinib in the setting of primary non-response were in steroid-free remission at Week 26. Prior biologic exposure did not influence response or remission rates. Dose escalation, however, recaptured response in approximately half of patients who had lost response. Dyslipidaemia was observed in 20% [27/134; 95% CI 1428%] of patients, but adverse events necessitating drug withdrawal were uncommon and no venous thromboembolic events occurred. CONCLUSIONS: In this multicentre real-world cohort, tofacitinib was well tolerated and clinically effective in a treatment-refractory UC population.

De-escalation of immunomodulator and biological therapy in inflammatory bowel disease.

Treatment strategies for inflammatory bowel disease (IBD) focus on the induction and long-term maintenance of deep remission to avoid complications of active disease and improve long-term outcomes. Medical therapies for IBD, notably the increasingly widespread use of biological therapy, are often effective at controlling disease, but these drugs are associated with substantial adverse events, which together with other factors-including increasing treatment costs and patient preferences-leads to concerns regarding indefinite use of medical therapy. Consequently, the need to consider the safety and feasibility of drug de-escalation once IBD remission has been achieved is clear. Here, we review the current evidence surrounding de-escalation of immunomodulator and biological therapy in Crohn's disease and ulcerative colitis. We discuss strategies for de-escalation, including the selection of patients who are appropriate for treatment de-escalation and the use of proactive drug monitoring, and review the evidence on subsequent optimal follow-up. We conclude by proposing an algorithm to guide de-escalation decisions, and highlight future perspectives, including the potential effect of emerging medication and personalised medicine for these diseases.

Ataxin-3 Links NOD2 and TLR2 Mediated Innate Immune Sensing and Metabolism in Myeloid Cells.

The interplay between NOD2 and TLR2 following recognition of components of the bacterial cell wall peptidoglycan is well-established, however their role in redirecting metabolic pathways in myeloid cells to degrade pathogens and mount antigen presentation remains unclear. We show NOD2 and TLR2 mediate phosphorylation of the deubiquitinase ataxin-3 via RIPK2 and TBK1. In myeloid cells ataxin-3 associates with the mitochondrial cristae protein MIC60, and is required for oxidative phosphorylation. Depletion of ataxin-3 leads to impaired induction of mitochondrial reactive oxygen species (mROS) and defective bacterial killing. A mass spectrometry analysis of NOD2/TLR2 triggered ataxin-3 deubiquitination targets revealed immunometabolic regulators, including HIF-1α and LAMTOR1 that may contribute to these effects. Thus, we define how ataxin-3 plays an essential role in NOD2 and TLR2 sensing and effector functions in myeloid cells.