An international RAND/UCLA expert panel to determine the optimal diagnosis and management of burn inhalation injury.

BACKGROUND: Burn inhalation injury (BII) is a major cause of burn-related mortality and morbidity. Despite published practice guidelines, no consensus exists for the best strategies regarding diagnosis and management of BII. A modified DELPHI study using the RAND/UCLA (University of California, Los Angeles) Appropriateness Method (RAM) systematically analysed the opinions of an expert panel. Expert opinion was combined with available evidence to determine what constitutes appropriate and inappropriate judgement in the diagnosis and management of BII. METHODS: A 15-person multidisciplinary panel comprised anaesthetists, intensivists and plastic surgeons involved in the clinical management of major burn patients adopted a modified Delphi approach using the RAM method. They rated the appropriateness of statements describing diagnostic and management options for BII on a Likert scale. A modified final survey comprising 140 statements was completed, subdivided into history and physical examination (20), investigations (39), airway management (5), systemic toxicity (23), invasive mechanical ventilation (29) and pharmacotherapy (24). Median appropriateness ratings and the disagreement index (DI) were calculated to classify statements as appropriate, uncertain, or inappropriate. RESULTS: Of 140 statements, 74 were rated as appropriate, 40 as uncertain and 26 as inappropriate. Initial intubation with ≥ 8.0 mm endotracheal tubes, lung protective ventilatory strategies, initial bronchoscopic lavage, serial bronchoscopic lavage for severe BII, nebulised heparin and salbutamol administration for moderate-severe BII and N-acetylcysteine for moderate BII were rated appropriate. Non-protective ventilatory strategies, high-frequency oscillatory ventilation, high-frequency percussive ventilation, prophylactic systemic antibiotics and corticosteroids were rated inappropriate. Experts disagreed (DI ≥ 1) on six statements, classified uncertain: the use of flexible fiberoptic bronchoscopy to guide fluid requirements (DI = 1.52), intubation with endotracheal tubes of internal diameter < 8.0 mm (DI = 1.19), use of airway pressure release ventilation modality (DI = 1.19) and nebulised 5000IU heparin, N-acetylcysteine and salbutamol for mild BII (DI = 1.52, 1.70, 1.36, respectively). CONCLUSIONS: Burns experts mostly agreed on appropriate and inappropriate diagnostic and management criteria of BII as in published guidance. Uncertainty exists as to the optimal diagnosis and management of differing grades of severity of BII. Future research should investigate the accuracy of bronchoscopic grading of BII, the value of bronchial lavage in differing severity groups and the effectiveness of nebulised therapies in different severities of BII.

RAND appropriateness panel to determine the applicability of UK guidelines on the management of acute respiratory distress syndrome (ARDS) and other strategies in the context of the COVID-19 pandemic.

BACKGROUND: COVID-19 has become the most common cause of acute respiratory distress syndrome (ARDS) worldwide. Features of the pathophysiology and clinical presentation partially distinguish it from 'classical' ARDS. A Research and Development (RAND) analysis gauged the opinion of an expert panel about the management of ARDS with and without COVID-19 as the precipitating cause, using recent UK guidelines as a template. METHODS: An 11-person panel comprising intensive care practitioners rated the appropriateness of ARDS management options at different times during hospital admission, in the presence or absence of, or varying severity of SARS-CoV-2 infection on a scale of 1-9 (where 1-3 is inappropriate, 4-6 is uncertain and 7-9 is appropriate). A summary of the anonymised results was discussed at an online meeting moderated by an expert in RAND methodology. The modified online survey comprising 76 questions, subdivided into investigations (16), non-invasive respiratory support (18), basic intensive care unit management of ARDS (20), management of refractory hypoxaemia (8), pharmacotherapy (7) and anticoagulation (7), was completed again. RESULTS: Disagreement between experts was significant only when addressing the appropriateness of diagnostic bronchoscopy in patients with confirmed or suspected COVID-19. Adherence to existing published guidelines for the management of ARDS for relevant evidence-based interventions was recommended. Responses of the experts to the final survey suggested that the supportive management of ARDS should be the same, regardless of a COVID-19 diagnosis. For patients with ARDS with COVID-19, the panel recommended routine treatment with corticosteroids and a lower threshold for full anticoagulation based on a high index of suspicion for venous thromboembolic disease. CONCLUSION: The expert panel found no reason to deviate from the evidence-based supportive strategies for managing ARDS outlined in recent guidelines.

Effectiveness and Safety of Ustekinumab in Inflammatory Bowel Disease: A Systematic Review and Meta-Analysis.

INTRODUCTION: Ustekinumab, an interleukin-12 and interleukin-23 antagonist, is licensed for the treatment of Crohn's disease (CD) and ulcerative colitis (UC) after the phase III trial programs demonstrated efficacy over placebo. However, these findings may not be directly transferable to the real-world due to the stringent inclusion criteria of clinical trials. METHODS: We conducted a systematic review and meta-analysis of the safety and effectiveness of ustekinumab in inflammatory bowel disease (IBD). A systematic literature search was conducted via Medline and Embase from inception to April 21, 2020. Observational studies assessing ustekinumab's safety and effectiveness by reporting response, remission and/or adverse events (AE) in either CD or UC were included. Two reviewers independently assessed risk of bias and extracted study data. Random-effects meta-analysis was performed to pool rates of clinical response, remission, and safety data. RESULTS: Following deduplication, 2147 records were identified of which 41 studies (38 CD, 3 UC) comprising 4400 patients were included for quantitative analysis. Pooled clinical remission rates for CD were 34% (95% CI, 26%-42%) following induction and 31% (95% CI, 25%-38%) at one year. For UC, post-induction clinical remission rates were 39% (95% CI, 23%-56%). Serious AEs were reported in 5.6% of patients. Pregnancy outcomes were similar to the general population. One-third of patients with active baseline perianal disease responded or had fistula healing with ustekinumab. CONCLUSIONS: In the most comprehensive systematic review and meta-analysis to date, and the first to include UC, ustekinumab was shown to be effective and safe in the real-world treatment of IBD.

Adaptations to the current ECCO/ESPGHAN guidelines on the management of paediatric acute severe colitis in the context of the COVID-19 pandemic: a RAND appropriateness panel.

OBJECTIVE: Paediatric acute severe colitis (ASC) management during the novel SARS-CoV-2/COVID-19 pandemic is challenging due to reliance on immunosuppression and the potential for surgery. We aimed to provide COVID-19-specific guidance using the European Crohn's and Colitis Organisation/European Society for Paediatric Gastroenterology, Hepatology and Nutrition guidelines for comparison. DESIGN: We convened a RAND appropriateness panel comprising 14 paediatric gastroenterologists and paediatric experts in surgery, rheumatology, respiratory and infectious diseases. Panellists rated the appropriateness of interventions for ASC in the context of the COVID-19 pandemic. Results were discussed at a moderated meeting prior to a second survey. RESULTS: Panellists recommended patients with ASC have a SARS-CoV-2 swab and expedited biological screening on admission and should be isolated. A positive swab should trigger discussion with a COVID-19 specialist. Sigmoidoscopy was recommended prior to escalation to second-line therapy or colectomy. Methylprednisolone was considered appropriate first-line management in all, including those with symptomatic COVID-19. Thromboprophylaxis was also recommended in all. In patients requiring second-line therapy, infliximab was considered appropriate irrespective of SARS-CoV-2 status. Delaying colectomy due to SARS-CoV-2 infection was considered inappropriate. Corticosteroid tapering over 8-10 weeks was deemed appropriate for all. After successful corticosteroid rescue, thiopurine maintenance was rated appropriate in patients with negative SARS-CoV-2 swab and asymptomatic patients with positive swab but uncertain in symptomatic COVID-19. CONCLUSION: Our COVID-19-specific adaptations to paediatric ASC guidelines using a RAND panel generally support existing recommendations, particularly the use of corticosteroids and escalation to infliximab, irrespective of SARS-CoV-2 status. Consideration of routine prophylactic anticoagulation was recommended.

Adaptations to the British Society of Gastroenterology guidelines on the management of acute severe UC in the context of the COVID-19 pandemic: a RAND appropriateness panel.

OBJECTIVE: Management of acute severe UC (ASUC) during the novel COVID-19 pandemic presents significant dilemmas. We aimed to provide COVID-19-specific guidance using current British Society of Gastroenterology (BSG) guidelines as a reference point. DESIGN: We convened a RAND appropriateness panel comprising 14 gastroenterologists and an IBD nurse consultant supplemented by surgical and COVID-19 experts. Panellists rated the appropriateness of interventions for ASUC in the context of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection. Median scores and disagreement index (DI) were calculated. Results were discussed at a moderated meeting prior to a second survey. RESULTS: Panellists recommended that patients with ASUC should be isolated throughout their hospital stay and should have a SARS-CoV-2 swab performed on admission. Patients with a positive swab should be discussed with COVID-19 specialists. As per BSG guidance, intravenous hydrocortisone was considered appropriate as initial management; only in patients with COVID-19 pneumonia was its use deemed uncertain. In patients requiring rescue therapy, infliximab with continuing steroids was recommended. Delaying colectomy because of COVID-19 was deemed inappropriate. Steroid tapering as per BSG guidance was deemed appropriate for all patients apart from those with COVID-19 pneumonia in whom a 4-6 week taper was preferred. Post-ASUC maintenance therapy was dependent on SARS-CoV-2 status but, in general, biologics were more likely to be deemed appropriate than azathioprine or tofacitinib. Panellists deemed prophylactic anticoagulation postdischarge to be appropriate in patients with a positive SARS-CoV-2 swab. CONCLUSION: We have suggested COVID-19-specific adaptations to the BSG ASUC guideline using a RAND panel.

Reliability among central readers in the evaluation of endoscopic disease activity in pouchitis.

BACKGROUND AND AIMS: Pouchitis is a common adverse event after proctocolectomy with ileal pouch anal anastomosis for ulcerative colitis. Evaluation of pouchitis disease activity and response to treatment requires use of validated indices. We assessed the reliability of items evaluating endoscopic pouchitis disease activity. METHODS: Twelve panelists used a modified RAND appropriateness methodology to rate the appropriateness of items evaluating endoscopic pouchitis disease activity derived from a systematic review and also identified additional potential endoscopic items based on expert opinion. Four central readers then evaluated 50 pouchoscopy videos in triplicate, in random order. Intra- and inter-rater reliability for each item was assessed by calculating and comparing intraclass correlation coefficients (ICCs). A Delphi process identified common sources of disagreement among the readers. RESULTS: Ten existing endoscopic items were identified from the systematic review and an additional 7 exploratory items from the panelists. ICCs for inter-rater reliability were highest for the existing item of pouch ulceration (.72; 95% confidence interval [CI], .60-.82) and for the exploratory item of ulcerated surface in the pouch body (.67; 95% CI, .53-.75). Inter-rater reliability for all other existing and exploratory items was "moderate" (ICC < .60). The item "ulcerated surface in the pouch body" demonstrated the best correlation with a global evaluation of lesion severity (r = .80; 95% CI, .73-.85). CONCLUSION: Substantial reliability was observed only for the endoscopic items of ulceration and ulcerated surface in the pouch body. Future studies should assess responsiveness to treatment in the next stage toward development of an endoscopic pouchitis disease activity index.

Long term outcomes of initial infliximab therapy for inflammatory pouch pathology: a multi-Centre retrospective study.

BACKGROUND: Restorative proctocolectomy with ileal pouch-anal anastomosis is considered the procedure of choice in patients with ulcerative colitis refractory to medical therapy. Subsequent inflammation of the pouch is a common complication and in some cases, pouchitis fails to respond to antibiotics, the mainstay of treatment. In such cases, corticosteroids, immunomodulatory or biologic treatments are options. However, our understanding of the efficacy of anti-tumour necrosis factor medications in both chronic pouchitis and Crohn's-like inflammation is based on studies that include relatively small numbers of patients. METHODS: This was an observational, retrospective, multi-centre study to assess the long-term effectiveness and safety of infliximab (IFX) for inflammatory disorders related to the ileoanal pouch. The primary outcome was the development of IFX failure defined by early failure to IFX or secondary loss of response to IFX. RESULTS: Thirty-four patients met the inclusion criteria; 18/34 (53%) who were initiated on IFX for inflammatory disorders of the pouch had IFX failure, 3/34 (8%) had early failure and 15/34 (44%) had secondary loss of response with a median follow-up of 280 days (range 3-47 months). In total, 24/34 (71%) avoided an ileostomy by switching to other medical therapies at a median follow-up of 366 days (1-130 months). CONCLUSIONS: Initial IFX therapy for pouch inflammatory conditions is associated with IFX failure in just over half of all patients. Despite a high failure rate, an ileostomy can be avoided in almost three-quarters of patients at four years by using other medical therapies.

Endoscopic scoring indices for evaluation of disease activity in ulcerative colitis.

BACKGROUND: Endoscopic assessment of mucosal disease activity is routinely used to determine eligibility and response to therapy in clinical trials of ulcerative colitis. The operating properties of the existing endoscopic scoring indices are unclear. OBJECTIVES: A systematic review was undertaken to evaluate the development and operating characteristics of endoscopic scoring indices for the evaluation of ulcerative colitis. SEARCH METHODS: We searched MEDLINE, Embase and CENTRAL from inception to 5 July 2016. We also searched references and conference proceedings (Digestive Disease Week, United European Gastroenterology Week, European Crohn's and Colitis Organization). SELECTION CRITERIA: Any study design (e.g. randomized controlled trials, cohort studies, case series) that evaluated endoscopic indices for evaluation of ulcerative colitis disease activity were considered for inclusion. Eligible participants were adult patients (> 16 years), diagnosed with ulcerative colitis using conventional clinical, radiologic and endoscopic criteria. DATA COLLECTION AND ANALYSIS: Two authors independently reviewed the studies identified from the literature search. These authors also independently extracted and recorded data on the number of patients enrolled; number of patients per treatment arm; patient characteristics including age and gender distribution; endoscopic index; and outcomes such as reliability (intra-rater and inter-rater), validity (content, construct, criterion), responsiveness and feasibility. Any disagreements regarding study inclusion or data extraction were resolved by discussion and consensus with a third author. Risk of bias was assessed by determining whether assessors were blinded to clinical information and whether assessors scored the endoscopic index independently. We also assessed the methodological quality of the validation studies using the COSMIN checklist MAIN RESULTS: A total of 23 reports of 20 studies met the pre-defined inclusion criteria and were included in the review. Of the 20 included validation studies, 19 endoscopic scoring indices were assessed, including the Azzolini Classification, Baron Score, Blackstone Endoscopic Interpretation, Chinese Grading System of Ulcerative Colitis, Endoscopic Activty Index, Jeroen Score, Magnifying Colonoscopy Grade, Matts Score, Mayo Clinic Endoscopic Subscore, Modified Baron Score, Modified Mayo Clinic Endoscopic Subscore, Osada Score, Rachmilewtiz Endoscopic Score, St. Mark's Index, Ulcerative Colitis Colonoscopic Index of Serverity (UCCIS), endoscopic component of the Ulcerative Colitis Disease Activity Index (UCDAI), Ulcerative Colitis Endoscopic Index of Severity (UCEIS), Witts Sigmoidoscopic Score and Watson Grade. The individuals who performed the endoscopic scoring were blinded to clinical and/or histologic information in ten of the included studies, not blinded to clinical and/or histologic information in one of the included studies, and it was unclear whether blinding occurred in the remaining nine included studies. Independent observation was confirmed in four of the included studies, unclear in five of the included studies, and non-applicable (since inter-rater reliability was not assessed) in the remaining eleven included studies. The methodological quality (COSMIN checklist) of most of the included studies was rated as 'good' or 'excellent'. One study that assessed responsiveness was rated as 'fair'. The inter-rater reliability of nine endoscopic scoring indices including the Baron Score, Blackstone Endoscopic Interpretation, Endoscopic Activity Index, Matts Score, Mayo Clinic Endoscopic Subscore, Osada Score, UCCIS, UCEIS, Watson Grade was assessed in seven studies, with estimates of correlation, ƙ, ranging from 0.44 to 0.97. The iIntra-rater reliability of seven endoscopic scoring indices including the Baron Score, Blackstone Endoscopic Interpretation, Matts Score, Mayo Clinic Endoscopic Subscore, Osada Score, UCCIS and UCEIS was assessed in three studies, with estimates of correlation, ƙ, ranging from 0.41 to 0.86. No studies assessed content validity. Three studies evaluated the criterion validity of three endoscopic scoring indices including the Rachmilewitz Endoscopic Score, Magnifying Colonoscopy Grade and the UCCIS. These indices were correlated with objective markers of disease activity including albumin, blood leukocytes, C-reactive protein, fecal calprotectin, hemoglobin, mucosal interleukin-8 concentration and platelet count. Correlation estimates ranged from r = -0.19 to 0.83. Thirteen endoscopic scoring indices were tested for construct validity in 13 studies. Estimates of correlation between the endoscopic scoring indices and other measures of disease activity ranged from r = 0.27 to 0.93. Two studies explored the responsiveness of four endoscopic scoring indices including the Mayo Endoscopic Subscore, Modified Baron Score, Modified Mayo Endoscopic Subscore and UCEIS. One study concluded that the Modified Baron Score, Modified Mayo Endoscopic Subscore and UCEIS had similar responsiveness for detecting disease change in ulcerative colitis. The other included study concluded that the UCEIS may be the most accurate endoscopic scoring tool. None of the included studies formally assessed feasibility. AUTHORS' CONCLUSIONS: While the UCEIS, UCCIS and Mayo Clinic Endoscopic Subscore have undergone extensive validation, none of these instruments have been fully validated and only two studies assessed responsiveness. Further research on the operating properties of these indices is needed given the lack of a fully-validated endoscopic scoring instrument for the evaluation of disease activity in ulcerative colitis.

Development and validation of a histological index for UC.

OBJECTIVE: Although the Geboes score (GS) and modified Riley score (MRS) are commonly used to evaluate histological disease activity in UC, their operating properties are unknown. Accordingly, we developed an alternative instrument. DESIGN: Four pathologists scored 48 UC colon biopsies using the GS, MRS and a visual analogue scale global rating. Intra-rater and inter-rater reliability for each index and individual index items were measured using intraclass correlation coefficients (ICCs). Items with high reliability were used to develop the Robarts histopathology index (RHI). The responsiveness/validity of the RHI and multiple histological, endoscopic and clinical outcome measures were evaluated by analyses of change scores, standardised effect size (SES) and Guyatt's responsiveness statistic (GRS) using data from a clinical trial of an effective therapy. RESULTS: Inter-rater ICCs (95% CIs) for the total GS and MRS scores were 0.79 (0.63 to 0.87) and 0.80 (0.69 to 0.87). The correlation estimates between change scores in RHI and change score in GS and MRS were 0.75 (0.67 to 0.82) and 0.84 (0.79 to 0.88), respectively. The SES and GRS estimates for GS, MRS and RHI were: 1.87 (1.54 to 2.20) and 1.23 (0.97 to 1.50), 1.29 (1.02 to 1.56) and 0.88 (0.65 to 1.12), and 1.05 (0.79 to 1.30) and 0.88 (0.64 to 1.12), respectively. CONCLUSIONS: The RHI is a new histopathological index with favourable operating properties.

Placebo response and remission rates in randomised trials of induction and maintenance therapy for ulcerative colitis.

BACKGROUND: It is important to minimize placebo rates in randomised controlled trials (RCTs) to efficiently detect treatment differences between interventions. Historically, high placebo rates have been observed in clinical trials of ulcerative colitis (UC). A better understanding of factors influencing placebo rates may lead to more informed clinical trial design. OBJECTIVES: A systematic review and meta-analysis was conducted to evaluate placebo response and remission rates in RCTs evaluating UC treatments in adult patients. SEARCH METHODS: Electronic databases (i.e. MEDLINE, EMBASE, and CENTRAL) were searched from inception to 1 March 2017 with no language restrictions applied. Reference lists and conference proceedings of major gastroenterology meetings were also handsearched to identify additional studies. SELECTION CRITERIA: Placebo-controlled RCTs of adult patients with UC treated with corticosteroids, aminosalicylates, immunosuppressives or biologics were eligible, provided enrolment and outcome assessment was conducted using the Ulcerative Colitis Disease Activity Index (UCDAI) or the Mayo Clinic Score. The minimum trial duration was two weeks for induction trials and four months maintenance trials. DATA COLLECTION AND ANALYSIS: Pairs of authors independently determined study eligibility and extracted data with any disagreements resolved through consensus. Outcomes of interest included the proportion of patients with clinical response and remission. Trial characteristics such as the design, participant demographics and disease history, interventions, and enrolment and assessment criteria were also recorded. The methodological quality of the included studies was evaluated using the Cochrane risk of bias tool. Pooled placebo response and remission rates and 95% confidence intervals (95% CI) were calculated using a binomial normal model for proportions. Induction of remission and maintenance studies were pooled separately. The impact of study-level characteristics on placebo response and remission rates was investigated using mixed-effects meta-regression analyses with logits of event rates as the outcome variables. An assessment of pooled placebo rates over time was conducted using a cumulative meta-analysis based on date of publication. Publication bias was examined using funnel plots. MAIN RESULTS: The screening process identified 61 included studies which encompass 58 induction phases (5111 patients randomised to placebo) and 12 maintenance phases (1579 patients randomised to placebo). For induction trials, the pooled estimate of placebo response was 33% (95% CI 30% to 36%) while the pooled estimate of placebo remission was 12% (95% CI 9% to 15%). For maintenance trials, the pooled estimate of placebo response was 23% (95% CI 19% to 28%) while the pooled estimate of placebo remission was 17% (95% CI 10% to 27%).Studies enrolling patients with more active disease confirmed objectively by endoscopy were associated with significantly lower placebo remission and response rates than trials enrolling patients with less active disease (27% versus 4%, OR 2.60, 95% CI 1.25 to 5.42, P = 0.01 for UCDAI endoscopy sub score ≥1 versus ≥ 2 for remission; and 27% versus 4%, OR 1.70, 95% CI 1.02 to 2.82, P = 0.02 for UCDAI endoscopy sub score greater than or equal to one versus greater than or equal to two for response). With respect to drug class, the lowest placebo response and remission rates were observed in trials evaluating corticosteroids (23%; 95% CI 19 to 29%, and 5%; 95% CI 2 to 11%, respectively). Trials of biologics had the highest placebo response rate (35%; 95% CI 30 to 41%), while trials evaluating aminosalicylates had the highest placebo remission rate (18%; 95% CI 12 to 24%). Disease duration of greater than five years prior to enrolment was associated with a significantly lower placebo response rate compared to disease duration of less than or equal to five years (29% versus 47%, respectively; OR 0.54, 95% CI 0.32 to 0.92, P = 0.02). The requirement of a minimum rectal bleeding score for study eligibility was associated with an increased placebo response rate compared to studies that did not use rectal bleeding for trial eligibility (37% versus 32%, respectively; OR 1.70, 95% CI 1.02 to 2.82, P = 0.02). Finally, the time point of primary outcome assessment was found to be significantly associated with placebo remission rates such that every one week increment in endpoint assessment was associated with a 6% increase in the placebo remission rate (OR 1.06, 95% CI 1.02 to 1.10, P = 0.01).Cumulative meta-analysis indicated a consistent increase in the placebo response rate from 1987 to 2007 (from 13% to 33%), although rates have remained constant from 2008 to 2015 (32% to 34%). Similarly, placebo remission rates increased from 1987 to 2007 (5% to 14%) but have remained constant from 2008 to 2015 (12 to 14%). On meta-regression, there were no statistically significant differences between the 1987-2007 and 2008-2015 point estimates for both response (P = 0.81) and remission (P = 0.32). AUTHORS' CONCLUSIONS: Placebo response and remission rates vary according to endoscopic disease severity and rectal bleeding score at trial entry, class of agent, disease duration, and the time point at which the primary outcome was measured. These observations have important implications for the design and conduct of future clinical trials in UC and will help researchers design trials, determine required sample sizes and also provide useful information about trial design features which should be considered when planning new trials.

Reproducibility of histological assessments of disease activity in UC.

OBJECTIVE: Histopathology is potentially an important outcome measure in UC. Multiple histological disease activity (HA) indices, including the Geboes score (GS) and modified Riley score (MRS), have been developed; however, the operating properties of these instruments are not clearly defined. We assessed the reproducibility of existing measures of HA. DESIGN: Five experienced pathologists with GI pathology fellowship training and expertise in IBD evaluated, on three separate occasions at least two weeks apart, 49 UC colon biopsies and scored the GS, MRS and a global rating of histological severity using a 100 mm visual analogue scale (VAS). The reproducibility of each grading system and for individual instrument items was quantified by estimates of intraclass correlation coefficients (ICCs) based on two-way random effects models. Uncertainty of estimates was quantified by 95% two-sided CIs obtained using the non-parametric cluster bootstrap method. Biopsies responsible for the greatest disagreement based on the ICC estimates were identified. A consensus process was used to determine the most common sources of measurement disagreement. Recommendations for minimising disagreement were subsequently generated. RESULTS: Intrarater ICCs (95% CIs) for the total GS, MRS and VAS scores were 0.82 (0.73 to 0.88), 0.71 (0.63 to 0.80) and 0.79 (0.72 to 0.85), respectively. Corresponding inter-rater ICCs were substantially lower: 0.56 (0.39 to 0.67), 0.48 (0.35 to 0.66) and 0.61 (0.47 to 0.72). Correlation between the GS and VAS was 0.62 and between the MRS and VAS was 0.61. CONCLUSIONS: Although 'substantial' to 'almost perfect' ICCs for intrarater agreement were found in the assessment of HA in UC, ICCs for inter-rater agreement were considerably lower. According to the consensus process results, standardisation of item definitions and modification of the existing indices is required to create an optimal UC histological instrument.

Safety and Feasibility of Using the Second-Generation Pillcam Colon Capsule to Assess Active Colonic Crohn's Disease.

BACKGROUND & AIMS: The second-generation Pillcam Colon Capsule Endoscope (PCCE-2; Given Imaging Ltd, Yoqneam, Israel) is an ingestible capsule for visualization of the colon. We performed a multicenter pilot study to assess its safety and feasibility in evaluating the severity of Crohn's disease (CD). METHODS: In a prospective study, 40 patients with active colonic CD underwent PCCE-2 and optical colonoscopy procedures. Using both techniques, we generated values for the Crohn's Disease Endoscopic Index of Severity (CDEIS), the Simple Endoscopic Score for CD, and global evaluation of lesion severity. In the first stage of the study, we calculated the correlation between PCCE-2 and optical colonoscopy scores. In the second stage, we performed interobserver agreement analysis for a random subset of 20 PCCE-2 recordings, graded in duplicate by 2 independent readers. RESULTS: There was substantial agreement between PCCE-2 and optical colonoscopy in the measurement of the CDEIS (intraclass correlation coefficient [ICC], 0.65; 95% confidence interval [CI], 0.43-0.80). There was substantial interobserver agreement between 2 independent PCCE-2 readers for the CDEIS (ICC, 0.67; 95% CI, 0.35-0.86) and the Simple Endoscopic Score for CD (ICC, 0.66; 95% CI, 0.32-0.85). However, the PCCE-2 scoring systematically underestimated the severity of disease compared with optical colonoscopy; based on our results, PCCE-2 detected colonic ulcerations with 86% sensitivity and 40% specificity. No adverse events were observed and PCCE-2 was better tolerated than colonoscopy. CONCLUSIONS: PCCE-2 is feasible, safe, and well tolerated for the assessment of mucosal CD activity in selected populations. Larger studies are needed to assess its operating characteristics further. European clinical trials database number: 2014-003854-15.

Rationalizing polyp matching criteria in colon capsule endoscopy: an international expert consensus through RAND (modified DELPHI) process.

Background: Colon capsule endoscopy (CCE) has gained momentum as an alternative modality for the investigation of the lower gastrointestinal tract. Of the few challenges that remain, the comparison and - eventually - matching of polyps at different timestamps leads to the potential for double reporting and can contribute to false-positive findings and inaccuracies. With the impending artificial intelligence integration, the risk of double reporting the same polyp due to the lack of information on spatial orientation underscores the necessity for establishing criteria for polyp matching. Objectives: This RAND/University of California, Los Angeles (modified Delphi) process aims to identify the key factors or components used to match polyps within a CCE video. This involves exploring the attributes of each factor to create comprehensive polyp-matching criteria based on international expert consensus. Design: A systematic qualitative study using surveys. Methods: A panel of 11 international CCE experts convened to assess a survey comprised of 60 statements. Participants anonymously rated statement appropriateness on a 1-9 scale (1-3: inappropriate, 4-6: uncertain and 7-9: appropriate). Following a virtual group discussion of the Round 1 results, a Round 2 survey was developed and completed before the final analysis. Results: The factors that were agreed to be essential for polyp matching include (1) timestamp, (2) polyp localization, (3) polyp vascular pattern, (4) polyp size, (5) time interval of the polyp appearance between the green and yellow camera, (6) surrounding tissue, (7) polyp morphology and (8) polyp surface and contour. When five or more factors are satisfied, it was agreed that the comparing polyps are likely the same polyp. Conclusion: This study has established the first complete criteria for polyp matching in CCE. While it might not provide a definitive solution for matching difficult, small and common polyps, these criteria serve as a framework to guide and facilitate the process of polyp-matching.

Creating criteria and standards for matching polyps (abnormal growth in the bowels) on colon capsule video analysis: an international expert agreement using the RAND (modified Delphi process) process Background: Doctors often use colon capsule endoscopy (CCE), a high-tech capsule with two cameras, to record and check for diseases in the small and large bowels as the capsule travels through the intestines. One of the most common conditions in the large bowel is polyps, which are abnormal growths in the lining of the bowel. Comparing and matching polyps in the same video from the capsule can be tricky as they look very similar, leading to the possibility of incorrectly reporting the same polyp twice or more. This can lead to wrong results and inaccuracies. The literature did not have any criteria or standards for matching polyps in CCE before. Aim: Using the RAND/UCLA (modified Delphi) process, this study aims to identify the key factors or components used to match polyps within a CCE video. The goal is to explore each factor and create complete criteria for polyp matching based on the agreement from international experts. Method: A group of 11 international CCE experts came together to evaluate a survey with 60 statements. They anonymously rated each statement on a scale from 1 to 9 (1-3: inappropriate, 4-6: uncertain, and 7-9: appropriate). After discussing the Round 1 results virtually, a Round 2 survey with the same but revised questions was created and completed before the final analysis of their agreement. Results: The main factors for matching polyps are 1) the timing when the polyp was seen, 2) where it is in the bowel, 3) its blood vessel pattern, 4) size, 5) the timing of its appearance between cameras, 6) surrounding tissue features, 7) its shape, and 8) surface features. If five or more of these factors match, the compared polyps are likely the same. Conclusion: This study establishes the first complete criteria for matching polyps in CCE. While it may not provide a definitive solution for matching challenging and small polyps, these criteria serve as a guide to help and make the process of polyp matching easier.

Baseline Data and Measurement Instruments Reported in Observational Studies in Inflammatory Bowel Disease: Results from a Systematic Review.

BACKGROUND: Heterogeneity in demographic and outcomes data with corresponding measurement instruments [MIs] creates barriers to data pooling and analysis. Several core outcome sets have been developed in inflammatory bowel disease [IBD] to homogenize outcomes data. A parallel Minimum Data Set [MDS] for baseline characteristics is lacking. We conducted a systematic review to develop the first MDS. METHODS: A systematic review was made of observational studies from three databases [2000-2021]. Titles and abstracts were screened, full-text articles were reviewed, and data were extracted by two reviewers. Baseline data were grouped into ten domains: demographics, clinical features, disease behaviour/complications, biomarkers, endoscopy, histology, radiology, healthcare utilization and patient-reported data. Frequency of baseline data and MIs within respective domains are reported. RESULTS: From 315 included studies [600 552 subjects], most originated from Europe [196; 62%] and North America [59; 19%], and were published between 2011 and 2021 [251; 80%]. The most frequent domains were demographics [311; 98.7%] and clinical [289; 91.7%]; 224 [71.1%] studies reported on the triad of sex [306; 97.1%], age [289; 91.7%], and disease phenotype [231; 73.3%]. Few included baseline data for radiology [19; 6%], healthcare utilization [19; 6%], and histology [17; 5.4%]. Ethnicity [19; 6%], race [17; 5.4%], and alcohol/drug consumption [6; 1.9%] were the least reported demographics. From 25 MIs for clinical disease activity, the Harvey-Bradshaw Index [n = 53] and Mayo score [n = 37] were most frequently used. CONCLUSIONS: Substantial variability exists in baseline population data reporting. These findings will inform a future consensus for MDS in IBD to enhance data harmonization and credibility of real-world evidence.

JAK inhibitors for the treatment of inflammatory bowel disease: results of an international survey of perceptions, attitudes, and clinical practice.

BACKGROUND: Janus kinase inhibitors (JAKi) are small molecule drugs with demonstrated efficacy in inflammatory bowel disease (IBD). However, widespread utilisation may be hindered by safety concerns. AIMS: This is the first study assessing risk-benefit perceptions and clinical practices of those using JAKi for IBD. METHODS: A prospective, cross-sectional study was conducted using a 23-item survey distributed to IBD healthcare providers worldwide. RESULTS: Of 385 respondents from 48 countries, 72% were tertiary-centre based and 50% were gastroenterologists with ≥10 years experience. JAKi were commonly used outside market authorisation (31%), though many (17%) were unconfident discussing JAKi risk-benefit profile and 7% had never prescribed JAKi. If venous thromboembolism risks were present, 15% preferentially referred for surgery than initiate JAKi; 21% would do this even if the patient was already anticoagulated. For patients relapsing on dose reduction, 8% would switch treatment rather than dose escalate. Conversely, 45% felt that cardiovascular safety concerns from post-marketing studies were irrelevant to IBD. Despite the lack of detailed, long-term safety data, safety profiles of JAK1-selective drugs were perceived to be favourable to tofacitinib by most (62%). CONCLUSION: The study indicates that while clinical practice appears to be in keeping with international guidance, a significant minority remain deterred by safety concerns.

Development of a Core Outcome Set for Real-world Data in Inflammatory Bowel Disease: A European Crohn's and Colitis Organisation [ECCO] Position Paper.

BACKGROUND AND AIMS: The utility of real-world data is dependent on the quality and homogeneity of reporting. We aimed to develop a core outcome set for real-world studies in adult patients with inflammatory bowel disease [IBD]. METHODS: Candidate outcomes and outcome measures were identified and categorised in a systematic review. An international panel including patients, dietitians, epidemiologists, gastroenterologists, nurses, pathologists, radiologists, and surgeons participated in a modified Delphi consensus process. A consensus meeting was held to ratify the final core outcome set. RESULTS: A total of 26 panellists from 13 countries participated in the consensus process. A total of 271 items [130 outcomes, 141 outcome measures] in nine study domains were included in the first-round survey. Panellists agreed that real-world studies on disease activity should report clinical, endoscopic, and biomarker disease activity. A disease-specific clinical index [Harvey-Bradshaw Index, Partial Mayo Score, Simple Clinical Colitis Activity Index] should be used, rather than physician global assessment. In ulcerative colitis [UC], either the UC Endoscopic Index of Severity or the Mayo Endoscopic Score can be used, but there was no consensus on an endoscopic index for Crohn's disease, nor was there consensus on the use of the presence of ulcers. There was consensus on using faecal calprotectin and C-reactive protein. There was no consensus on the use of histology in real-world studies. CONCLUSIONS: A core outcome set for real-world studies in IBD has been developed based on international multidisciplinary consensus. Its adoption will facilitate synthesis in the generation of real-world evidence.

How achievable are STRIDE-II treatment targets in real-world practice and do they predict long-term treatment outcomes?

Objective: The second iteration of the Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE-II) initiative recommends use of the Simple Endoscopic Score for Crohn's disease (SES-CD) as a treatment target for patients with CD. We aimed to assess whether the STRIDE-II endoscopic endpoints are achievable and whether the degree of mucosal healing (MH) affects long-term outcomes. Design/method: We performed a retrospective observational study between 2015 and 2022. Patients with CD who had baseline and follow-up SES-CD scores after biological therapy initiation were included. The primary outcome was treatment failure, defined as the need for: (1) change of biological therapy for active disease (2) corticosteroid use (3) CD-related hospitalisation or (4) surgery. We compared rates of treatment failure with the degree of MH achieved. Patients were followed up until treatment failure or study end (August 2022). Results: 50 patients were included and followed up for median 39.9 (34.6-48.6) months. Baseline characteristics: 62% male, median age 36.4 (27.8-43.9) years, disease distribution (L1: 4, L2: 11, L3: 35, perianal: 18). The proportion of patients achieving STRIDE-II end-points were: SES-CD≤2-25 (50%) and >50% reduction in SES-CD-35 (70%). Failure to achieve SES-CD≤2 (HR 11.62; 95% CI 3.33 to 40.56, p=0.003) or >50% improvement in SES-CD (HR 30.30; 95% CI 6.93 to 132.40, p<0.0001) predicted treatment failure. Conclusion: Use of SES-CD is feasible in real-world clinical practice. Achieving an SES-CD≤2 or a greater than 50% reduction, as set out by STRIDE-II, is associated with reduced rates of overall treatment failure including CD-related surgery.