Standardizing Scoring Conventions for Crohn's Disease Endoscopy: An International RAND/UCLA Appropriateness Study.

BACKGROUND AND AIMS: Endoscopic assessment of disease activity is integral for evaluating treatment response in patients with Crohn's disease (CD). We aimed to define appropriate items for evaluating endoscopic activity and conventions for consistent endoscopic scoring rules in CD. METHODS: A 2-round modified RAND/University of California at Los Angeles Appropriateness Method study was conducted. A panel of 15 gastroenterologists used a 9-point Likert scale to rate the appropriateness of statements pertaining to the Simple Endoscopic Score for CD, Crohn's Disease Endoscopic Index of Severity, and additional items relevant to endoscopy scoring in CD. Each statement was voted as appropriate, uncertain, or inappropriate based on the median panel rating and presence of disagreement. RESULTS: Panelists voted that it is appropriate for all ulcers to contribute to endoscopic scoring in CD, including aphthous ulcers, ulcerations at a surgical anastomosis, and anal canal ulcers (scored in the rectum). Endoscopic healing should reflect an absence of ulcers. Narrowing should be defined as a clear decrease in luminal diameter; stenosis should be defined by an impassable narrowing, and if occurring at the junction of 2 segments, scored in the distal segment. Scarring and inflammatory polyps were considered inappropriate for including in the affected area score. The optimal method for defining ulcer depth remains uncertain. CONCLUSIONS: We outlined scoring conventions for the Simple Endoscopic Score for CD and Crohn's Disease Endoscopic Index of Severity, noting that both scores have limitations. Therefore, we identified priorities for future research and steps for developing and validating a more representative endoscopic index in CD.

Agreement between patients and physicians on scores of inflammatory bowel disease activity and burden assessed on a telemonitoring platform.

BACKGROUND AND AIMS: Telemonitoring is increasingly used in the management of IBD patients. We investigated the agreement between patients and physicians on scores of disease activity and burden. METHODS: Consecutive outpatients at one IBD clinic were recruited between February and December 2021. Enrolled patients completed a questionnaire for disease activity (Harvey-Bradshaw Index [HBI] for Crohn's disease or Simple Clinical Colitis Activity Index [SCCAI] for ulcerative colitis) and a test of disease burden (Pictorial Representation of Illness and Self Measure [PRISM]). They did the tests within 5 days of an outpatient visit, working independently on IBD Tool, a new web-based telemonitoring application. Concomitantly, the senior and junior physicians who examined them completed the same tests. The agreement was tested for every pair of scores. RESULTS: Five hundred and sixty patients (289 Crohn's disease; 271 ulcerative colitis) completed disease questionnaires on IBD Tool (in total, 742 times). By Spearman's correlation, the agreement was substantial both for HBI (rho 0.685-0.837) and SCCAI (rho 0.694-0.888) for comparisons between patients, junior and senior physicians. The agreement was moderate-to-substantial for PRISM (rho 0.406-0.725) for the same comparisons. The correlation between disease activity (HBI/SCCAI) and PRISM scores was substantial for senior (rho 0.757-0.788) or junior (rho 0.746-0.753) physicians and moderate for patients (rho 0.458-0.486). The median PRISM score difference was 2.3-1.6 points lower between patients and senior-junior physicians. CONCLUSION: Agreement between IBD patients and physicians was substantial for disease activity and moderate for disease impact. The inclusion of disease burden scoring in telemonitoring platforms provides important information for the management of IBD patients.Study highlightsWhat IS known•Continuous response to treatments and patient-reported outcomes became an essential goal for IBD patient management.•The use of tele-monitoring and eHealth technologies allows for regular disease assessments and for managing more efficiently IBD patients; disease questionnaires and tests are key to support eHealth tools.What is new here•Agreement between IBD patients and physicians was substantial for disease activity and moderate for disease burden, while agreement among junior and senior physicians was substantial for both.•PRISM performs as well for ulcerative colitis as for Crohn's patients.•The inclusion of disease burden tests might add to eHealth platforms valuable information, complemental to disease activity questionnaires.

SARS-CoV-2 infection in patients with inflammatory bowel disease: comparison between the first and second pandemic waves.

BACKGROUND: In Italy, the incidence of SARS-CoV-2 infection peaked in April and November 2020, defining two pandemic waves of coronavirus disease 2019 (COVID-19). This study compared the characteristics and outcomes of patients with inflammatory bowel disease (IBD) and SARS-CoV-2 infections between pandemic waves. METHODS: Observational longitudinal study of IBD patients with SARS-CoV-2 infection. Patients with established diagnoses of IBD and of SARS-CoV-2 infection were consecutively enrolled in two periods: (i) first wave, from 1 March 2020 to 31 May 2020; and (ii) second wave, from 15 September to 15 December 2020. RESULTS: We enrolled 937 IBD patients (219 in the first wave, 718 in the second wave). Patients of the first wave were older (mean ± SD: 46.3 ± 16.2 vs. 44.1 ± 15.4 years, p = 0.06), more likely to have ulcerative colitis (58.0% vs. 44.4%, p < 0.001) and comorbidities (48.9% vs. 38.9%; p < 0.01), and more frequently residing in Northern Italy (73.1% vs. 46.0%, p < 0.001) than patients of the second wave. There were no significant differences between pandemic waves in sex (male: 54.3% vs. 53.3%, p = 0.82) or frequency of active IBD (44.3% vs. 39.0%, p = 0.18). The rates of negative outcomes were significantly higher in the first than second wave: pneumonia (27.8% vs. 11.7%, p < 0.001), hospital admission (27.4% vs. 9.7%, p < 0.001), ventilatory support (11.9% vs. 5.4%, p < 0.003) and death (5.5% vs. 1.8%, p < 0.007). CONCLUSION: Between the first and second SARS-CoV-2 pandemic waves, demographic, clinical and geographical features of IBD patients were different as were the symptoms and outcomes of infection. These differences are likely due to the different epidemiological situations and diagnostic possibilities between the two waves.

Predicting endoscopic remission in Crohn's disease by the modified multiplier SES-CD (MM-SES-CD).

BACKGROUND AND AIMS: The Simple Endoscopic Score for Crohn's disease (SES-CD) is the primary tool for measurement of mucosal inflammation in clinical trials but lacks prognostic potential. We set to develop and validate a modified multiplier of the SES-CD (MM-SES-CD), which takes into consideration each individual parameter's prognostic value for achieving endoscopic remission (ER) while on active therapy. METHODS: In this posthoc analysis of three CD clinical trial programmes (n=350 patients, baseline SES-CD ≥ 3 with confirmed ulceration), data were pooled and randomly split into a 70% training and 30% testing cohort. The MM-SES-CD was designed using weights for individual parameters as determined by logistic regression modelling, with 1-year ER (SES-CD < 3) being the dependent variable. A cut point score for low and high probability of ER was determined by using the maximum Youden Index and validated in the testing cohort. RESULTS: Baseline ulcer size, extent of ulceration and presence of non-passable strictures had the strongest association with 1-year ER as compared with affected surface area, with differential weighting of individual parameters across disease segments being observed during logistic regression. The MM-SES-CD was generated using this weighted regression model and demonstrated strong discrimination for ER in the training dataset (area under the receiver operator curve (AUC) 0.83, 95% CI 0.78 to 0.94) and in the testing dataset (AUC 0.82, 95% CI 0.77 to 0.92). In comparison to the MM-SES-CD scoring model, the original SES-CD score lacks accuracy (AUC 0.60, 95% CI 0.55 to 0.65) for predicting the achievement of ER. CONCLUSIONS: We developed and internally validated the MM-SES-CD as an endoscopic severity assessment tool to predict one-year ER in patients with CD on active therapy.

An International Multicenter Real-Life Prospective Study of Electronic Chromoendoscopy Score PICaSSO in Ulcerative Colitis.

BACKGROUND & AIMS: Endoscopic and histologic remission are important goals in the treatment of ulcerative colitis (UC). We investigated the correlation of the recently developed Paddington International Virtual ChromoendoScopy ScOre (PICaSSO) and other established endoscopic scores against multiple histological indices and prospectively assessed outcomes. METHODS: In this prospective multicenter international study, inflammatory activity was assessed with high-definition and virtual chromoendoscopy in the rectum and sigmoid using the Mayo Endoscopic Score (MES), UC Endoscopic Index of Severity (UCEIS), and PICaSSO. Targeted biopsies were taken for assessment using Robarts Histological Index (RHI), Nancy Histological index (NHI), ECAP (Extent, Chronicity, Activity, Plus score), Geboes, and Villanacci. Follow-up data were obtained at 6 and 12 months after colonoscopy. RESULTS: A total of 307 patients were recruited. There was strong correlation between PICaSSO and histology scores, significantly superior to correlation coefficients of MES and UCEIS with histology scores. A PICaSSO score of ≤3 detected histologic remission by RHI (≤3 + absence of neutrophils) with area under the receiver operating characteristic curve (AUROC) 0.90 (95% confidence interval [CI] 0.86-0.94) and NHI (≤1) AUROC 0.82 (95% CI 0.77-0.87). The interobserver agreement for PICaSSO was 0.88 (95% CI 0.83-0.92). At 6- and 12-months follow-up, PICaSSO score ≤3 predicted better outcomes than PICaSSO >3 (hazard ratio [HR] 0.19 [0.11-0.33] and 0.22 [0.13-0.34], respectively),} as well as PICaSSO 4-8 (HR 0.25 [0.12-0.53] and 0.22 (0.12-0.39), respectively) and similar to histologic remission. CONCLUSION: In this first real-life multicenter study, the PICaSSO score correlated strongly with multiple histological indices. Furthermore, PICaSSO score predicted specified clinical outcomes at 6 and 12 months, similar to histology. Thus, PICaSSO can be a useful endoscopic tool in the therapeutic management of UC.

Endoscopy and central reading in inflammatory bowel disease clinical trials: achievements, challenges and future developments.

Central reading, that is, independent, off-site, blinded review or reading of imaging endpoints, has been identified as a crucial component in the conduct and analysis of inflammatory bowel disease clinical trials. Central reading is the final step in a workflow that has many parts, all of which can be improved. Furthermore, the best reading algorithm and the most intensive central reader training cannot make up for deficiencies in the acquisition stage (clinical trial endoscopy) or improve on the limitations of the underlying score (outcome instrument). In this review, academic and industry experts review scoring systems, and propose a theoretical framework for central reading that predicts when improvements in statistical power, affecting trial size and chances of success, can be expected: Multireader models can be conceptualised as statistical or non-statistical (social). Important organisational and operational factors, such as training and retraining of readers, optimal bowel preparation for colonoscopy, video quality, optimal or at least acceptable read duration times and other quality control matters, are addressed as well. The theory and practice of central reading and the conduct of endoscopy in clinical trials are interdisciplinary topics that should be of interest to many, regulators, clinical trial experts, gastroenterology societies and those in the academic community who endeavour to develop new scoring systems using traditional and machine learning approaches.

Impact of various central endoscopy reading models on treatment outcome in Crohn's disease using data from the randomized, controlled, exploratory cohort arm of the BERGAMOT trial.

BACKGROUND AND AIMS: Endoscopic assessment of mucosal appearance by independent central reading has become the standard method to assess Crohn's disease activity in clinical trials. The performance characteristics of various endoscopy reading models have yet to be systematically evaluated. METHODS: This substudy included patients with Crohn's disease in the exploratory induction cohort of the BERGAMOT trial (NCT02394028) randomly assigned to etrolizumab or placebo. Endoscopies conducted at baseline and week 14 were independently scored using the Simple Endoscopic Score for Crohn's Disease (SES-CD) by a local reader (LR) and 2 central readers (CRs). Five endoscopy reading models were compared: single LR, single CR, average of 2 CRs, and 2 models incorporating the LR and 1 or 2 CRs depending on alignment between the LR and the CR, defined according to a sliding scale applied to a range of scores. RESULTS: Five hundred thirty-five videos were scored. Models involving 2 readers demonstrated lower placebo rates (3.4%) than the single LR (11.9%) and the single CR (6.8%) models. Treatment effect size based on endoscopic improvement (≥50% reduction in SES-CD from baseline) was highest with the 2 models incorporating the LR and 1 or 2 CRs (Δ = 16.2%). Further, in the etrolizumab arm, models with 2 readers demonstrated the lowest variability for the SES-CD. CONCLUSIONS: Central endoscopy reading models in Crohn's disease have an impact on placebo response rates and effect size. Incorporating the LR appears to be important because models using both CRs and LRs resulted in the greatest treatment effect size for endoscopic improvement with etrolizumab, lower placebo rates, and reduced variability.

Scoring Endoscopy in Pediatric Inflammatory Bowel Disease: A Way to Improve Quality.

OBJECTIVES AND STUDY: There is a large interobserver variability in evaluating mucosal lesions of inflammatory bowel disease (IBD), especially in pediatric patients. This multicenter prospective observational study aims to evaluate interobserver agreement (IOA) among pediatric endoscopists in assigning validated IBD endoscopic scores in children. METHODS: Fifteen videos of follow-up ileocolonoscopies in children with IBD were recorded and selected as cases. Eleven pediatric endoscopists from different centers blindly evaluated all videos and calculated scores: either Ulcerative Colitis Endoscopic Index of Severity (UCEIS) or Simple Endoscopic Score for Crohn Disease (SES-CD). Scores from all reviewers were compared in order to calculate IOA for general videos and specific sections. Scores from an expert adult reader were used to calculate possible reviewer's characteristics affecting scores' reliability. RESULTS: Intraclass correlation was 0.298 (95% confidence interval [CI]: 0.13-0.55) for ulcerative colitis (UC) and 0.266 (0.11-0.52) for Crohn disease (CD). When a disease activity categorization was adopted (remission, mild, moderate, severe activity) Fleiss kappa coefficient was 0.408 (0.29-0.53) for UC and 0.552 (0.43-0.73) for CD. When stratified by item, vascular pattern of UC was the most reliable item IC: 0.624 (0.321-0.854). In multivariable analysis, none of the reviewer's characteristics affected the readers' errors. CONCLUSIONS: This multicenter study shows low agreement among pediatric endoscopists in evaluating endoscopic scores in children with IBD. By using disease activity categorization, agreement slightly increased, mostly for CD. All readers showed a low-grade concordance with the expert adult gastroenterologist's evaluations. Future-specific training programs should be considered to increase IOA in using IBD endoscopic activity scores.

Risk factors of SARS-CoV-2 seroprevalence among hospital employees in Italy: a single-centre study.

BACKGROUND: The SARS-CoV-2 outbreak early in 2020 overwhelmed the Italian national health system, and hospitals were considered places at high risk of spreading the infection. We explored specific antibody seroprevalence of all employees at a single hospital in the epicentre of the outbreak, to identify areas of risk in nosocomial setting and to evaluate the usefulness of antibody testing. AIMS: Aim of this study was to explore SARS-CoV-2 seroprevalence in a single hospital workers cohort. METHODS: All hospital workers were invited to fill in a questionnaire and undergo a blood test for SARS-CoV-2 IgG, using two commercial tests (DiaSorin and Abbott). Seropositivity was determined overall and according to demographic and occupations characteristics, for both tests singly and combined. RESULTS: The study enrolled 1562 hospital workers (95% of the eligible population). Overall, 153 (9.8%) participants were positive for SARS-CoV-2 IgG on DiaSorin test, and 150 (9.6%) were positive on Abbott test; both tests were positive in 123 (7.9%) cases and at least one was positive in 180 (11.5%) cases. Factors associated with SARS-CoV-2 seropositivity included: being a smoker, working in emergency or medicine departments, being a healthcare practitioner, self-reporting a relative with COVID-19 or symptoms suggestive of COVID-19, and having undergone a nasopharyngeal swab test. The tests were accurate in discriminating infected cases, with an area under the receiver operating characteristic curve of 0.867 using manufacturer-suggested cut-offs and 0.929 using optimised cut-offs. For discriminating symptomatic subjects, this value was 0.915 using optimised cut-offs. CONCLUSIONS: Seroprevalence for SARS-CoV-2 in this population of hospital workers was overall about 10%, with an excess prevalence in roles and departments associated with contacts with COVID-19 patients.

Outcomes of COVID-19 in 79 patients with IBD in Italy: an IG-IBD study.

OBJECTIVES: COVID-19 has rapidly become a major health emergency worldwide. Patients with IBD are at increased risk of infection, especially when they have active disease and are taking immunosuppressive therapy. The characteristics and outcomes of COVID-19 in patients with IBD remain unclear. DESIGN: This Italian prospective observational cohort study enrolled consecutive patients with an established IBD diagnosis and confirmed COVID-19. Data regarding age, sex, IBD (type, treatments and clinical activity), other comorbidities (Charlson Comorbidity Index (CCI)), signs and symptoms of COVID-19 and therapies were compared with COVID-19 outcomes (pneumonia, hospitalisation, respiratory therapy and death). RESULTS: Between 11 and 29 March 2020, 79 patients with IBD with COVID-19 were enrolled at 24 IBD referral units. Thirty-six patients had COVID-19-related pneumonia (46%), 22 (28%) were hospitalised, 7 (9%) required non-mechanical ventilation, 9 (11%) required continuous positive airway pressure therapy, 2 (3%) had endotracheal intubation and 6 (8%) died. Four patients (6%) were diagnosed with COVID-19 while they were being hospitalised for a severe flare of IBD. Age over 65 years (p=0.03), UC diagnosis (p=0.03), IBD activity (p=0.003) and a CCI score >1 (p=0.04) were significantly associated with COVID-19 pneumonia, whereas concomitant IBD treatments were not. Age over 65 years (p=0.002), active IBD (p=0.02) and higher CCI score were significantly associated with COVID-19-related death. CONCLUSIONS: Active IBD, old age and comorbidities were associated with a negative COVID-19 outcome, whereas IBD treatments were not. Preventing acute IBD flares may avoid fatal COVID-19 in patients with IBD. Further research is needed.

Development and validation of the SIMPLE endoscopic classification of diminutive and small colorectal polyps.

BACKGROUND: Prediction of histology of small polyps facilitates colonoscopic treatment. The aims of this study were: 1) to develop a simplified polyp classification, 2) to evaluate its performance in predicting polyp histology, and 3) to evaluate the reproducibility of the classification by trainees using multiplatform endoscopic systems. METHODS: In phase 1, a new simplified endoscopic classification for polyps - Simplified Identification Method for Polyp Labeling during Endoscopy (SIMPLE) - was created, using the new I-SCAN OE system (Pentax, Tokyo, Japan), by eight international experts. In phase 2, the accuracy, level of confidence, and interobserver agreement to predict polyp histology before and after training, and univariable/multivariable analysis of the endoscopic features, were performed. In phase 3, the reproducibility of SIMPLE by trainees using different endoscopy platforms was evaluated. RESULTS: Using the SIMPLE classification, the accuracy of experts in predicting polyps was 83 % (95 % confidence interval [CI] 77 % - 88 %) before and 94 % (95 %CI 89 % - 97 %) after training (P â€Š= 0.002). The sensitivity, specificity, positive predictive value, and negative predictive value after training were 97 %, 88 %, 95 %, and 91 %. The interobserver agreement of polyp diagnosis improved from 0.46 (95 %CI 0.30 - 0.64) before to 0.66 (95 %CI 0.48 - 0.82) after training. The trainees demonstrated that the SIMPLE classification is applicable across endoscopy platforms, with similar post-training accuracies for narrow-band imaging NBI classification (0.69; 95 %CI 0.64 - 0.73) and SIMPLE (0.71; 95 %CI 0.67 - 0.75). CONCLUSIONS: Using the I-SCAN OE system, the new SIMPLE classification demonstrated a high degree of accuracy for adenoma diagnosis, meeting the ASGE PIVI recommendations. We demonstrated that SIMPLE may be used with either I-SCAN OE or NBI.

Asymptotic distributions of kappa statistics and their differences with many raters, many rating categories and two conditions.

In clinical research and in more general classification problems, a frequent concern is the reliability of a rating system. In the absence of a gold standard, agreement may be considered as an indication of reliability. When dealing with categorical data, the well-known kappa statistic is often used to measure agreement. The aim of this paper is to obtain a theoretical result about the asymptotic distribution of the kappa statistic with multiple items, multiple raters, multiple conditions, and multiple rating categories (more than two), based on recent work. The result settles a long lasting quest for the asymptotic variance of the kappa statistic in this situation and allows for the construction of asymptotic confidence intervals. A recent application to clinical endoscopy and to the diagnosis of inflammatory bowel diseases (IBDs) is shortly presented to complement the theoretical perspective.

Development and reliability of the new endoscopic virtual chromoendoscopy score: the PICaSSO (Paddington International Virtual ChromoendoScopy ScOre) in ulcerative colitis.

BACKGROUND AND AIMS: Endoscopic inflammation and healing are important therapeutic endpoints in ulcerative colitis (UC). We developed and validated a new electronic virtual chromoendoscopy (EVC) score that could reflect the full spectrum of mucosal and vascular changes including mucosal healing in UC. METHODS: Eight participants reviewed a 60-minute training module outlining 3 different i-SCAN modes demonstrating the entire spectrum of inflammatory mucosal and vascular changes in UC. Performance characteristics in endoscopic scoring and predicting the histologic inflammation with EVC (i-SCAN) by using 20 video clips before (pre-test) and after (post-test) were evaluated. Exploratory univariate factor analysis was performed on Paddington International Virtual Chromoendoscopy Score (PICaSSO) covariates for mucosal and vascular score separately. Subsequently, a proportional odds logistic regression model for the prediction of histologic scores was analyzed. RESULTS: The interobserver agreement for Mayo endoscopic score in the pre-test (κ = .85; 95% CI, .78-.90) and the post-test (κ = .85; 95% CI, .77-.90) evaluation were very good. This was also true for the Ulcerative Colitis Endoscopic Index of Severity in the pre-test and post-test score interobserver agreement (κ = .86; 95% CI, .77-.92; and κ = .84; 95% CI, .75-.91, respectively). The interobserver agreement of the PICaSSO endoscopic score was very good in the pre-test and post-test evaluations (κ = .92; 95% CI, .87-.96; and κ = .89; 95% CI, .84-.94, respectively). The accuracy of the overall PICaSSO in assessing histologic abnormalities and inflammation by Harpaz score was 57% (95% CI, 48%-65%), by Robarts Histological Index 72% (95% CI, 64%-79%), and by the extent, chronicity, activity, plus system (full spectrum of histologic changes) 83% (95% CI, 76%-88%). CONCLUSIONS: The EVC score "PICaSSO" showed very good interobserver agreement. The new EVC score may be used to define the endoscopic findings of mucosal and vascular healing in UC and reflected the full spectrum of histologic changes.

Reliability among central readers in the evaluation of endoscopic findings from patients with Crohn's disease.

OBJECTIVE: The Crohn's Disease Endoscopic Index of Severity (CDEIS) and Simple Endoscopic Score for Crohn's Disease (SES-CD) are commonly used to assess Crohn's disease (CD) activity; however, neither instrument has been fully validated. We assessed intra-rater and inter-rater reliability of these indices. DESIGN: Video recordings of colonoscopies obtained from 50 patients with CD who participated in an induction trial of a biological therapy were triplicated and reviewed in random order by four central readers. Data were used to assess intra-rater and inter-rater reliability for CDEIS, SES-CD and a global evaluation of lesion severity (GELS). Subsequently, readers participated in a consensus process that identified common sources of disagreement. RESULTS: Intraclass correlation coefficients (ICCs) for intra-rater reliability for CDEIS, SES-CD and GELS (95% CIs) were 0.89 (0.86 to 0.93), 0.91 (0.89 to 0.95) and 0.81 (0.77 to 0.89), respectively, with standard error of measurement (SEM) of 2.10, 2.42 and 1.15. The corresponding ICCs for inter-rater reliability were 0.71 (0.63 to 0.76), 0.83 (0.75 to 0.88) and 0.62 (0.52 to 0.70), with SEM of 3.42, 3.07 and 1.63, respectively. Correlation between CDEIS and GELS was 0.75, between SES-CD and GELS was 0.74 and between CDEIS and SES-CD was 0.92. The most common sources of disagreement were interpretation of superficial ulceration, definition of disease site at the ileocolonic anastomosis, assessment of anorectal lesions and grading severity of stenosis. CONCLUSIONS: Central reading of CDEIS and SES-CD had 'substantial' to 'almost perfect' intra-rater and inter-rater reliability; however, the responsiveness of these instruments is yet to be determined. TRIAL REGISTRATION NUMBER: Clinicaltrials.gov NCT01466374.

Application of multiple laboratory tests for Mycobacterium avium ssp. paratuberculosis detection in Crohn's disease patient specimens.

The difficulties involved in detecting and enumerating Mycobacterium avium subsp. paratuberculosis (MAP) as a pathogen potentially involved in Crohn's disease (CD) are well known. This study aimed to improve this situation through the application of multiple laboratory diagnostic tests to detect and isolate this bacterium from different specimens collected from CD-patients and non-CD subjects as controls. A total of 120 samples (terminal ileum and colon biopsies, blood and stool) were obtained from 19 CD-patients and from 11 individuals who did not have a clinicopathological diagnosis of CD (non-CD controls) attending for ileocolonoscopy. All samples were processed by staining techniques, culture on both solid and liquid media, and Insertion Sequence 900/F57 real-time PCR. The MAP frequency in CD-patients was found in a significantly greater proportion than in non-CD subjects; the most positive samples were biopsies from CD-patients tested by real-time PCR. MAP detection in biopsies, and in the other samples, by applying multiple and validated laboratory diagnostic tests, could be a marker of active infection, supporting MAP involvement in CD.

Estimation of patients affected by inflammatory bowel disease potentially eligible for biological treatment in a real-world setting.

BACKGROUND/AIMS: This analysis estimated the number of inflammatory bowel disease (IBD) patients presenting criteria of eligibility for biological therapies in an Italian real-world setting. METHODS: An observational analysis was performed on administrative databases of a sample of Local Health Units, covering 11.3% of the national population. Adult IBD patients (CD or UC) from 2010 to the end of data availability were included. Eligibility criteria for biologics were the following: Criterion A, steroid-refractory active disease; Criterion B, steroid-dependent patients; Criterion C, intolerance or contraindication to conventional therapies; Criterion D, severe relapsing disease; Criterion E (CD only), highly active CD disease and poor prognosis. RESULTS: Of 26,781 IBD patient identified, 18,264 (68.2%) were treated: 3,125 (11.7%) with biologics and 15,139 (56.5%) non-biotreated. Among non-biotreated, 7,651 (28.6%) met at least one eligibility criterion for biologics, with criterion B (steroid-dependence) and criterion D (relapse) as the most represented (58-27% and 56-76%, respectively). Data reportioned to the Italian population estimated 67,635 patients as potentially eligible for biologics. CONCLUSIONS: This real-world analysis showed a trend towards undertreatment with biologics in IBD patients with 28.6% being potentially eligible, suggesting that an unmet medical need still exists among the Italian general clinical practice for IBD management.

Timing of proper introduction, optimization and maintenance of anti-TNF therapy in IBD: Results from a Delphi consensus.

BACKGROUND: Crohn's disease and ulcerative colitis are inflammatory bowel diseases (IBDs) with a rapidly growing worldwide incidence. The last decades presented rapid progress in pharmacological treatment leading in many cases to clinical and endoscopic remission, including biological treatment with anti-TNF agents. AIM: The exact timing of introduction, optimization and maintenance of anti-TNF therapy in IBDs is not thoroughly covered in current guidelines. METHODS: We used the Delphi panel methodology to gather the IBD experts' views and achieve consensus for clinical recommendations on introducing and maintaining anti-TNF therapy for patients with IBDs. RESULTS: Twelve recommendations achieved a high level of consensus in two assessment rounds by 52 (1st round) and 47 (2nd round) IBD experts. CONCLUSION: In many clinical situations, the early use of anti-TNF therapy is recommended. Nowadays, the cost-efficacy profile of anti-TNF biosimilars makes them the first-line drug in a substantial proportion of patients, thus providing the opportunity to increase access to biological therapy.

Reliability and Responsiveness of Clinical and Endoscopic Outcome Measures in Crohn's Disease.

BACKGROUND: Regulatory guidance for Crohn's disease trials recommends coprimary efficacy end points that evaluate both symptoms and mucosal inflammation. We aimed to characterize the operating properties of commonly used disease activity assessments alone and in combination. METHODS: Endoscopic and clinical data were available for 129 participants from the Study of Biologic and Immunomodulator Naïve Patients in Crohn's Disease trial. Readers scored the Simple Endoscopic Score for Crohn's Disease and the Crohn's Disease Endoscopic Index of Severity using standardized conventions. Index reliability was determined using intraclass correlation coefficients. Index responsiveness was assessed using standardized effect sizes based upon treatment assignment. Outcomes were evaluated for optimal sensitivity to treatment effect. RESULTS: Substantial inter-rater reliability was observed when the Simple Endoscopic Score for Crohn's Disease and Crohn's Disease Endoscopic Index of Severity were used as continuous measures (intraclass correlation coefficient, 0.64; 95% confidence interval [CI], 0.50-0.73; and 0.62 95% CI, 0.36-0.77) compared with moderate reliability when dichotomized (0.46; 95% CI, 0.26-0.65; and 0.51; 95% CI, 0.00-0.78). The Simple Endoscopic Score for Crohn's Disease, Crohn's Disease Endoscopic Index of Severity, patient-reported outcome-2, and Crohn's Disease Activity Index were similarly responsive (standardized effect size, 0.43, 95% CI, 0.05-0.81; 0.38, 95% CI, 0.0-0.76; 0.53, 95% CI, 0.15-0.91). A composite outcome of Crohn's Disease Activity Index score <150 and Crohn's Disease Endoscopic Index of Severity score <6 was most sensitive to treatment effect (28.9%; 95% CI, 11.0%-46.8%; P = .003). CONCLUSION: Endoscopic indices were more reliable as continuous measures. Composite outcomes including endoscopy improved sensitivity to treatment effect.

This study largely supports current regulatory guidance for Crohn's disease trials recommending coprimary efficacy end points evaluating both symptoms and mucosal inflammation. Continuous endoscopic measures are most reliable and improve sensitivity to treatment effect when employed in composite outcomes.

Clinical trial: Clinical and endoscopic outcomes with ustekinumab in patients with Crohn's disease: Results from the long-term extension period of STARDUST.

BACKGROUND: STARDUST, a phase 3b randomised trial, compared ustekinumab therapeutic strategies in patients with Crohn's disease (CD) using early endoscopic assessment and treat-to-target (T2T) versus standard of care (SoC). AIM: To assess the efficacy of ustekinumab extended treatment in a long-term extension (LTE) of up to 104 weeks with dosing adapted according to clinical, biomarker and endoscopy outcomes. METHODS: Adults with moderately-to-severely active CD received intravenous ustekinumab approximating 6 mg/kg at Week 0 and subcutaneous ustekinumab 90 mg at Week 8. At Week 16, 440 ≥70-point responders were randomised to T2T or SoC and 323 entered the LTE. At Week 48, a unified, protocol-defined ustekinumab dose frequency escalation/de-escalation was applied based on achieving endoscopic remission and corticosteroid-free clinical remission. Achieving corticosteroid-free clinical remission and biomarker remission at consecutive visits determined ustekinumab dosing frequency. Dichotomous variables were analysed using non-responder imputation. RESULTS: Among patients who entered the LTE, 7.7%, 48.6% and 43.7% received doses every 4, 8 and 12 weeks, respectively. Ustekinumab dose frequency was escalated in 23.5% and de-escalated in 19.7%. Endoscopic response and remission rates were 28.9% and 10.73% (all randomised) and 39.3% and 14.6% (patients entering the LTE), respectively, at Week 104. Clinical remissiona rates at week 104 were 50.2% (all randomised) and 68.4% (patients entering the LTE). There were no new safety signals. CONCLUSION: STARDUST LTE is the first interventional ustekinumab efficacy study to show a favourable benefit-risk profile with preservation of clinical and endoscopic outcomes through Week 104 using flexible, algorithm-driven dose adjustment including de-escalation.