Pick Topic
Review Topic
List Experts
Examine Expert
Save Expert
  Site Guide ··   
Crohn Disease: HELP
Articles by GuangYong Zou
Based on 19 articles published since 2010
(Why 19 articles?)
||||

Between 2010 and 2020, G. Zou wrote the following 19 articles about Crohn Disease.
 
+ Citations + Abstracts
1 Review Systematic review with meta-analysis: placebo rates in induction and maintenance trials of Crohn's disease. 2017

Jairath, V / Zou, G / Parker, C E / MacDonald, J K / Mosli, M H / AlAmeel, T / Al Beshir, M / AlMadi, M / Al-Taweel, T / Atkinson, N S S / Biswas, S / Chapman, T P / Dulai, P S / Glaire, M A / Hoekman, D / Kherad, O / Koutsoumpas, A / Minas, E / Restellini, S / Samaan, M A / Khanna, R / Levesque, B G / D'Haens, G / Sandborn, W J / Feagan, B G. ·London, ON, Canada. · Oxford, UK. · Jeddah, Saudi Arabia. · Dammam, Saudi Arabia. · Riyadh, Saudi Arabia. · Jabriya, Kuwait. · La Jolla, CA, USA. · Amsterdam, The Netherlands. · Geneva, Switzerland. · London, UK. ·Aliment Pharmacol Ther · Pubmed #28164348.

ABSTRACT: BACKGROUND: Minimising placebo response is essential for drug development. AIM: To conduct a meta-analysis to determine placebo response and remission rates in trials and identify the factors affecting these rates. METHODS: MEDLINE, EMBASE and CENTRAL were searched from inception to April 2014 for placebo-controlled trials of pharmacological interventions for Crohn's disease. Placebo response and remission rates for induction and maintenance trials were pooled by random-effects and mixed-effects meta-regression models to evaluate effects of study-level characteristics on these rates. RESULTS: In 100 studies containing 67 induction and 40 maintenance phases and 7638 participants, pooled placebo remission and response rates for induction trials were 18% [95% confidence interval (CI) 16-21%] and 28% (95% CI 24-32%), respectively. Corresponding values for maintenance trials were 32% (95% CI 25-39%) and 26% (95% CI 19-35%), respectively. For remission, trials enrolling patients with more severe disease activity, longer disease duration and more study centres were associated with lower placebo rates, whereas more study visits and longer study duration was associated with higher placebo rates. For response, findings were opposite such that trials enrolling patients with less severe disease activity and longer study duration were associated with lower placebo rates. Placebo rates varied by drug class and route of administration, with the highest placebo response rates observed for biologics. CONCLUSIONS: Placebo rates vary according to whether trials are designed for induction or maintenance and the factors influencing them differ for the endpoints of remission and response. These findings have important implications for clinical trial design in Crohn's disease.

2 Review Endoscopic scoring indices for evaluation of disease activity in Crohn's disease. 2016

Khanna, Reena / Nelson, Sigrid A / Feagan, Brian G / D'Haens, Geert / Sandborn, William J / Zou, G Y / MacDonald, John K / Parker, Claire E / Jairath, Vipul / Levesque, Barrett G. ·Department of Medicine, University of Western Ontario, London, ON, Canada. ·Cochrane Database Syst Rev · Pubmed #27501379.

ABSTRACT: BACKGROUND: Endoscopic assessment of mucosal disease activity is widely used to determine eligibility and response to therapy in clinical trials of treatment for Crohn's disease. However, the operating properties of the currently available endoscopic indices remain unclear. OBJECTIVES: A systematic review was undertaken to evaluate the development and operating characteristics of the Crohn's Disease Endoscopic Index of Severity (CDEIS) and Simple Endoscopic Scale for Crohn's Disease (SES-CD). SEARCH METHODS: Electronic searches of the MEDLINE (1966 to December 2015), EMBASE (1980 to December 2015), and Cochrane CENTRAL Register of Controlled Trials (Issue 12, 2015) databases were supplemented by manual reviews of reference listings 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 either or both the CDEIS or SES-CD in patients with Crohn's disease was considered for inclusion. Eligible participants were adult patients (> 16 years), diagnosed with Crohn's disease using conventional clinical, radiographic, and endoscopic criteria. DATA COLLECTION AND ANALYSIS: Two authors (RK, JKM) independently reviewed the titles and abstracts of the studies identified from the literature search. The full texts of potentially relevant citations were reviewed for inclusion and the study investigators were contacted to clarify any unclear data. Any disagreements were resolved by discussion and consensus with a third author. A standardized form was used to assess eligibility of trials for inclusion in the study and for data extraction.Two authors independently extracted and recorded data (RK, SAN). The number of patients enrolled; number of patients per treatment arm; patient characteristics including age and gender distribution; endoscopic index; and outcomes such as intra-rater reliability, inter-rater reliability responsiveness, validity, feasibility, construct validity, and criterion validity were recorded for each trial. MAIN RESULTS: Forty-three reports of 30 studies fulfilled the inclusion criteria.For the SES-CD, inter-rater reliability was assessed in four studies. In the development study for the SES-CD (Daperno 2004), the overall ICC (0.9815, 95% CI 0.9705 to 0.9884) and the kappa for the regions is high; however the paired raters were in the same room which introduces the potential for bias.For the CDEIS, inter-rater reliability was assessed in six studies. Daperno 2014 reported that the ICC for the CDEIS was 0.985 (95% CI 0.939-1.000) for average measures of video score and was 0.835 (95% CI 0.540-0.995) for single measures of video score.With respect to validity, correlation between the CDEIS and clinical measures, including C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR), was also reported. The estimates of correlation with CRP were r = 0.521 (Sipponen 2010b), r = 0.553 (Sipponen 2008a) and r = 0.608 (Sipponen 2008c). For the SES-CD, the corresponding values for correlation with CRP ranged from r = 0.46 (Jones 2008) to r = 0.68 (Green 2011).Responsiveness data for the CDEIS were available in nine studies. Seven studies demonstrated statistically significant decreases in the CDEIS score after administration of a treatment of known efficacy. Minimal responsiveness data were available for the SES-CD. Sipponen 2010a and Sipponen 2010b demonstrated statistically significant changes in the SES-CD score after subjects were administered a treatment of known efficacy.No studies were identified that explicitly evaluated the feasibility for either the SES-CD or the CDEIS. The SES-CD requires fewer calculations and may therefore be easier to use than the CDEIS. AUTHORS' CONCLUSIONS: Although they are used in clinical trials, the CDEIS and SES-CD remain incompletely validated. Future research is required to determine the operating properties and to define the optimal index.

3 Review C-Reactive Protein, Fecal Calprotectin, and Stool Lactoferrin for Detection of Endoscopic Activity in Symptomatic Inflammatory Bowel Disease Patients: A Systematic Review and Meta-Analysis. 2015

Mosli, Mahmoud H / Zou, Guangyong / Garg, Sushil K / Feagan, Sean G / MacDonald, John K / Chande, Nilesh / Sandborn, William J / Feagan, Brian G. ·1] Department of Medicine, University of Western Ontario, London, Ontario, Canada [2] Department of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia [3] Robarts Clinical Trials, Robarts Research Institute, London, Ontario, Canada. · 1] Robarts Clinical Trials, Robarts Research Institute, London, Ontario, Canada [2] Department of Epidemiology and Biostatistics, University of Western Ontario, London, Ontario, Canada. · Department of Medicine, University of Minnesota, Minneapolis, MN, USA. · Robarts Clinical Trials, Robarts Research Institute, London, Ontario, Canada. · 1] Department of Medicine, University of Western Ontario, London, Ontario, Canada [2] London Health Sciences Centre, Victoria Hospital, London, Ontario, Canada. · 1] Robarts Clinical Trials, Robarts Research Institute, London, Ontario, Canada [2] Division of Gastroenterology, University of California San Diego, La Jolla, California, USA. · 1] Department of Medicine, University of Western Ontario, London, Ontario, Canada [2] Robarts Clinical Trials, Robarts Research Institute, London, Ontario, Canada [3] Department of Epidemiology and Biostatistics, University of Western Ontario, London, Ontario, Canada. ·Am J Gastroenterol · Pubmed #25964225.

ABSTRACT: OBJECTIVES: Persistent disease activity is associated with a poor prognosis in inflammatory bowel disease (IBD). Therefore, monitoring of patients with intent to suppress subclinical inflammation has emerged as a treatment concept. As endoscopic monitoring is invasive and resource intensive, identification of valid markers of disease activity is a priority. The objective was to evaluate the diagnostic accuracy of C-reactive protein (CRP), fecal calprotectin (FC), and stool lactoferrin (SL) for assessment of endoscopically defined disease activity in IBD. METHODS: Databases were searched from inception to November 6, 2014 for relevant cohort and case-control studies that evaluated the diagnostic accuracy of CRP, FC, or SL and used endoscopy as a gold standard in patients with symptoms consistent with active IBD. Sensitivities and specificities were pooled to generate operating property estimates for each test using a bivariate diagnostic meta-analysis. RESULTS: Nineteen studies (n=2499 patients) were eligible. The pooled sensitivity and specificity estimates for CRP, FC, and SL were 0.49 (95% confidence interval (CI) 0.34-0.64) and 0.92 (95% CI 0.72-0.96), 0.88 (95% CI 0.84-0.90) and 0.73 (95% CI 0.66-0.79), and 0.82 (95% CI 0.73-0.88) and 0.79 (95% CI 0.62-0.89), respectively. FC was more sensitive than CRP in both diseases and was more sensitive in ulcerative colitis than Crohn's disease. CONCLUSIONS: Although CRP, FC, and SL are useful biomarkers, their value in managing individual patients must be considered in specific clinical contexts.

4 Clinical Trial A prospective cohort study to determine the relationship between serum infliximab concentration and efficacy in patients with luminal Crohn's disease. 2014

Levesque, B G / Greenberg, G R / Zou, G / Sandborn, W J / Singh, S / Hauenstein, S / Ohrmund, L / Wong, C J / Stitt, L W / Shackelton, L M / King, D / Lockton, S / Ducharme, J / Feagan, B G. ·Robarts Clinical Trials, Inc., Robarts Research Institute, Western University, London, ON, Canada; Division of Gastroenterology, University of California San Diego, La Jolla, CA, USA. ·Aliment Pharmacol Ther · Pubmed #24689499.

ABSTRACT: BACKGROUND: Patients with Crohn's disease (CD) may experience disease relapse on maintenance infliximab. Anti-drug antibodies likely contribute to loss of response, and serum infliximab levels likely correlate with efficacy. AIM: To prospectively evaluate the relationship between trough serum infliximab concentration and disease activity. METHODS: Adult patients (N = 327) with a diagnosis of CD who had received at least five consecutive infliximab infusions and who planned to receive at least two additional infusions were enrolled. The Crohn's Disease Activity Index (CDAI), serum infliximab, C-reactive protein (CRP) and antibodies-to-infliximab (ATI) were assessed at baseline, week 4 and week 8. Receiver operating characteristic (ROC) analysis examined the relationship between infliximab concentrations and disease activity. RESULTS: The mean CDAI score, which decreased 1.05 points between infusions, did not correlate with the mean change in trough infliximab concentration (+0.39 μg/mL; r = 0.099, P = 0.083), but was associated with the mean change in CRP concentration (r = 0.19, P < 0.001). Trough infliximab concentrations below 2.8-4.6 μg/mL best predicted a ≥ 70 point increase in the CDAI between infusions, and those below 2.7-2.8 μg/mL best predicted CRP >5 mg/mL at the second infusion. ATI at either visit decreased the proportion of patients with therapeutic infliximab trough levels compared with patients who were ATI negative (17.5% vs. 77.3% at visit 1 and 13.8% vs. 75.6% at visit 3; P < 0.001 for both comparisons). CONCLUSIONS: This prospective study confirms the relationship between trough infliximab concentrations, inflammation and antibodies-to-infliximab. Infliximab trough concentrations below 3 μg/mL may increase the likelihood of symptoms and inflammation (ClinicalTrials.gov identifier: NCT00676988).

5 Article Development and Validation of a Magnetic Resonance Index for Assessing Fistulas in Patients With Crohn's Disease. 2019

Hindryckx, Pieter / Jairath, Vipul / Zou, Guangyong / Feagan, Brian G / Sandborn, William J / Stoker, Jaap / Khanna, Reena / Stitt, Larry / van Viegen, Tanja / Shackelton, Lisa M / Taylor, Stuart A / Santillan, Cynthia / Mearadji, Banafsche / D'Haens, Geert / Richard, Marie-Paule / Panes, Julian / Rimola, Jordi. ·Robarts Clinical Trials, Inc, London, Ontario, Canada; Department of Gastroenterology, University of Ghent, Ghent, Belgium. · Robarts Clinical Trials, Inc, London, Ontario, Canada; Department of Medicine, Division of Gastroenterology, University of Western Ontario, London, Ontario, Canada; Department of Epidemiology and Biostatistics, University of Western Ontario, London, Ontario, Canada. Electronic address: vjairath@uwo.ca. · Robarts Clinical Trials, Inc, London, Ontario, Canada; Department of Epidemiology and Biostatistics, University of Western Ontario, London, Ontario, Canada. · Robarts Clinical Trials, Inc, London, Ontario, Canada; Department of Medicine, Division of Gastroenterology, University of Western Ontario, London, Ontario, Canada; Department of Epidemiology and Biostatistics, University of Western Ontario, London, Ontario, Canada. · Robarts Clinical Trials, Inc, London, Ontario, Canada; Division of Gastroenterology, University of California San Diego, La Jolla, California. · Department of Radiology and Nuclear Medicine, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands. · Robarts Clinical Trials, Inc, London, Ontario, Canada; Department of Medicine, Division of Gastroenterology, University of Western Ontario, London, Ontario, Canada. · Robarts Clinical Trials, Inc, London, Ontario, Canada. · Centre for Medical Imaging, University College London, London, UK. · Department of Radiology, University of California San Diego, La Jolla, California. · Robarts Clinical Trials, Inc, London, Ontario, Canada; Inflammatory Bowel Disease Centre, Academic Medical Centre, Amsterdam, The Netherlands. · Tigenix, SAU, Madrid, Spain. · Department of Gastroenterology, Hospital Clínic de Barcelona, The August Pi i Sunyer Biomedical Research Institute, Biomedical Research Networking Center in Hepatic and Digestive Diseases, Barcelona, Spain. · Department of Radiology, Hospital Clínic de Barcelona, Barcelona, Spain. ·Gastroenterology · Pubmed #31336124.

ABSTRACT: BACKGROUND & AIMS: There is no validated magnetic resonance imaging (MRI) index for assessment of perianal fistulas in patients with Crohn's disease (CD). We developed and internally validated a new instrument. METHODS: We used paired baseline and week-24 MRI scans from 160 participants in a randomized placebo-controlled trial of stem cell therapy for patients with perianal fistulizing CD. Four radiologists scored disease activity using index items identified during previous studies and exploratory items. Reliability was assessed using intraclass correlation coefficients. We developed an index using backward elimination linear regression analysis, in which potential independent variables were items having intraclass correlation coefficients of at least 0.4 and the dependent variable was perianal fistulizing disease activity, measured on a 100-mm visual analogue scale. The final model was internally validated using the .632 bootstrap method to correct model optimism and quantify calibration accuracy. We evaluated responsiveness of the index by assessing longitudinal validity and estimating standardized effect sizes. RESULTS: We developed the magnetic resonance novel index for fistula imaging in CD (MAGNIFI-CD) using 6 items. The optimism-corrected R CONCLUSIONS: We developed an index called the MAGNIFI-CD, which is based on 6 items. It assesses MRI data and determines perianal fistulizing CD activity with improved operating characteristics compared to previous indices. This index may be used as an outcome measure in clinical trials comparing treatment effects in patients with perianal fistulizing CD. Although the performance of the MAGNIFI-CD indicates its stability and reasonable external validity, external validation is needed.

6 Article Evaluation of optimal biopsy location for assessment of histological activity, transcriptomic and immunohistochemical analyses in patients with active Crohn's disease. 2019

Novak, Gregor / Stevens, Toer / Van Viegen, Tanja / Bossuyt, Peter / Štabuc, Borut / Jeyarajah, Jenny / Zou, Guangyong / Gaemers, Ingrid C / McKee, Trevor D / Fu, Fred / Shackelton, Lisa M / Khanna, Reena / van den Brink, Gijs R / Sandborn, William J / Feagan, Brian G / Pai, Rish K / Jairath, Vipul / Vande Casteele, Niels / D'Haens, Geert. ·Robarts Clinical Trials Inc, London, ON, Canada. · Department of Gastroenterology, Ljubljana University Medical Centre, University of Ljubljana, Ljubljana, Slovenia. · Inflammatory Bowel Disease Centre, Academic Medical Center, Amsterdam, The Netherlands. · Imelda General Hospital, Bonheiden, Belgium. · Department of Epidemiology and Biostatistics, University of Western Ontario, London, ON, Canada. · Amsterdam UMC, University of Amsterdam, Tytgat Institute for Liver and Intestinal Research, Amsterdam, The Netherlands. · STTARR Innovation Centre, University Health Network, Toronto, ON, Canada. · Department of Medicine, University of Western Ontario, London, ON, Canada. · Department of Medicine, University of California San Diego, La Jolla, California. · Department of Laboratory Medicine and Pathology, Mayo Clinic, Scottsdale, Arizona. ·Aliment Pharmacol Ther · Pubmed #30983024.

ABSTRACT: BACKGROUND: The appropriate location for biopsy procurement relative to an ulcer in active Crohn's disease is unknown. AIM: To explore the relationship between biopsy location, histological disease activity, proinflammatory gene expression and the presence of inflammatory cells. METHODS: Fifty-one patients with Crohn's disease and ulcers >0.5 cm diameter in the colon and/or ileum were prospectively enrolled at three centres. Biopsies were obtained from 0 mm, 7 to 8 mm and 21 to 24 mm from the edge of the largest ulcer. Histological activity was blindly assessed with the Global Histological Disease Activity Score, the Robarts Histopathology and Nancy Histological indices. Messenger ribonucleic acid (mRNA) levels for interleukins-6, -8 and -23 (p19 and p40 subunits), CD31 and S100A9 were measured using quantitative polymerase chain reaction. The number of CD3+, CD68+ and myeloperoxidase-positive cells was quantified by immunohistochemistry. Data were analysed using mixed models with location and segment as fixed effects and patients as random effect to account for correlation among segments within a patient. RESULTS: Histological disease activity scores (P < 0.0001), proinflammatory gene expression levels (P < 0.005) and numbers of myeloperoxidase-positive cells (P < 0.0001) were highest in biopsies from the ulcer edge in the colon and ileum, with decreasing gradients observed with distance from the edge (P < 0.05). No differences between colonic and ileal samples were detected for the parameters measured at any location. CONCLUSIONS: Biopsies from the ulcer edge in patients with Crohn's disease yielded the greatest histological disease activity and mRNA levels and had similar readouts in the colon and ileum. Research is needed to confirm this conclusion for other measures.

7 Article Early combined immunosuppression may be effective and safe in older patients with Crohn's disease: post hoc analysis of REACT. 2019

Singh, Siddharth / Stitt, Larry W / Zou, Guangyong / Khanna, Reena / Dulai, Parambir S / Sandborn, William J / Feagan, Brian G / Jairath, Vipul. ·Division of Gastroenterology, University of California San Diego, La Jolla, California. · Division of Biomedical Informatics, University of California San Diego, La Jolla, California. · Robarts Research Institute, London, Ontario, Canada. · Department of Epidemiology and Biostatistics, Western University, London, Ontario, Canada. · Department of Medicine, Division of Gastroenterology, University Hospital, Ontario, Canada. ·Aliment Pharmacol Ther · Pubmed #30891808.

ABSTRACT: BACKGROUND: Physicians may be reluctant to prescribe combined immunosuppression in older patients with Crohn's disease due to perceived risk of treatment-related complications. AIM: To evaluate the impact of age on risk of Crohn's disease-related complications in patients treated with early combined immunosuppression vs conventional management in a post hoc analysis of the randomised evaluation of an algorithm for Crohn's treatment (REACT), a cluster-randomised trial. METHODS: We compared efficacy (time to major adverse outcome of Crohn's disease-related surgery, hospitalisation or serious complications; corticosteroid-free clinical remission) and safety outcomes at 24 months, between patients aged <60 vs ≥60 years randomised to early combined immunosuppression or conventional management, using Cox proportional hazard analysis or modified Poisson model. In the early combined immunosuppression arm, patients with failure to achieve clinical remission within 4-12 weeks of corticosteroids were treated with a combination of tumour necrosis factor-α antagonist plus anti-metabolite and sequentially escalated in a stepwise algorithm. RESULTS: Of 1981 patients, 311 were ≥60 years (15.7%; 173 randomised to early combined immunosuppression and 138 to conventional management). Over 24 months, 10% of older patients developed Crohn's disease-related complications (early combined immunosuppression vs conventional management: 6.4% vs 14.5%) and 14 patients died (3.5% vs 5.8%). There was no difference between younger and older patients in risk of achieving corticosteroid-free clinical remission (<60 years, early combined immunosuppression (72.6%) vs conventional management (64.4%): relative risk [RR], 1.06 [95% CI, 0.98-1.15] vs ≥60 years, early combined immunosuppression (74.8%) vs conventional management (63.0%): RR, 1.09 [0.90-1.33], P-interaction = 0.78) or time to major adverse outcome (<60 years: hazard ratio [HR], 0.71 [0.53-0.96] vs ≥60 years: HR, 0.69 [0.31-1.51], P-interaction = 0.92) with early combined immunosuppression vs conventional management. CONCLUSIONS: We observed no difference in efficacy and safety of early combined immunosuppression compared to conventional management in older and younger patients. Early combined immunosuppression may be considered as a treatment option in selected older patients with Crohn's disease with suboptimal disease control. Clinical Trial Identifier: NCT01030809.

8 Article Development and Validation of a Scoring System to Predict Outcomes of Vedolizumab Treatment in Patients With Crohn's Disease. 2018

Dulai, Parambir S / Boland, Brigid S / Singh, Siddharth / Chaudrey, Khadija / Koliani-Pace, Jenna L / Kochhar, Gursimran / Parikh, Malav P / Shmidt, Eugenia / Hartke, Justin / Chilukuri, Prianka / Meserve, Joseph / Whitehead, Diana / Hirten, Robert / Winters, Adam C / Katta, Leah G / Peerani, Farhad / Narula, Neeraj / Sultan, Keith / Swaminath, Arun / Bohm, Matthew / Lukin, Dana / Hudesman, David / Chang, John T / Rivera-Nieves, Jesus / Jairath, Vipul / Zou, G Y / Feagan, Brian G / Shen, Bo / Siegel, Corey A / Loftus, Edward V / Kane, Sunanda / Sands, Bruce E / Colombel, Jean-Frederic / Sandborn, William J / Lasch, Karen / Cao, Charlie. ·University of California-San Diego, La Jolla, California. Electronic address: pdulai@ucsd.edu. · University of California-San Diego, La Jolla, California. · Mayo Clinic, Rochester, Minnesota. · Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire. · Cleveland Clinic Foundation, Cleveland, Ohio. · Icahn School of Medicine at Mount Sinai, New York, New York. · Indiana University, Indianapolis, Indiana. · North Shore University Hospital, Manhasset, New York. · Icahn School of Medicine at Mount Sinai, New York, New York; University of Alberta, Edmonton, Alberta, Canada. · Icahn School of Medicine at Mount Sinai, New York, New York; McMaster University Medical Centre, Hamilton, Ontario, Canada. · Lenox Hill Hospital, New York, New York. · Montefiore Medical Center, New York, New York. · New York University (NYU), New York, New York. · University of Western Ontario, London, Ontario, Canada. · Takeda Pharmaceuticals USA Inc., Deerfield, Illinois. ·Gastroenterology · Pubmed #29857091.

ABSTRACT: BACKGROUND & AIMS: As more treatment options for inflammatory bowel diseases become available, it is important to identify patients most likely to respond to different therapies. We created and validated a scoring system to identify patients with Crohn's disease (CD) who respond to vedolizumab. METHODS: We collected data from the GEMINI 2 phase 3 trial of patients with active CD treated with vedolizumab for 26 weeks (n = 814) and performed logistic regression analysis to identify factors associated with clinical, steroid-free, and durable remission (derivation set). We used these data to develop a clinical decision support tool, which we validated using data from 366 participants in a separate clinical practice observational cohort of patients with active CD treated with vedolizumab for 26 weeks (the VICTORY cohort). We evaluated the ability of this tool to identify patients in clinical remission or corticosteroid-free remission, or those with mucosal healing (MH), clinical remission with MH, or corticosteroid-free remission with MH after vedolizumab therapy using receiver operating characteristic area under the curve (AUC) analyses. The primary outcome was to develop and validate a list of factors associated with achieving remission by vedolizumab in patients with active CD. RESULTS: In the derivation analysis, we identified absence of previous treatment with a tumor necrosis factor antagonist (+3 points), absence of prior bowel surgery (+2 points), absence of prior fistulizing disease (+2 points), baseline level of albumin (+0.4 points per g/L), and baseline concentration of C-reactive protein (reduction of 0.5 points for values between 3.0 and 10.0 mg/L and 3.0 points for values >10.0 mg/L) as factors associated with remission. In the validation set, our model identified patients in clinical remission with an AUC of 0.67, patients in corticosteroid-free remission with an AUC of 0.66, patients with MH with an AUC of 0.72, patients in clinical remission with MH with an AUC of 0.73, and patients in corticosteroid-free clinical remission with MH with an AUC of 0.75. A cutoff value of 13 points identified patients in clinical remission after vedolizumab therapy with 92% sensitivity, patients in corticosteroid-free remission with 94% sensitivity, patients with MH with 98% sensitivity, patients with clinical remission and MH with 100% sensitivity, and patients with corticosteroid-free clinical remission with MH with 100% sensitivity. CONCLUSIONS: We developed and validated a scoring system to identify patients with CD most likely to respond to 26 weeks of vedolizumab therapy. Further studies are needed to optimize its accuracy in select populations and determine its cost-effectiveness.

9 Article Reliability of Measuring Ileo-Colonic Disease Activity in Crohn's Disease by Magnetic Resonance Enterography. 2018

Jairath, Vipul / Ordas, Ingrid / Zou, Guangyong / Panes, Julian / Stoker, Jaap / Taylor, Stuart A / Santillan, Cynthia / Horsthuis, Karin / Samaan, Mark A / Shackelton, Lisa M / Stitt, Larry W / Hindryckx, Pieter / Khanna, Reena / Sandborn, William J / D'Haens, Geert / Feagan, Brian G / Levesque, Barrett G / Rimola, Jordi. ·Department of Medicine, Division of Gastroenterology, University of Western Ontario, London, Ontario, Canada. · Department of Epidemiology and Biostatistics, University of Western Ontario, London, Ontario, Canada. · Robarts Clinical Trials Inc, London, Ontario, Canada. · Hospital Clinic Barcelona, IDIBAPS, CIBERehd, Barcelona, Spain. · Academic Medical Center, Amsterdam, The Netherlands. · University College London, London, United Kingdom. · University of California San Diego, La Jolla, United States. · VU Medical Center, Amsterdam, The Netherlands. · Department of Gastroenterology, Guy's & St Thomas' Hospital, London, UK. · Ghent University, Ghent, Belgium. ·Inflamm Bowel Dis · Pubmed #29361096.

ABSTRACT: Background: Magnetic resonance enterography is increasingly utilized for assessment of luminal Crohn's disease activity. The Magnetic Resonance Index of Activity and the London Index are the most commonly used outcome measures in clinical trials. We assessed the reliability of these indices and several additional items. Methods: A consensus process clarified scoring conventions and identified additional items based on face validity. Four experienced radiologists evaluated 50 images in triplicate, in random order, at least 1 month apart, using a central image management system. Intra- and interrater reliability were assessed by calculating and comparing intraclass correlation coefficients. Results: Intrarater intraclass correlation coefficients (95% confidence intervals) for the Magnetic Resonance Index of Activity, London, and London "extended" indices and a visual analogue scale were 0.89 (0.84 to 0.91), 0.87 (0.83 to 0.90), 0.89 (0.85 to 0.92), and 0.86 (0.81 to 0.90). Corresponding interrater intraclass correlation coefficients were 0.71 (0.61 to 0.77), 0.67 (0.55 to 0.75), 0.70 (0.61 to 0.76), and 0.71 (0.62 to 0.77). Reliability for each index was greatest in the terminal ileum and poorest in the rectum. All 3 indices were highly correlated with the visual analogue scale; 0.79 (0.71 to 0.85), 0.78 (0.71 to 0.84), and 0.79 (0.72 to 0.85) for the Magnetic Resonance Index of Activity, London, and the London "extended" indices, respectively. Conclusions: "Substantial" interrater reliability was observed for all 3 indices. Future studies should assess responsiveness to treatment in order to confirm their utility as evaluative indices in clinical trials and clinical practice.

10 Article Development of Clinical Prediction Models for Surgery and Complications in Crohn's Disease. 2018

Guizzetti, Leonardo / Zou, Guangyong / Khanna, Reena / Dulai, Parambir S / Sandborn, William J / Jairath, Vipul / Feagan, Brian G. ·Robarts Clinical Trials Inc., University of Western Ontario, London, ON, Canada. · Department of Epidemiology and Biostatistics, University of Western Ontario, London, ON, Canada. · Department of Medicine, Division of Gastroenterology, University of Western Ontario, London, ON, Canada. · Division of Gastroenterology, University of California San Diego, La Jolla, CA, USA. ·J Crohns Colitis · Pubmed #29028958.

ABSTRACT: Background and Aims: Crohn's disease-related complications account for a substantial proportion of inflammatory bowel disease-associated health care expenditure. Identifying patients at risk for complications may allow for targeted use of early therapeutic interventions to offset this natural course. We aimed to develop risk prediction models for Crohn's disease-related surgery and complications. Methods: Using data from the Randomised Evaluation of an Algorithm for Crohn's Disease cluster-randomised clinical Trial [REACT], which involved 1898 patients from 40 community practices, separate prediction models were derived and internally validated for predicting Crohn's disease-related surgery and disease-related complications [defined as the first disease-related surgery, hospitalisation, or complication within 24 months]. Model performance was assessed in terms of discrimination and calibration, decision curves, and net benefit analyses. Results: There were 130 [6.8%] disease-related surgeries and 504 [26.6%] complications during the 24-month follow-up period. Selected baseline predictors of surgery included age, gender, disease location, Harvey-Bradshaw Index [HBI] score, stool frequency, antimetabolite or 5-aminosalicylate use, and the presence of a fistula, abscess, or abdominal mass. Selected predictors of complications included those same factors for surgery, plus corticosteroid or anti-tumour necrosis factor use, but excluded 5-aminosalicylate use. Discrimination ability, as measured by validated c-statistics, was 0.70 and 0.62 for the surgery and complication models, respectively. Score charts and nomograms were developed to facilitate future risk score calculation. Conclusions: Separate risk prediction models for Crohn's disease-related surgery and complications were developed using clinical trial data involving community gastroenterology practices. These models could be used to guide Crohn's disease management. External validation is warranted.

11 Article The development of a magnetic resonance imaging index for fistulising Crohn's disease. 2017

Samaan, M A / Puylaert, C A J / Levesque, B G / Zou, G Y / Stitt, L / Taylor, S A / Shackelton, L M / Vandervoort, M K / Khanna, R / Santillan, C / Rimola, J / Hindryckx, P / Nio, C Y / Sandborn, W J / D'Haens, G / Feagan, B G / Jairath, V / Stoker, J. ·Department of Gastroenterology, Guy's & St Thomas' Hospital, London, UK. · Robarts Clinical Trials, Inc, London, Canada. · Department of Radiology, Academic Medical Centre, Amsterdam, The Netherlands. · Department of Gastroenterology, University of California San Diego, La Jolla, CA, USA. · Robarts Clinical Trials, Inc, San Diego, CA, USA. · Department of Epidemiology and Biostatistics, University of Western Ontario, London, Canada. · Department of Medical Imaging, University College London, London, UK. · Department of Medicine, University of Western Ontario, London, Canada. · Department of Radiology, University of California San Diego, La Jolla, CA, USA. · Department of Radiology, Hospital Clínic de Barcelona, Barcelona, Spain. · Department of Gastroenterology, University Hospital of Ghent, Ghent, Belgium. · Department of Gastroenterology, Academic Medical Centre, Amsterdam, The Netherlands. · Robarts Clinical Trials, BV, Amsterdam, The Netherlands. ·Aliment Pharmacol Ther · Pubmed #28653753.

ABSTRACT: BACKGROUND: Magnetic resonance imaging (MRI) is the gold standard for assessment of perianal fistulising Crohn's disease (CD). The Van Assche index is the most commonly used MRI fistula index. AIMS: To assess the reliability of the Van Assche index, and to modify the instrument to improve reliability and create a novel index for fistulising CD. METHODS: A consensus process developed scoring conventions for existing Van Assche index component items and new items. Four experienced radiologists evaluated 50 MRI images in random order on three occasions. Reliability was assessed by estimates of intraclass correlation coefficients (ICCs). Common sources of disagreement were identified and recommendations made to minimise disagreement. A mixed effects model used a 100 mm visual anologue scale (VAS) for global severity as outcome and component items as predictors to create a modified Van Assche index. RESULTS: Intraclass correlation coefficients (95% confidence intervals) for intra-rater reliability of the original and modified Van Assche indices and the VAS were 0.86 (0.81-0.90), 0.90 (0.86-0.93) and 0.86 (0.82-0.89). Corresponding ICCs for inter-rater reliability were 0.66 (0.52-0.76), 0.67 (0.55-0.75) and 0.58 (0.47-0.66). Sources of disagreement included number, location, and extension of fistula tracts, and rectal wall involvement. A modified Van Assche index (range 0-24) was created that included seven component items. CONCLUSIONS: Although "almost perfect" intra-rater reliability was observed for the assessment of MRI images for fistulising CD using the Van Assche index, inter-rater reliability was considerably lower. Our modification of this index should result in a more optimal instrument.

12 Article Responsiveness of Endoscopic Indices of Disease Activity for Crohn's Disease. 2017

Khanna, Reena / Zou, GuangYong / Stitt, Larry / Feagan, Brian G / Sandborn, William J / Rutgeerts, Paul / McDonald, John W D / Dubcenco, Elena / Fogel, Ronald / Panaccione, Remo / Jairath, Vipul / Nelson, Sigrid / Shackelton, Lisa M / Huang, Bidan / Zhou, Qian / Robinson, Anne M / Levesque, Barrett G / D'Haens, Geert. ·Robarts Clinical Trials, University of Western Ontario, London, Ontario, Canada. · Division of Gastroenterology, Department of Medicine, University of Western Ontario, London, Ontario, Canada. · Department of Epidemiology and Biostatistics, University of Western Ontario, London, Ontario, Canada. · Division of Gastroenterology, University of California San Diego, La Jolla, California, USA. · Department of Gastroenterology, University Hospital Gasthuisberg, Leuven, Belgium. · Digestive Health Center of Michigan, Chesterfield, Michigan, USA. · Inflammatory Bowel Disease Clinic, University of Calgary, Calgary, Alberta, Canada. · Nuffield Department of Medicine, University of Oxford, Oxford, UK. · AbbVie, Inc, North Chicago, Illinois, USA. · Inflammatory Bowel Disease Centre, Academic Medical Centre, Amsterdam, The Netherlands. ·Am J Gastroenterol · Pubmed #28071654.

ABSTRACT: OBJECTIVES: The Crohn's Disease Endoscopic Index of Severity (CDEIS) and the Simple Endoscopic Score for Crohn's Disease (SES-CD) are commonly used to assess Crohn's disease (CD) activity; however neither instrument is fully validated. We evaluated the responsiveness to change of the SES-CD and CDEIS using data from a trial of adalimumab, a drug therapy of known efficacy. METHODS: Paired video recordings (N=112) of colonoscopies (baseline and week 8-12) obtained from patients with CD who participated in a trial of adalimumab therapy were reviewed in random order, in duplicate, by four central readers (56 pairs of videos by 2 groups of readers). Responsiveness of the SES-CD and the CDEIS was evaluated by comparing correlations between the observed and pre-specified predictions of change scores for these endoscopic indices with a global endoscopic evaluation of severity (GELS), a patient reported outcome (PRO2), and the Crohn's disease activity index (CDAI), and by calculation of the standardized effect size, and Guyatt's Responsiveness statistic (GRS) using 2 definitions of change; (1) treatment assignment and (2) an absolute change in total PRO2 of 50. The potential application of effect size estimates was demonstrated by calculating hypothetical sample sizes for comparing two independent groups. The impact of removing stenosis as an index item and adjusting for the number of segments observed was also assessed. RESULTS: Changes in both endoscopic instruments and the GELS were highly correlated. The SES-CD displayed numerically higher effect sizes for both definitions of change. The standardized effect size and GRS estimates (95% confidence interval) for the SES-CD based on treatment assignment were 0.84 (0.53, 1.15) and 0.79 (0.48, 1.09). Corresponding values for the CDEIS were 0.72 (0.42, 1.02) and 0.75 (0.45, 1.06). The standardized effect size and GRS estimates for the SES-CD based on an absolute change in total PRO2 of 50 points or greater were 0.76 (0.49, 1.02) and 0.93 (0.64, 1.21). Corresponding values for CDEIS were 0.70 (0.44, 0.97), 0.83 (0.55, 1.10). Removal of stenosis as an index item and adjusting for observed segments did not improve responsiveness estimates. CONCLUSIONS: Although both the SES-CD and CDEIS are valid measures of endoscopic disease activity that are moderately responsive to changes in endoscopic disease activity, the SES-CD displayed numerically greater responsiveness in this data set.

13 Article Effect of Standardised Scoring Conventions on Inter-rater Reliability in the Endoscopic Evaluation of Crohn's Disease. 2016

Dubcenco, Elena / Zou, Guangyong / Stitt, Larry / Baker, Jeffrey P / Jeejeebhoy, Khursheed N / Kandel, Gabor / Kim, Young-In / Grover, Samir C / McDonald, John W D / Shackelton, Lisa M / Khanna, Reena / D'Haens, Geert / Sandborn, William J / Feagan, Brian G / Levesque, Barrett G. ·Robarts Clinical Trials, University of Western Ontario, London, ON, Canada. · St Michaels Hospital, University of Toronto, Toronto, ON, Canada. · Department of Gastroenterology, University Hospital, Gasthuisberg, Leuven, Belgium. · Division of Gastroenterology, University of California San Diego, La Jolla, CA, USA. · Robarts Clinical Trials, University of Western Ontario, London, ON, Canada brian.feagan@robartsinc.com brian.feagan@robartsinc.com. ·J Crohns Colitis · Pubmed #27385400.

ABSTRACT: BACKGROUND AND AIMS: The Crohn's Disease Endoscopic Index of Severity [CDEIS] and Simplified Endoscopic Score for Crohn's Disease [SES-CD] demonstrate consistent overall intra- and inter-rater reliability. However, the reliability of some index items is relatively poor. We evaluated scoring conventions to improve the reliability of these items. METHODS: Five gastroenterologists with no previous experience scoring the CDEIS or SES-CD were trained on their use. A total of 65 video recordings of colonoscopies were scored blindly by each gastroenterologist before and after additional training on index scoring conventions. Intra-class correlation coefficients [ICCs] assessed the effect of application of these conventions on the reliability of the CDEIS, SES-CD, and a Global Evaluation of Lesion Severity [GELS] score. RESULTS: Following training on scoring conventions, inter-rater ICCs (95% confidence interval [CI]) for the total SES-CD score increased from 0.78 [0.71, 0.85] to 0.85 [0.79, 0.89]. The ICCs for the total CDEIS and GELS scores were not affected: corresponding inter-rater ICCs were 0.74 [0.65, 0.81] and 0.49, [0.38, 0.61] before and 0.73 [0.65, 0.81] and 0.53 [0.42, 0.64] following application of scoring conventions. Estimations of ulcer depth, surface area, anatomical location, and stenosis were important sources of variability. CONCLUSIONS: Use of scoring conventions previously developed by expert central readers enhanced the reliability of the SES-CD but did not similarly affect the CDEIS or GELS. As the SES-CD is more likely to be reliable than the CDEIS and can be optimised with targeted training, it is the preferred instrument for use in clinical trials.

14 Article Reliability among central readers in the evaluation of endoscopic findings from patients with Crohn's disease. 2016

Khanna, Reena / Zou, Guangyong / D'Haens, Geert / Rutgeerts, Paul / McDonald, J W D / Daperno, Marco / Feagan, Brian G / Sandborn, William J / Dubcenco, Elena / Stitt, Larry / Vandervoort, Margaret K / Donner, Allan / Luo, Allison / Levesque, Barrett G. ·Robarts Clinical Trials, Robarts Research Institute, University of Western Ontario, London, Ontario, Canada Department of Medicine, University of Western Ontario, London, Ontario, Canada. · Robarts Clinical Trials, Robarts Research Institute, University of Western Ontario, London, Ontario, Canada Department of Epidemiology and Biostatistics, University of Western Ontario, London, Ontario, Canada. · Robarts Clinical Trials, Robarts Research Institute, University of Western Ontario, London, Ontario, Canada Inflammatory Bowel Disease Centre, Academic Medical Centre, Amsterdam, The Netherlands. · Department of Gastroenterology, University Hospital, Gasthuisberg, Leuven, Belgium. · Robarts Clinical Trials, Robarts Research Institute, University of Western Ontario, London, Ontario, Canada. · Gastroenterology Division, A.O. Ordine Mauriziano, Torino, Italy. · Robarts Clinical Trials, Robarts Research Institute, University of Western Ontario, London, Ontario, Canada Department of Medicine, University of Western Ontario, London, Ontario, Canada Department of Epidemiology and Biostatistics, University of Western Ontario, London, Ontario, Canada. · Robarts Clinical Trials, Robarts Research Institute, University of Western Ontario, London, Ontario, Canada Division of Gastroenterology, University of California San Diego, La Jolla, California, USA. · Bristol-Myers Squibb, Princeton, New Jersey, USA. ·Gut · Pubmed #25935574.

ABSTRACT: 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.

15 Article Early combined immunosuppression for the management of Crohn's disease (REACT): a cluster randomised controlled trial. 2015

Khanna, Reena / Bressler, Brian / Levesque, Barrett G / Zou, Guangyong / Stitt, Larry W / Greenberg, Gordon R / Panaccione, Remo / Bitton, Alain / Paré, Pierre / Vermeire, Séverine / D'Haens, Geert / MacIntosh, Donald / Sandborn, William J / Donner, Allan / Vandervoort, Margaret K / Morris, Joan C / Feagan, Brian G / Anonymous6910841. ·Robarts Clinical Trials Inc, Robarts Research Institute, London, ON, Canada; Department of Medicine, University of Western Ontario, London, ON, Canada. · Department of Gastroenterology, St Paul's Hospital, Vancouver, BC, Canada. · Robarts Clinical Trials Inc, Robarts Research Institute, London, ON, Canada; Division of Gastroenterology, University of California San Diego, La Jolla, CA, USA. · Robarts Clinical Trials Inc, Robarts Research Institute, London, ON, Canada; Department of Epidemiology and Biostatistics, University of Western Ontario, London, ON, Canada. · Robarts Clinical Trials Inc, Robarts Research Institute, London, ON, Canada. · Division of Gastroenterology, Mount Sinai Hospital, Toronto, ON, Canada. · Division of Gastroenterology and Hepatology, Department of Medicine, University of Calgary, Calgary, AB, Canada. · Division of Gastroenterology, McGill University Health Centre, McGill University, Montreal, QC, Canada. · Laval University, CHAUQ, Hôpital du St-Sacrement, Quebec City, QC, Canada. · Department of Clinical and Experimental Medicine, Translational Research Center for Gastrointestinal Disorders, Leuven, Belgium. · Robarts Clinical Trials Inc, Robarts Research Institute, London, ON, Canada; Department of Gastroenterology, Academic Medical Centre, University of Amsterdam, Amsterdam, Netherlands. · Division of Gastroenterology, Dalhousie University, Halifax, NS, Canada. · Robarts Clinical Trials Inc, Robarts Research Institute, London, ON, Canada; Department of Medicine, University of Western Ontario, London, ON, Canada; Department of Epidemiology and Biostatistics, University of Western Ontario, London, ON, Canada. Electronic address: brian.feagan@robartsinc.com. ·Lancet · Pubmed #26342731.

ABSTRACT: BACKGROUND: Conventional management of Crohn's disease features incremental use of therapies. However, early combined immunosuppression (ECI), with a TNF antagonist and antimetabolite might be a more effective strategy. We compared the efficacy of ECI with that of conventional management for treatment of Crohn's disease. METHODS: In this open-label cluster randomised controlled trial (Randomised Evaluation of an Algorithm for Crohn's Treatment, REACT), we included community gastroenterology practices from Belgium and Canada that were willing to be assigned to either of the study groups, participate in all aspects of the study, and provide data on up to 60 patients with Crohn's disease. These practices were randomly assigned (1:1) to either ECI or conventional management. The computer-generated randomisation was minimised by country and practice size. Up to 60 consecutive adult patients were assessed within practices. Patients who were aged 18 years or older; documented to have Crohn's disease; able to speak or understand English, French, or Dutch; able to access a telephone; and able to provide written informed consent were followed up for 2 years. The primary outcome was the proportion of patients in corticosteroid-free remission (Harvey-Bradshaw Index score ≤ 4) at 12 months at the practice level. This trial is registered with ClinicalTrials.gov, number NCT01030809. FINDINGS: This study took place between March 15, 2010, and Oct 1, 2013. Of the 60 practices screened, 41 were randomly assigned to either ECI (n=22) or conventional management (n=19). Two practices (one in each group) discontinued because of insufficient resources. 921 (85%) of the 1084 patients at ECI practices and 806 (90%) of 898 patients at conventional management practices completed 12 months follow-up and were included in an intention-to-treat analysis. The 12 month practice-level remission rates were similar at ECI and conventional management practices (66·0% [SD 14·0] and 61·9% [16·9]; adjusted difference 2·5%, 95% CI -5·2% to 10·2%, p=0·5169). The 24 month patient-level composite rate of major adverse outcomes defined as occurrence of surgery, hospital admission, or serious disease-related complications was lower at ECI practices than at conventional management practices (27·7% and 35·1%, absolute difference [AD] 7·3%, hazard ratio [HR]: 0·73, 95% CI 0·62 to 0·86, p=0·0003). There were no differences in serious drug-related adverse events. INTERPRETATION: Although ECI was not more effective than conventional management for controlling Crohn's disease symptoms, the risk of major adverse outcomes was lower. The latter finding should be considered hypothesis-generating for future trials. ECI was not associated with an increased risk of serious drug-related adverse events or mortality. FUNDING: AbbVie Pharmaceuticals.

16 Article Validation of gene expression biomarker analysis for biopsy-based clinical trials in Crohn's disease. 2015

Boland, Brigid S / Boyle, David L / Sandborn, William J / Firestein, Gary S / Levesque, Barrett G / Hillman, Joshua / Zhang, Bing / Proudfoot, James / Eckmann, Lars / Ernst, Peter B / Rivera-Nieves, Jesus / Pola, Suresh / Copur-Dahi, Nedret / Zou, Guangyong / Chang, John T. ·*Inflammatory Bowel Disease Center, Division of Gastroenterology, Department of Medicine, University of California San Diego, La Jolla, California; †San Diego Digestive Disease Research Center, University of California San Diego, La Jolla, California; ‡Department of Medicine, Division of Gastroenterology, University of California San Diego, La Jolla, California; §Clinical and Translational Research Institute, University of California San Diego, La Jolla, California; ‖Department of Medicine, Division of Rheumatology, University of California San Diego, La Jolla, California; ¶Department of Pathology, University of California San Diego, La Jolla, California; **Division of Gastroenterology & Hepatology, Kaiser Permanente, San Diego, California; and ††Department of Epidemiology and Biostatistics, Western University, London, ON, Canada. ·Inflamm Bowel Dis · Pubmed #25545378.

ABSTRACT: BACKGROUND: The ability to measure the expression of proinflammatory cytokines from intestinal biopsies in patients with Crohn's disease in an accurate and reproducible way is critical for proof-of-concept and mechanism-of-action trials; however, the number of biopsies from a segment of the ileum or colon required to yield reproducible results has not been rigorously evaluated. We examined intestinal biopsies from patients with Crohn's disease to validate methods for detecting changes in inflammatory gene expression. METHODS: To evaluate the reproducibility of gene expression measurements, intestinal biopsies were obtained from designated segments from 6 healthy controls, 6 patients with active Crohn's disease, and 6 patients with inactive Crohn's disease. Disease activity was based on the simple endoscopic score for Crohn's disease. Expression of 7 proinflammatory genes was measured from each biopsy using quantitative polymerase chain reaction. Using a linear mixed effects model, the power to detect transcriptional changes corresponding to active and inactive Crohn's disease was calculated. RESULTS: Total simple endoscopic score for Crohn's disease score corresponds with expression of most inflammatory biomarkers. For most genes, 2 to 5 biopsies are needed to reduce sampling error to <25% for most genes. To measure changes in mRNA expression corresponding to active versus inactive Crohn's disease, 1 to 2 intestinal biopsies from 3 patients before and after treatment are needed to yield power of at least 80%. CONCLUSIONS: Measuring proinflammatory gene expression from mucosal biopsies from patients with Crohn's disease is practicable and provides objective biomarkers that can be used in proof-of-concept and mechanism-of-action trials to assess response to therapy.

17 Article A retrospective analysis: the development of patient reported outcome measures for the assessment of Crohn's disease activity. 2015

Khanna, R / Zou, G / D'Haens, G / Feagan, B G / Sandborn, W J / Vandervoort, M K / Rolleri, R L / Bortey, E / Paterson, C / Forbes, W P / Levesque, B G. ·Department of Medicine, University of Western Ontario, London, ON, Canada; Robarts Clinical Trials Inc., University of Western Ontario, London, ON, Canada. ·Aliment Pharmacol Ther · Pubmed #25348809.

ABSTRACT: BACKGROUND: The Crohn's Disease Activity Index (CDAI) is a measure of disease activity based on symptoms, signs and a laboratory test. The US Food and Drug Administration has indicated that patient reported outcomes (PROs) should be the primary outcome in randomised controlled trials for Crohn's disease (CD). AIM: As no validated PRO exists for CD, to investigate whether CDAI diary card items could be modified for this purpose. METHODS: Data from a trial of rifaximin-extended intestinal release were used to identify cut-points for stool frequency, pain and general well-being using receiver operating characteristic curves with CDAI <150 as criterion. The operating properties of 2- and 3-item PRO were evaluated using data from a trial of methotrexate in CD. Regression analysis determined PRO2 and PRO3 scores that correspond to CDAI-defined thresholds of 150, 220 and 450 and changes of 50, 70 and 100 points. RESULTS: Optimum cut-points for CDAI remission were mean daily stool frequency ≤1.5, abdominal pain ≤1, and general well-being score of ≤1 (areas under the ROC curve 0.79, 0.91 and 0.89, respectively). The effect estimates were similar using 2- and 3-item PROs or CDAI. PRO2 and PRO3 values corresponding to CDAI scores of 150, 220 and 450 points were 8, 14, 34 and 13, 22, 53. The corresponding values for CDAI changes of 50, 70 and 100, were 2, 5, 8 and 5, 9, 14. Responsiveness to change was similar for both PROs. CONCLUSION: Patient reported outcomes derived from CDAI diary items may be appropriate for use in clinical trials for CD.

18 Article The relationship between infliximab concentrations, antibodies to infliximab and disease activity in Crohn's disease. 2015

Vande Casteele, Niels / Khanna, Reena / Levesque, Barrett G / Stitt, Larry / Zou, G Y / Singh, Sharat / Lockton, Steve / Hauenstein, Scott / Ohrmund, Linda / Greenberg, Gordon R / Rutgeerts, Paul J / Gils, Ann / Sandborn, William J / Vermeire, Séverine / Feagan, Brian G. ·KU Leuven Department of Pharmaceutical and Pharmacological Sciences, Leuven, Belgium Division of Gastroenterology, University of California San Diego, La Jolla, California, USA Robarts Clinical Trials, Western University, London, Ontario, Canada. · Robarts Clinical Trials, Western University, London, Ontario, Canada. · Division of Gastroenterology, University of California San Diego, La Jolla, California, USA Robarts Clinical Trials, Western University, London, Ontario, Canada. · Prometheus Laboratories, Inc., San Diego, California, USA. · University of Toronto, Mount Sinai Hospital, Toronto, Ontario, Canada. · KU Leuven Department of Clinical and Experimental Medicine, Leuven, Belgium. · KU Leuven Department of Pharmaceutical and Pharmacological Sciences, Leuven, Belgium. · Division of Gastroenterology, University of California San Diego, La Jolla, California, USA. ·Gut · Pubmed #25336114.

ABSTRACT: OBJECTIVE: Although low infliximab trough concentrations and antibodies to infliximab (ATI) are associated with poor outcomes in patients with Crohn's disease (CD), the clinical relevance of ATI in patients with adequate infliximab concentrations is uncertain. We evaluated this question using an assay sensitive for identification of ATI in the presence of infliximab. DESIGN: In an observational study, 1487 trough serum samples from 483 patients with CD who participated in four clinical studies of maintenance infliximab therapy were analysed using a fluid phase mobility shift assay. Infliximab and ATI concentrations most discriminant for remission, defined as a C-reactive protein concentration of ≤ 5 mg/L, were determined by receiver operating characteristic curves. A multivariable regression model evaluated these factors as independent predictors of remission. RESULTS: Based upon analysis of 1487 samples, 77.1% of patients had detectable and 22.9% had undetectable infliximab concentrations, of which 9.5% and 71.8%, respectively, were positive for ATI. An infliximab concentration of > 2.79 μg/mL (area under the curve (AUC) = 0.681; 95% CI 0.632 to 0.731) and ATI concentration of < 3.15 U/mL (AUC = 0.632; 95% CI 0.589 to 0.676) were associated with remission. Multivariable analysis showed that concentrations of both infliximab trough (OR 1.8; 95% CI 1.3 to 2.5; p < 0.001) and ATI (OR 0.57; 95% CI 0.39 to 0.81; p = 0.002) were independent predictors of remission. CONCLUSIONS: The development of ATI increases the probability of active disease even at low concentrations and in the presence of a therapeutic concentration of drug during infliximab maintenance therapy. Evaluation of strategies to prevent ATI formation, including therapeutic drug monitoring with selective infliximab dose intensification, is needed.

19 Article Methotrexate in combination with infliximab is no more effective than infliximab alone in patients with Crohn's disease. 2014

Feagan, Brian G / McDonald, John W D / Panaccione, Remo / Enns, Robert A / Bernstein, Charles N / Ponich, Terry P / Bourdages, Raymond / Macintosh, Donald G / Dallaire, Chrystian / Cohen, Albert / Fedorak, Richard N / Paré, Pierre / Bitton, Alain / Saibil, Fred / Anderson, Frank / Donner, Allan / Wong, Cindy J / Zou, Guangyong / Vandervoort, Margaret K / Hopkins, Marybeth / Greenberg, Gordon R. ·Robarts Clinical Trials, Western University, London, Ontario, Canada; Department of Medicine, Western University, London, Ontario, Canada; Department of Epidemiology and Biostatistics, Western University, London, Ontario, Canada. Electronic address: brian.feagan@robartsinc.com. · Robarts Clinical Trials, Western University, London, Ontario, Canada. · Inflammatory Bowel Disease Clinic, University of Calgary, Calgary, Alberta, Canada. · St. Paul's Hospital, University of British Columbia, Vancouver, British Columbia, Canada. · Health Sciences Centre, University of Manitoba, Winnipeg, Manitoba, Canada. · Department of Medicine, Western University, London, Ontario, Canada; London Health Sciences Centre, South Street Hospital, London, Ontario, Canada. · Hôtel-Dieu de Lévis, Lévis, Quebec, Canada. · Dalhousie University, Halifax, Nova Scotia, Canada. · Centre Hospitalier Universitaire de Québec-Pavillon St. François d'Assise, Quebec City, Quebec, Canada. · Jewish General Hospital, Montreal, Quebec, Canada. · University of Alberta, Edmonton, Alberta, Canada. · Hôpital St. Sacrement, Quebec City, Quebec, Canada. · McGill University Health Centre, Montreal, Quebec, Canada. · Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ontario, Canada. · The Liver and Intestinal Research Centre, Vancouver, British Columbia, Canada. · Robarts Clinical Trials, Western University, London, Ontario, Canada; Department of Epidemiology and Biostatistics, Western University, London, Ontario, Canada. · Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada. ·Gastroenterology · Pubmed #24269926.

ABSTRACT: BACKGROUND & AIMS: Methotrexate and infliximab are effective therapies for Crohn's disease (CD). In the combination of maintenance methotrexate-infliximab trial, we evaluated the potential superiority of combination therapy over infliximab alone. METHODS: In a 50-week, double-blind, placebo-controlled trial, we compared methotrexate and infliximab with infliximab alone in 126 patients with CD who had initiated prednisone induction therapy (15-40 mg/day) within the preceding 6 weeks. Patients were assigned randomly to groups given methotrexate at an initial weekly dose of 10 mg, escalating to 25 mg/week (n = 63), or placebo (n = 63). Both groups received infliximab (5 mg/kg of body weight) at weeks 1, 3, 7, and 14, and every 8 weeks thereafter. Prednisone was tapered, beginning at week 1, and discontinued no later than week 14. The primary outcome was time to treatment failure, defined as a lack of prednisone-free remission (CD Activity Index, <150) at week 14 or failure to maintain remission through week 50. RESULTS: Patients' baseline characteristics were similar between groups. By week 50, the actuarial rate of treatment failure was 30.6% in the combination therapy group compared with 29.8% in the infliximab monotherapy group (P = .63; hazard ratio, 1.16; 95% confidence interval, 0.62-2.17). Prespecified subgroup analyses failed to show a benefit in patients with short disease duration or an increased level of C-reactive protein. No clinically meaningful differences were observed in secondary outcomes. Combination therapy was well tolerated. CONCLUSIONS: The combination of infliximab and methotrexate, although safe, was no more effective than infliximab alone in patients with CD receiving treatment with prednisone. ClincialTrials.gov number, NCT00132899.