Pediatric inflammatory bowel disease clinical innovations meeting of the Crohn's and colitis foundation: Charting the future of pediatric IBD

The Crohn's & Colitis Foundation has facilitated transformational research in pediatric inflammatory bowel disease (IBD), through the RISK and PROTECT studies, that has laid the groundwork for a comprehensive understanding of molecular mechanisms of disease and predictors of therapeutic response in children. Despite these advances, children have lacked timely and informed access to the latest therapeutic advancements in IBD. The Crohn's & Colitis Foundation convened a Pediatric Resource Organization for Kids with Inflammatory Intestinal Diseases (PRO-KIIDS) Clinical Innovations Meeting at the inaugural Crohn's and Colitis Congress in January 2018 to devise how to advance the care of children with IBD. The working group selected 2 priorities: (1) accelerating therapies to children with IBD and (2) stimulating investigator-initiated research while fostering sustainable collaboration; and proposed 2 actions: (a) the convening of a task force to specifically address how to accelerate pharmacotherapies to children with IBD and (b) the funding of a multicenter clinical and translational research study that incorporates the building of critical research infrastructure

Mucosal Expression of Type 2 and Type 17 Immune Response Genes Distinguishes Ulcerative Colitis From Colon-Only Crohn's Disease in Treatment-Naive Pediatric Patients

Background & Aims There is controversy regarding the role of the type 2 immune response in the pathogenesis of ulcerative colitis (UC)?few data are available from treatment-naive patients. We investigated whether genes associated with a type 2 immune response in the intestinal mucosa are up-regulated in treatment-naive pediatric patients with UC compared with patients with Crohn's disease (CD)-associated colitis or without inflammatory bowel disease (IBD), and whether expression levels are associated with clinical outcomes. Methods We used a real-time reverse-transcription quantitative polymerase chain reaction array to analyze messenger RNA (mRNA) expression patterns in rectal mucosal samples from 138 treatment-naive pediatric patients with IBD and macroscopic rectal disease, as well as those from 49 children without IBD (controls), enrolled in a multicenter prospective observational study from 2008 to 2012. Results were validated in real-time reverse-transcription quantitative polymerase chain reaction analyses of rectal RNA from an independent cohort of 34 pediatric patients with IBD and macroscopic rectal disease and 17 controls from Cincinnati Children's Hospital Medical Center. Results We measured significant increases in mRNAs associated with a type 2 immune response (interleukin [IL]5 gene, IL13, and IL13RA2) and a type 17 immune response (IL17A and IL23) in mucosal samples from patients with UC compared with patients with colon-only CD. In a regression model, increased expression of IL5 and IL17A mRNAs distinguished patients with UC from patients with colon-only CD (P =.001; area under the receiver operating characteristic curve, 0.72). We identified a gene expression pattern in rectal tissues of patients with UC, characterized by detection of IL13 mRNA, that predicted clinical response to therapy after 6 months (odds ratio [OR], 6.469; 95% confidence interval [CI], 1.553?26.94), clinical response after 12 months (OR, 6.125; 95% CI, 1.330?28.22), and remission after 12 months (OR, 5.333; 95% CI, 1.132?25.12). Conclusions In an analysis of rectal tissues from treatment-naive pediatric patients with IBD, we observed activation of a type 2 immune response during the early course of UC. We were able to distinguish patients with UC from those with colon-only CD based on increased mucosal expression of genes that mediate type 2 and type 17 immune responses. Increased expression at diagnosis of genes that mediate a type 2 immune response is associated with response to therapy and remission in pediatric patients with UC

Serologic Reactivity Reflects Clinical Expression of Ulcerative Colitis in Children

Background In contrast to pediatric Crohn's disease (CD), little is known in pediatric ulcerative colitis (UC) about the relationship between disease phenotype and serologic reactivity to microbial and other antigens. Aim The aim of this study was to examine disease phenotype and serology in a well-characterized inception cohort of children newly diagnosed with UC during the PROTECT Study (Predicting Response to Standardized Pediatric Colitis Therapy). Methods Patients were recruited from 29 participating centers. Demographic, clinical, laboratory, and serologic (pANCA, ASCA IgA/IgG, Anti-CBir1, and Anti-OmpC) data were obtained from children 4-17 years old with UC. Results Sixty-five percent of the patients had positive serology for pANCA, with 62% less than 12 years old and 66% 12 years old or older. Perinuclear anti-neutrophil cytoplasmic antibodies did not correspond to a specific phenotype though pANCA ò100, found in 19%, was strongly associated with pancolitis (P = 0.003). Anti-CBir1 was positive in 19% and more common in younger children with 32% less than 12 years old as compared with 14% 12 years old or older (P < 0.001). No association was found in any age group between pANCA and Anti-CBir1. Relative rectal sparing was more common in +CBir1, 16% versus 7% (P = 0.02). Calprotectin was lower in Anti-CBir1+ (Median [IQR] 1495 mcg/g [973-3333] vs 2648 mcg/g [1343-4038]; P = 0.04). Vitamin D 25-OH sufficiency was associated with Anti-CBir1+ (P = 0.0009). Conclusions The frequency of pANCA in children was consistent with adult observations. High titer pANCA was associated with more extensive disease, supporting the idea that the magnitude of immune reactivity may reflect disease severity. Anti-CBir1+ was more common in younger ages, suggesting host-microbial interactions may differ by patient age

Variation in care in the management of children with Crohn's disease: Data from a multicenter inception cohort study

Background: Variation in care is common in medical practice. Reducing variation in care is shown to improve quality and increase favorable outcomes in chronic diseases. We sought to identify factors associated with variation in care in children with newly diagnosed Crohn's disease (CD). Methods: Prospectively collected data from a 28-site multicenter inception CD cohort were analyzed for variations in diagnostic modalities, treatment, and follow-up monitoring practices, along with complicated disease outcomes over 3 years in 1046 children. Generalized linear mixed effects models were used to investigate the intercenter variations in each outcome variable. Results: The mean age at diagnosis was 12 years, and 25.9% were nonwhite. The number of participants ranged from 5 to 112 per site. No variation existed in the initial diagnostic approach. When medication exposure was analyzed, steroid exposure varied from 28.6% to 96.9% (P 0.99). Use of immunomodulators (IMs) varied among centers both within 90 days (P < 0.01) and during 3 years of follow-up (P < 0.01). A significant variation was seen at the geographic level with follow-up small bowel imaging and colonoscopy surveillance after initial therapy. Conclusions: Intercenter variation in care was seen with the initial use of steroids and anti-TNF, but there was no difference in total 3-year exposure to these drugs. Variation in the initiation and long-term use of IMs was significant among sites, but further research with objective measures is needed to explain this variation of care. Small bowel imaging or repeat colonoscopy in CD patients was not uniformly performed across sites. As our data show the widespread existence of variation in care and disease monitoring at geographic levels among pediatric CD patients, future implementation of various practice strategies may help reduce the variation in care

Factors associated with early outcomes following standardised therapy in children with ulcerative colitis (PROTECT): a multicentre inception cohort study

Background Previous retrospective studies of paediatric ulcerative colitis have had limited ability to describe disease progression and identify predictors of treatment response. In this study, we aimed to identify characteristics associated with outcomes following standardised therapy after initial diagnosis. Methods The PROTECT multicentre inception cohort study was based at 29 centres in the USA and Canada and included paediatric patients aged 4?17 years who were newly diagnosed with ulcerative colitis. Guided by the Pediatric Ulcerative Colitis Activity Index (PUCAI), patients received initial standardised treatment with mesalazine (PUCAI 10?30) oral corticosteroids (PUCAI 35?60), or intravenous corticosteroids (PUCAI ò65). The key outcomes for this analysis were week 12 corticosteroid-free remission, defined as PUCAI less than 10 and taking only mesalazine, and treatment escalation during the 12 study weeks to anti-tumour necrosis factor à (TNFà) agents, immunomodulators, or colectomy among those initially treated with intravenous corticosteroids. We identified independent predictors of outcome through multivariable logistic regression using a per-protocol approach. This study is registered with ClinicalTrials.gov, number NCT01536535. Findings Patients were recruited between July 10, 2012, and April 21, 2015. 428 children initiated mesalazine (n=136), oral corticosteroids (n=144), or intravenous corticosteroids (n=148). Initial mean PUCAI was 31ú1 (SD 13ú3) in children initiating with mesalazine, 50ú4 (13ú8) in those initiating oral corticosteroids, and 66ú9 (13ú7) in those initiating intravenous corticosteroids (p<0ú0001 for between-group comparison). Week 12 outcome data were available for 132 patients who initiated with mesalazine, 141 with oral corticosteroids, and 143 with intravenous corticosteroids. Corticosteroid-free remission with the patient receiving mesalazine treatment only at 12 weeks was achieved by 64 (48%) patients in the mesalazine group, 47 (33%) in the oral corticosteroid group, and 30 (21%) in the intravenous corticosteroid group (p<0ú0001). Treatment escalation was required by nine (7%) patients in the mesalazine group, 21 (15%) in the oral corticosteroid group, and 52 (36%) in the intravenous corticosteroid group (p<0ú0001). Eight patients, all of whom were initially treated with intravenous corticosteroids, underwent colectomy. Predictors of week 12 corticosteroid-free remission were baseline PUCAI less than 35 (odds ratio 2ú44, 95% CI 1ú41?4ú22; p=0ú0015), higher baseline albumin by 1 g/dL increments among children younger than 12 years (4ú05, 1ú90?8ú64; p=0ú00030), and week 4 remission (6ú26, 3ú79?10ú35; p<0ú0001). Predictors of treatment escalation by week 12 in patients initially treated with intravenous corticosteroids included baseline total Mayo score of 11 or higher (2ú59, 0ú93?7ú21; p=0ú068 [retained in model due to clinical relevance]), rectal biopsy eosinophil count less than or equal to 32 cells per high power field (4ú55, 1ú62?12ú78; p=0ú0040), rectal biopsy surface villiform changes (3ú05, 1ú09?8ú56; p=0ú034), and not achieving week 4 remission (30ú28, 6ú36?144ú20; p<0ú0001). Interpretation Our findings provide guidelines to assess the response of children newly diagnosed with ulcerative colitis to standardised initial therapy and identify predictors of treatment response and failure. These data suggest that additional therapeutic interventions might be warranted to improve early outcomes, especially in patients presenting with severe disease and requiring intravenous corticosteroids. Funding National Institutes of Health

Clinical and biological predictors of response to standardised paediatric colitis therapy (PROTECT): a multicentre inception cohort study

Background: Lack of evidence-based outcomes data leads to uncertainty in developing treatment regimens in children who are newly diagnosed with ulcerative colitis. We hypothesised that pretreatment clinical, transcriptomic, and microbial factors predict disease course. Methods: In this inception cohort study, we recruited paediatric patients aged 4?17 years with newly diagnosed ulcerative colitis from 29 centres in the USA and Canada. Patients initially received standardised mesalazine or corticosteroids, with pre-established criteria for escalation to immunomodulators (ie, thiopurines) or anti-tumor necrosis factor-à (TNFà) therapy. We used RNA sequencing to define rectal gene expression before treatment, and 16S sequencing to characterise rectal and faecal microbiota. The primary outcome was week 52 corticosteroid-free remission with no therapy beyond mesalazine. We assessed factors associated with the primary outcome using logistic regression models of the per-protocol population. This study is registered with ClinicalTrials.gov, number NCT01536535. Findings: Between July 10, 2012, and April 21, 2015, of 467 patients recruited, 428 started medical therapy, of whom 400 (93%) were evaluable at 52 weeks and 386 (90%) completed the study period with no protocol violations. 150 (38%) of 400 participants achieved week 52 corticosteroid-free remission, of whom 147 (98%) were taking mesalazine and three (2%) were taking no medication. 74 (19%) of 400 were escalated to immunomodulators alone, 123 (31%) anti-TNFà therapy, and 25 (6%) colectomy. Low baseline clinical severity, high baseline haemoglobin, and week 4 clinical remission were associated with achieving week 52 corticosteroid-free remission (n=386, logistic model area under the curve [AUC] 0ú70, 95% CI 0ú65?0ú75; specificity 77%, 95% CI 71?82). Baseline severity and remission by week 4 were validated in an independent cohort of 274 paediatric patients with newly diagnosed ulcerative colitis. After adjusting for clinical predictors, an antimicrobial peptide gene signature (odds ratio [OR] 0ú57, 95% CI 0ú39?0ú81; p=0ú002) and abundance of Ruminococcaceae (OR 1ú43, 1ú02?2ú00; p=0ú04), and Sutterella (OR 0ú81, 0ú65?1ú00; p=0ú05) were independently associated with week 52 corticosteroid-free remission. Interpretation: Our findings support the utility of initial clinical activity and treatment response by 4 weeks to predict week 52 corticosteroid-free remission with mesalazine alone in children who are newly diagnosed with ulcerative colitis. The development of personalised clinical and biological signatures holds the promise of informing ulcerative colitis therapeutic decisions. Funding: US National Institutes of Health

IBD risk loci are enriched in multigenic regulatory modules encompassing putative causative genes.

GWAS have identified >200 risk loci for Inflammatory Bowel Disease (IBD). The majority of disease associations are known to be driven by regulatory variants. To identify the putative causative genes that are perturbed by these variants, we generate a large transcriptome data set (nine disease-relevant cell types) and identify 23,650 cis-eQTL. We show that these are determined by ∼9720 regulatory modules, of which ∼3000 operate in multiple tissues and ∼970 on multiple genes. We identify regulatory modules that drive the disease association for 63 of the 200 risk loci, and show that these are enriched in multigenic modules. Based on these analyses, we resequence 45 of the corresponding 100 candidate genes in 6600 Crohn disease (CD) cases and 5500 controls, and show with burden tests that they include likely causative genes. Our analyses indicate that ≥10-fold larger sample sizes will be required to demonstrate the causality of individual genes using this approach

Active wait-list management through pre-clinic interventions: are we really helping patients or just ticking boxes

Poster http://www.canadianpainsociety.ca/resource/resmgr/Events/2016_SP/Poster_Package_/Revised_(11)_37th_Annual_Sci.pdfAnne Burke, Linley Denson, Jane Mathia

Consent, capacity and the right to say no

Peter D Bastian, Adeleen Eng, Linley A Denson, Lynn War

Cognitive deficit awareness in schizophrenia: absent, intact, or somewhere in-between?

INTRODUCTION: Cognitive impairment is a pervasive feature of schizophrenia, and is a major determinant of the functional disability that is characteristic of the disorder. However, research investigating whether patients with schizophrenia show a deficit awareness remains unclear. The present study aimed to replicate and extend previous research comparing subjective and objective measures of cognition. METHODS: . Thirty patients with a diagnosis of schizophrenia or schizoaffective disorder were administered the subjectively assessed Schizophrenia Cognitive Rating Scale (SCoRS) and the objective Brief Assessment of Cognition in Schizophrenia (BACS), which each assess overall global functioning and four specific neurocognitive domains (i.e., Verbal Memory, Working Memory, Processing Speed, and Reasoning and Problem Solving). Because deficit awareness may influence the likelihood of patients engaging in treatments designed to improve cognitive functioning, patients' attitudes towards such therapies were also contrasted with these subjective and objective measures of cognitive functioning. RESULTS: Patients' subjective appraisals did not significantly correlate with the objective neuropsychological assessments for global functioning or any specific neurocognitive domains. However, patients accurately deduced that their memory domains were more impaired than the other domains, and there was a trend for patients to exaggerate their Reasoning and Problem Solving deficits. This suggests that patients show some level of deficit awareness, when overestimating "deficits" for domains that are not impaired. Finally subjective, but not objective, measures of cognitive functioning correlated significantly with willingness to participate in cognitive-enhancing therapies. CONCLUSIONS: These results suggest that although patients' perceptions of their cognitive function are no substitute for objective neuropsychological test data, patients do possess a level of deficit awareness which may, in turn, influence willingness to participate in interventions such as cognitive rehabilitation.Ryan P. Balzan, Aaron Neaves, Linley A. Denson, Dennis Liu and Cherrie Galletl