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Objective: IBD prevalence is estimated to be rising, but no detailed, recent UK data are available. The last reported prevalence estimate in the UK was 0.40% in 2003. We aimed to establish the current, and project future, prevalence in Lothian, Scotland., Design: We conducted an all-age multiparameter search strategy using inpatient IBD international classification of disease (ICD-10) coding (K50/51)(1997-2018), IBD pathology coding (1990-2018), primary and secondary care prescribing data (2009-2018) and a paediatric registry, (1997-2018) to identify 'possible' IBD cases up to 31/08/2018. Diagnoses were manually confirmed through electronic health record review as per Lennard-Jones/Porto criteria. Autoregressive integrated moving average (ARIMA) regression was applied to forecast prevalence to 01/08/2028., Results: In total, 24 601 possible IBD cases were identified of which 10 499 were true positives. The point prevalence for IBD in Lothian on 31/08/2018 was 784/100 000 (UC 432/100 000, Crohn's disease 284/100 000 and IBD unclassified (IBDU) 68/100 000). Capture-recapture methods identified an additional 427 'missed' cases (95% CI 383 to 477) resulting in a 'true' prevalence of 832/100 000 (95% CI 827 to 837).Prevalence increased by 4.3% per year between 2008 and 2018 (95% CI +3.7 to +4.9%, p<0.0001). ARIMA modelling projected a point prevalence on 01/08/2028 of 1.02% (95% CI 0.97% to 1.07%) that will affect an estimated 1.53% (95% CI 1.37% to 1.69%) of those >80 years of age., Conclusions: We report a rigorously validated IBD cohort with all-age point prevalence on 31/08/2018 of 1 in 125, one of the highest worldwide., Competing Interests: Competing interests: NP has received consultancy fees from Takeda and speaker fees and travel support from AbbVie, Takeda and Norgine. SD has received travel support from AbbVie, Dr Falk and consultancy fees from Takeda. AGS has received travel support from AbbVie and Ferring. IA has received consultancy fees from Vifor and travel support from Takeda and Dr Falk. CWL has received research support from Gilead, Oshi Health and AbbVie, consultancy fees from AbbVie, Pfizer, Dr Falk, Hospira, MSD, Gilead, Pharmacosmos, Takeda and Vifor, and speaker fees and travel support from AbbVie, Pfizer, Ferring, Hospira and Takeda. GRJ, PWJ, ML, JF and GTH have no personal interests to declare. PH and SD are supported by an NHS Research Scotland Career Researcher Fellowship. DCW has received consultancy fees, speaker fees and/or travel support from Abbvie, Takeda, Roche, Ferring, Predictimmune, Dr Falk and 4D Pharma., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY. Published by BMJ.)

Background: Oral methotrexate (MTX) administration avoids weekly injections, reduces costs and may improve quality of life of patients with Crohn's disease (CD), especially children. Routes of administration have never been systematically compared in CD. We aimed to compare effectiveness and safety of orally (PO) versus subcutaneously (SC) administered MTX in paediatric CD., Methods: 226 children with CD treated with oral or subcutaneous MTX were included in a multicentre, retrospective 1-year cohort study (62% boys, mean age 13.8±2.8 years, 88% previous thiopurines). 38 (17%) were initially commenced on oral, 98 (43%) started subcutaneous and switched to oral and 90 (40%) were treated with subcutaneous only. Matching and 'doubly robust' weighted regression models were based on the propensity score method, controlling for confounding-by-indication bias. 11/23 pretreatment variables were different between the groups, but the propensity score modelling successfully balanced the treatment groups., Results: 76 children (34%) had sustained steroid-free remission with a difference that did not reach significance between the PO and the SC groups (weighted OR=1.72 (95% CI 0.5 to 5.9); p=0.52). There were no differences in need for treatment escalation (p=0.24), elevated liver enzymes (p=0.59) or nausea (p=0.85). Height velocity was lower in the PO group (p=0.006) and time to remission was delayed in the PO group (p=0.036; Fleming (0, 1) test)., Conclusions: In this largest paediatric CD cohort to date, SC administered MTX was superior to PO, but only in some of the outcomes and with a modest effect size. Therefore, it may be reasonable to consider switching children in complete remission treated with subcutaneous MTX to the oral route with close monitoring of inflammatory markers and growth., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

Objective: Although paediatric-onset IBD is becoming more common, few medications have a registered paediatric indication. There are multiple hurdles to performing clinical trials in children, emphasising the importance of choosing an appropriate outcome measure, which can facilitate enrolment, and thereby also drug approval. The aim of this consensus statement is to highlight paediatric specific issues and key factors critical for the optimal conduct of paediatric IBD trials., Design: The Paediatric European Crohn's and Colitis Organisation (ECCO) committee has established an international expert panel to determine the best outcome measures in paediatric IBD, following a literature search and a modified Delphi process. All recommendations were endorsed by at least 80% agreement., Results: Recognising the importance of mucosal healing (MH), the panel defined steroid-free MH as primary outcome measure for all drugs of new category with one or two postintervention endoscopies per trial (at 8-12 weeks and/or 54 weeks). Since endoscopic evaluation is a barrier for recruitment in children, trials with medications already shown to induce MH in children or adults, could use paediatric-specific disease activity scores as primary outcome, including a modified Paediatric Crohn's Disease Activity Index in Crohn's disease and the Paediatric Ulcerative Colitis Activity Index in UC. Secondary outcomes should include safety issues, MR enterography-based damage and inflammatory scores (in Crohn's disease), faecal calprotectin, quality of life scales, and a patient-reported outcome., Conclusions: It is crucial to perform paediatric trials early in the development of new drugs in order to reduce off-label use of IBD medication in children. The thoughtful choice of feasible and standardised outcome measures can help move us towards this goal., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Objective: Mutations in the nucleotide-binding oligomerisation domain-containing protein 2 (NOD2) gene remain the strongest genetic determinants for Crohn's disease (CD). Having previously identified vimentin as a novel NOD2-interacting protein, the authors aimed to investigate the regulatory effects of vimentin on NOD2 function and the association of variants in Vim with CD susceptibility., Design: Coimmunoprecipitation, fluorescent microscopy and fractionation were used to confirm the interaction between NOD2 and vimentin. HEK293 cells stably expressing wild-type NOD2 or a NOD2 frameshift variant (L1007fs) and SW480 colonic epithelial cells were used alongside the vimentin inhibitor, withaferin A (WFA), to assess effects on NOD2 function using the nuclear factor-kappaB (NF-κB) reporter gene, green fluorescent protein-LC3-based autophagy, and bacterial gentamicin protection assays. International genome-wide association meta-analysis data were used to test for associations of single-nucleotide polymorphisms in Vim with CD susceptibility., Results: The leucine-rich repeat domain of NOD2 contained the elements required for vimentin binding; CD-associated polymorphisms disrupted this interaction. NOD2 and vimentin colocalised at the cell plasma membrane, and cytosolic mislocalisation of the L1007fs and R702W variants correlated with an inability to interact with vimentin. Use of WFA demonstrated that vimentin was required for NOD2-dependent NF-κB activation and muramyl dipeptide-induced autophagy induction, and that NOD2 and vimentin regulated the invasion and survival properties of a CD-associated adherent-invasive Escherichia coli strain. Genetic analysis revealed an association signal across the haplotype block containing Vim., Conclusion: Vimentin is an important regulator of NOD2 function and a potential novel therapeutic target in the treatment of CD. In addition, Vim is a candidate susceptibility gene for CD, supporting the functional data.

Objective: The NOX2 NADPH oxidase complex produces reactive oxygen species and plays a critical role in the killing of microbes by phagocytes. Genetic mutations in genes encoding components of the complex result in both X-linked and autosomal recessive forms of chronic granulomatous disease (CGD). Patients with CGD often develop intestinal inflammation that is histologically similar to Crohn's colitis, suggesting a common aetiology for both diseases. The aim of this study is to determine if polymorphisms in NOX2 NADPH oxidase complex genes that do not cause CGD are associated with the development of inflammatory bowel disease (IBD)., Methods: Direct sequencing and candidate gene approaches were used to identify susceptibility loci in NADPH oxidase complex genes. Functional studies were carried out on identified variants. Novel findings were replicated in independent cohorts., Results: Sequence analysis identified a novel missense variant in the neutrophil cytosolic factor 2 (NCF2) gene that is associated with very early onset IBD (VEO-IBD) and subsequently found in 4% of patients with VEO-IBD compared with 0.2% of controls (p=1.3×10(-5), OR 23.8 (95% CI 3.9 to 142.5); Fisher exact test). This variant reduced binding of the NCF2 gene product p67(phox) to RAC2. This study found a novel genetic association of RAC2 with Crohn's disease (CD) and replicated the previously reported association of NCF4 with ileal CD., Conclusion: These studies suggest that the rare novel p67(phox) variant results in partial inhibition of oxidase function and are associated with CD in a subgroup of patients with VEO-IBD; and suggest that components of the NADPH oxidase complex are associated with CD.

Background and Aims: The OCTN1 (SLC22A4 1672C-->T) and OCTN2 (SLC22A5 -207G-->C) variants within the IBD5 locus have been associated with susceptibility to adult onset Crohn's disease (CD), but their contribution in children has not been examined., Methods: These OCTN1/2 variants and IBD5 marker single nucleotide polymorphisms (SNPs) (IGR2096a&#95;1, IGR2198a&#95;1, and IGR2230a&#95;1) were examined in 299 Scottish children (200 with CD, 74 with ulcerative colitis (UC), and 25 with indeterminate colitis (IC)), together with 502 parents (for transmission disequilibrium testing) and 256 controls., Results: All SNPs were in strong linkage disequilibrium (D' >0.94). TDT analysis showed association of the OCTN1 variant with inflammatory bowel disease (IBD) (p = 0.01) and CD (p = 0.04). Allele frequencies of the OCTN1/2 variants were significantly higher in IBD/CD cases (p<0.04). The homozygous mutant OCTN1/2 haplotype was increased in IBD (24.3% v 16.1%, p = 0.02) and UC (28.2% v 16.1%, p = 0.02) compared with controls. The OCTN1/2 variants were not independent of the background IBD5 risk haplotype in conferring disease susceptibility. Unifactorial analysis in CD patients showed that carriage of the TC haplotype was associated with lower weight, height, and BMI centile (<9(th) centile) at diagnosis (weight: 87.9% v 67.3% (p = 0.002), odds ratio (OR) = 3.52 (95% confidence interval, 1.51 to 8.22); height: 84.1% v 68.4% (p<0.05), OR = 2.44 (1.00 to 5.99); BMI: 79.6% v 61.1% (p = 0.02), OR = 2.49 (1.14 to 5.44)), and lower weight centile at follow up (87.5% v 64.6% (p = 0.03), OR = 3.83 (1.03 to 14.24)). Multifactorial binary logistic regression analysis confirmed association of the TC haplotype with lower weight centile at diagnosis (p = 0.02, OR = 3.41 (1.20 to 9.66))., Conclusions: These data implicate variants within the IBD5 haplotype, as determinants of disease susceptibility and growth indices in early onset IBD. The OCTN1/2 variants remain potential positional candidate genes, but require further analysis.