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.
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.
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.
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.
Human beta-defensin-2 (HBD2) is an antimicrobial peptide implicated in the pathogenesis of inflammatory bowel disease (IBD). Low copy number and concomitant low mRNA expression of the HBD2 gene have ...been implicated in susceptibility to colonic Crohn's Disease (CD). We investigated the colonic distribution of HBD2 mRNA expression, and the contributions of genetic and environmental factors on HBD2 protein production.
We examined HBD2 mRNA expression at three colonic locations by microarray analysis of biopsies from 151 patients (53 CD, 67 ulcerative colitis UC, 31 controls). We investigated environmental and genetic influences on HBD2 protein production using ex vivo cultured sigmoid colon biopsies from 69 patients (22 CD, 26 UC, 21 controls) stimulated with lipopolysaccharide (LPS) and/or nicotine for 24 hours. HBD2 and cytokines were measured in culture supernatants. Using DNA samples from these patients, regions in the HBD2 gene promoter were sequenced for NF-kappaB binding-sites and HBD2 gene copy number was determined. HBD2 mRNA expression was highest in inflamed (vs. uninflamed p = 0.0122) ascending colon in CD and in inflamed (vs. uninflamed p<0.0001) sigmoid colon in UC. HBD2 protein production was increased in inflamed UC biopsies (p = 0.0078). There was no difference in HBD2 protein production from unstimulated biopsies of CD, UC and controls. LPS-induced HBD2 production was significantly increased in CD (p = 0.0375) but not UC (p = 0.2017); this LPS-induced response was augmented by nicotine in UC (p = 0.0308) but not CD (p = 0.6872). Nicotine alone did not affect HBD2 production. HBD2 production correlated with IL8 production in UC (p<0.001) and with IL10 in CD (p<0.05). Variations in the HBD2 promoter and HBD2 gene copy number did not affect HBD2 production.
Colonic HBD2 was dysregulated at mRNA and protein level in IBD. Inflammatory status and stimulus but not germline variations influenced these changes.
Colonoscopy requires bowel cleansing for gut mucosa visualization; high-quality cleansing facilitates lesion detection. NER1006 is a 1L polyethylene glycol (PEG) bowel preparation. This post hoc ...analysis of two randomized trials investigated cleansing efficacy assessed, as in clinical practice, by site endoscopists.
Patients received NER1006, 2L PEG + ascorbate (2LPEG), or oral sulfate solution (OSS) as a 2-day evening/morning regimen (N2D) or NER1006 morning-only dosing (N1D). Treatment-blinded site endoscopists assessed cleansing using the Harefield Cleansing Scale (HCS). Analyses were conducted in a modified full analysis set, including (mFAS; n = 1378) or excluding (mFAS2; n = 1319) imputed failures, and in patients with 100% treatment adherence (mFAS100; n = 1047). Overall cleansing success (HCS grade A/B), overall high-quality cleansing (HCS grade A), and high-quality segments (HCS 3–4) per treatment population were analyzed.
Overall cleansing success was higher with N2D than 2LPEG (92.7–97.5% vs. 87.9–93.0%), and more patients had overall high-quality cleansing with N2D and N1D than 2LPEG (68.0–72.1% and 64.0–68.4% vs. 50.7–56.0%). Without imputed failures, N2D delivered more overall high-quality cleansing than OSS (74.5–77.3% vs. 67.8–69.8%). More high-quality segments were demonstrated with N2D and N1D versus 2 LPEG (82.5–87.1% and 79.4–84.4% vs. 70.4–76.3%) and with N2D versus OSS (82.7–89.5% vs. 78.1–84.4%).
When assessed by site endoscopists, NER1006 delivers greater high-quality cleansing than 2LPEG or OSS.
Aim
The dramatic curtailment of endoscopy and CT colonography capacity during the coronavirus pandemic has adversely impacted timely diagnosis of colorectal cancer (CRC). We describe a rapidly ...implemented COVID‐adapted diagnostic pathway to mitigate risk and maximize cancer diagnosis in patients referred with symptoms of suspected CRC.
Method
The ‘COVID‐adapted pathway’ integrated multiple quantitative faecal immunochemical tests (qFIT) to enrich for significant colorectal disease with judicious use of CT with oral contrast to detect gross pathology. Patients reporting ‘high‐risk’ symptoms were triaged to qFIT+CT and the remainder underwent an initial qFIT to inform subsequent investigation. Demographic and clinical data were prospectively collected. Outcomes comprised cancer detection frequency.
Results
Overall, 422 patients (median age 64 years, 220 women) were triaged using this pathway. Most (84.6%) were referred as ‘urgent suspicious of cancer’. Of the 422 patients, 202 (47.9%) were triaged to CT and qFIT, 211 (50.0%) to qFIT only, eight (1.9%) to outpatient clinic and one to colonoscopy. Fifteen (3.6%) declined investigation and seven (1.7%) were deemed unfit. We detected 13 cancers (3.1%), similar to the mean cancer detection rate from all referrals in 2017–2019 (3.3%). Compared with the period 1 April–31 May in 2017–2019, we observed a 43% reduction in all primary care referrals (1071 referrals expected reducing to 609).
Conclusion
This COVID‐adapted pathway mitigated the adverse effects on diagnostic capacity and detected cancer at the expected rate within those referred. However, the overall reduction in the number of referrals was substantial. The described risk‐mitigating measures could be a useful adjunct whilst standard diagnostic services remain constrained due to the ongoing pandemic.
As a result of technological and analytical advances, genome-wide characterization of key epigenetic alterations is now feasible in complex diseases. We hypothesized that this may provide important ...insights into gene-environmental interactions in Crohn's disease (CD) and is especially pertinent to early onset disease.
The Illumina 450K platform was applied to assess epigenome-wide methylation profiles in circulating leukocyte DNA in discovery and replication pediatric CD cohorts and controls. Data were corrected for differential leukocyte proportions. Targeted replication was performed in adults using pyrosequencing. Methylation changes were correlated with gene expression in blood and intestinal mucosa.
We identified 65 individual CpG sites with methylation alterations achieving epigenome-wide significance after Bonferroni correction (P < 1.1 × 10(-7)), and 19 differently methylated regions displaying unidirectional methylation change. There was a highly significant enrichment of methylation changes around GWAS single nucleotide polymorphisms (P = 3.7 × 10(-7)), notably the HLA region and MIR21. Two-locus discriminant analysis in the discovery cohort predicted disease in the pediatric replication cohort with high accuracy (area under the curve, 0.98). The findings strongly implicate the transcriptional start site of MIR21 as a region of extended epigenetic alteration, containing the most significant individual probes (P = 1.97 × 10(-15)) within a GWAS risk locus. In extension studies, we confirmed hypomethylation of MIR21 in adults (P = 6.6 × 10(-5), n = 172) and show increased mRNA expression in leukocytes (P < 0.005, n = 66) and in the inflamed intestine (P = 1.4 × 10(-6), n = 99).
We demonstrate highly significant and replicable differences in DNA methylation in CD, defining the disease-associated epigenome. The data strongly implicate known GWAS loci, with compelling evidence implicating MIR21 and the HLA region.
Background
Switching from Remicade to CT-P13 allows for significant cost savings and has been shown to be non-inferior to continued therapy with Remicade for the treatment of Crohn’s disease.
Aim
The ...aim of this work was to prospectively evaluate clinical outcomes in a cohort of patients with Crohn’s disease switching from Remicade to CT-P13.
Methods
A prospective service evaluation was performed. The Harvey-Bradshaw index, CRP, faecal calprotectin and serum for infliximab/antibody levels were collected prior to patients' final Remicade infusion and at 6 and 12 months after switching to CT-P13 as part of routine clinical care. All adverse events during follow-up were also recorded.
Results
One hundred and ten patients on Remicade switched to CT-P13. No significant difference was observed between the Harvey-Bradshaw Index (
p
= 0.07), CRP (
p
= 0.13), faecal calprotectin (
p
= 0.25) or trough infliximab levels (
p
= 0.47) comparing before and at 6 and 12 months after the switch to CT-P13. Seven patients developed new infliximab antibodies after switching from Remicade to CT-P13. The majority of patients remained on CT-P13 at 12 months (84.5%) and the rate of adverse events and serious adverse events was 53.8 and 13.5 per 100 patient-years of follow-up, respectively. Switching to CT-P13 resulted in a cost saving of approximately 46.4%.
Conclusion
The transition to CT-P13 from Remicade for the treatment of Crohn’s disease is safe and has no negative effect on clinical outcomes at 12 months.
Abstract
Background
Adalimumab is an established treatment for Crohn's disease. Limited data are available regarding the relationship between adalimumab drug levels and serum/fecal markers of gut ...inflammation. We therefore aimed to characterize the relationship between adalimumab levels and biologic remission during maintenance therapy.
Methods
A single-center prospective cross-sectional study was undertaken on Crohn's disease patients who had received adalimumab therapy for a minimum of 12 weeks after induction. Data on clinical activity (Harvey-Bradshaw Index), C-reactive protein (CRP), adalimumab drug and antibody levels, and fecal calprotectin were collected. Biologic remission was defined as a CRP <5 mg/L and fecal calprotectin <250 µg/g. Adalimumab drug and antibody levels were processed using the Immundiagnostik monitor enzyme-linked immunosorbent assay.
Results
One hundred fifty-two patients had drug and antibody samples matched with CRP and fecal calprotectin. Patients in biologic remission had significantly higher adalimumab levels compared with others (12.0 µg/mL vs 8.0 µg/mL, P < 0.0001). Receiver operating characteristic curve analysis demonstrated an optimal adalimumab level of >8.5 µg/mL (sensitivity, 82.2%; specificity, 55.7%; likelihood ratio, 1.9) for predicting biologic remission. Multivariable logistic regression revealed that adalimumab levels >8.5 µg/mL were independently associated with biologic remission (odds ratio, 5.27; 95% confidence interval, 2.43-11.44; P < 0.0001).
Conclusions
Higher adalimumab levels are associated with biologic remission. An optimal level of >8.5 µg/mL was identified.
Background:
Genome‐wide microarray expression analysis creates a comprehensive picture of gene expression at the cellular level. The aim of this study was to investigate differential intestinal gene ...expression in patients with Crohn's disease (CD) and controls with subanalysis of confirmed CD susceptibility genes, associated pathways, and cell lineage.
Methods:
In all, 172 biopsies from 53 CD and 31 control subjects were studied. Paired endoscopic biopsies were taken at ileocolonoscopy from five specific anatomical locations including the terminal ileum (TI) for RNA extraction and histology. The 41,058 expression sequence tags were analyzed using the Agilent platform.
Results:
Analysis of all CD biopsies versus controls showed 259 sequences were upregulated and 87 sequences were downregulated. Upregulated genes in CD included SAA1 (fold change FC +7.5, P = 1.47 × 10−41) and REGL (FC +7.3, P = 2.3 × 10−16), whereas cellular detoxification genes including‐SLC14A2 (FC‐2.49, P = 0.00002) were downregulated. In the CD TI biopsies diubiquitin (FC+11.3, P < 1 × 10−45), MMP3 (FC+7.4, P = 1.3 × 10−11), and IRTA1 (FC‐11.4, P = 4.7 × 10−12) were differentially expressed compared to controls. In the colon SAA1 (FC+6.3, P = 5.3 × 10−8) was upregulated and thymic stromal lymphopoietin (TSLP) (FC‐2.3, P = 2.7 × 10−6) was downregulated comparing noninflamed CD and control biopsies, and the colonic inflammatory CD signature was characterized by downregulation of the organic solute carriers‐SLC38A4, SLC26A2, and OST alpha. Of CD susceptibility genes identified by genome‐wide association scan IL‐23A, JAK2, and STAT3 were upregulated in the CD group, confirming the dysregulation of Th17 signaling.
Conclusions:
These data characterize the dysregulation of a series of specific inflammatory pathways highlighting potential pathogenic mechanisms as well as areas for translation to therapeutic targets. (Inflamm Bowel Dis 2010)
Abstract
Aim
To assess the pathobiological and translational importance of whole-blood transcriptomic analysis in inflammatory bowel disease IBD.
Methods
We analysed whole-blood expression profiles ...from paired-end sequencing in a discovery cohort of 590 Europeans recruited across six countries in the IBD Character initiative (newly diagnosed patients with Crohn’s disease CD; n = 156, ulcerative colitis UC; n = 167, and controls n = 267), exploring differential expression DESeq2, co-expression networks WGCNA, and transcription factor involvement EPEE, ChEA, DoRothEA. Findings were validated by analysis of an independent replication cohort 99 CD, 100 UC, 95 controls. In the discovery cohort, we also defined baseline expression correlates of future treatment escalation using cross-validated elastic-net and random forest modelling, along with a pragmatic ratio detection procedure.
Results
Disease-specific transcriptomes were defined in IBD 8697 transcripts, CD 7152, and UC 8521, with the most highly significant changes in single genes, including CD177 (log2-fold change LFC = 4.63, p = 4.05 × 10-118), MCEMP1 LFC = 2.45, p = 7.37 × 10-109, and S100A12 LFC = 2.31, p = 2.15 × 10-93. Significantly over-represented pathways included IL-1 p = 1.58 × 10-11, IL-4, and IL-13 p = 8.96 × 10-9. Highly concordant results were obtained using multiple regulatory activity inference tools applied to the discovery and replication cohorts. These analyses demonstrated central roles in IBD for the transcription factors NFE2, SPI1 PU.1, CEBPB, and IRF2, all regulators of cytokine signalling, based on a consistent signal across cohorts and transcription factor ranking methods. A number of simple transcriptome-based models were associated with the need for treatment escalation, including the binary CLEC5A/CDH2 expression ratio in UC (hazard ratio = 23.4, 95% confidence interval CI 5.3–102.0).
Conclusions
Transcriptomic analysis has allowed for a detailed characterisation of IBD pathobiology, with important potential translational implications.
Graphical Abstract
Graphical Abstract
Background & Aims: Recent data suggest that polymorphisms in the organic cation transporter (OCTN) genes OCTN1 (SLC22A4) and OCTN2 (SLC22A5) represent disease-causing mutations within the IBD5 locus ...(chromosome 5q31). We investigated associations with disease susceptibility, phenotype, and evidence for epistasis with CARD15 in 679 patients with Crohn’s disease (CD) or ulcerative colitis (UC). Methods: A total of 374 patients with CD, 305 patients with UC, and 294 healthy controls (HCs) were studied. Genotyping for single nucleotide polymorphisms IGR2096, IGR2198, and IGR2230, OCTN1 variant (SLC22A4 1672C→T), and OCTN2 variant (SLC22A5 −207G→C) was performed using the TaqMan system. Results: The IBD5 OCTN1 and OCTN2 polymorphisms were in strong linkage disequilibrium (D′, >0.959). IGR2198 variant allele frequency (49.1% vs 40.8%; P = .0046) and homozygosity (21% vs 14.8%; P = .044) were associated with CD versus HCs. Variant allelic frequency of OCTN1 (53.6% vs 43%; P = .0008) and OCTN2 (56.1% vs 48.4%; P = .0092) polymorphisms and homozygosity for the OCTN1/2-TC haplotype (28.4% vs 16%; P = .0042) were associated with CD versus HCs. IGR2198 homozygosity and TC homozygosity were associated with stricturing/penetrating disease at follow-up (P = .011 and P = .011, respectively) and disease progression (P = .038 and P = .049, respectively) on univariate analysis and with need for surgery on multivariate analysis (P = .016 and P = .004, respectively). In the absence of the IBD5 risk haplotype, no association of OCTN1/2 variants with CD was detected. No associations were seen with UC. Conclusions: The IBD5 locus influences susceptibility, progression, and need for surgery in CD. However, the contribution of OCTN1/2 variants is not independent of the IBD5 haplotype; a causative role for these genes remains plausible but is not yet proven. Further genetic, functional, and expression data are now required.
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