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Background and Aims: The opioid epidemic has become increasingly concerning, with the ever-increasing prescribing of opioid medications in recent years, especially in inflammatory bowel disease [IBD] patients with chronic pain. We aimed to isolate the effect of opioid use disorder [OUD] on 30-day readmission risk after an IBD-related hospitalization. Methods: We retrospectively extracted IBD-related adult hospitalizations and 30-day, any-cause, readmissions from the National Readmissions Database [period 2010-2014]. OUD and 30-day readmission trends were calculated. Conventional and exact-matched [EM] logistic regression and time-to-event analyses were conducted among patients who did not undergo surgery during the index hospitalization, to estimate the effect of OUD on 30-day readmission risk. Results: In total, 487 728 cases were identified: 6633 [1.4%] had documented OUD And 308 845 patients [63.3%] had Crohn's disease. Mean age was 44.8 ± 0.1 years, and 54.3% were women. Overall, 30-day readmission rate was 19.4% [n = 94,546], being higher in OUD patients [32.6% vs 19.2%; p < 0.001]. OUD cases have been increasing [1.1% to 1.7%; p-trend < 0.001], while 30-day readmission rates were stable [p-trend = 0.191]. In time-to-event EM analysis, OUD patients were 47% more likely (hazard ratio 1.47; 95% confidence interval [CI]:1.28-1.69; p < 0.001) to be readmitted, on average being readmitted 32% earlier [time ratio 0.68; 95% CI: 0.59-0.78; p < 0.001]. Conclusion: OUD prevalence has been increasing in hospitalized IBD patients from 2010 to 2014. On average, one in five patients will be readmitted within 30 days, with up to one in three among the OUD subgroup. OUD is significantly associated with increased 30-day readmission risk in IBD patients and further measures relating to closer post-discharge outpatient follow-up and pain management should be considered to minimize 30-day readmission risk.

Thesis (Ph.D.) - University of Glasgow, 2009. / Ph.D. thesis submitted to the Division of Developmental Medicine, Faculty of Medicine, University of Glasgow, 2009. Includes bibliographical references. Print version also available.

Background & aims: The inflammatory bowel diseases (IBD), Crohn‟s disease (CD) and ulcerative colitis (UC), are common causes of chronic gastrointestinal morbidity, affecting up to 1 in 250 of the general population in Northern Europe. Up to 25% of IBD is diagnosed during childhood or adolescence. The aims for this thesis were to study the epidemiology, natural history and novel genetic determinants of childhood onset IBD in Scotland. Methods: The existing repository of childhood onset and adult onset IBD patients, established at the Western General Hospital in Edinburgh, was used and expanded. Thus, anatomical location and behaviour of disease were assessed in 416 childhood onset (276 CD, 99 UC, 41 IBDU diagnosed before 17th birthday) and 1297 adult patients (596 CD, 701 UC) using the Montreal classification. Additional phenotypic (at diagnosis and at regular follow-up intervals) and epidemiological data were gathered. In this cohort, genotyping of germline variants in putative susceptibility genes (NOD1/CARD4, IL23R, ATG16L1, IRGM, FLG) was performed to enable single variant and haplotype-tagging association studies. Genotypic data of population-matched healthy controls were obtained locally (n=342) and from the Wellcome Trust Case Control Consortium (n=2937). Results: Compared with adults, childhood-onset CD was characterized by a more extensive, “panenteric” phenotype (ileocolonic plus upper GI; p<0.0001 OR23.3; 95% CI (13.4–40.6) with less isolated ileal (p<0.0001 OR 0.06 (0.03–0.1) or colonic disease (p<0.0001, OR 0.3 (0.2–0.5)). In 39%, the anatomic extent increased within 2 years. UC was also more extensive in children at diagnosis vs adults (p<0.0001 OR 5.1 (2.7–9.4)). In population-matched and age, sex and postcode-matched case-control analysis, childhood onset IBD and CD was associated with asthma (p<0.0001 OR 1.7 (1.3-2.1) and (p=0.005 OR 2.5 (1.3-4.8), respectively). Inherited variation of NOD1/CARD4 was not a strong determinant of disease susceptibility in the Scottish population (both in single marker and haplotype-tagging studies, all p>0.05 after Bonferroni correction). We found that the allelic frequency of rs11209026*A located within the IL23R gene, differed significantly between IBD/CD cases and controls (p=0.01 OR 0.51(0.3-0.9) and p=0.04 OR 0.5 (0.3-0.98)). Using a gene-wide haplotype-tagging strategy, we demonstrated that the multiple association signals of the IL23R locus are independent of rs11209026 in childhood onset IBD and CD. In Scottish children, the effect of germline variation of ATG16L1 and IRGM on CD susceptibility was relatively small (OR< 1.4), and appeared less than in adult disease. Genotype–phenotype analysis demonstrated an association of pure ileal disease with the ATG16L1 rs2241880G-allele (p=0.02 OR 1.3 (1.03–1.7)). Using binary logistic regression analysis, we confirmed the effect of rs2241880 genotype (GG) on ileal disease versus colonic disease (p=0.03 OR 2.4 (1.05–5.6)). Null alleles of the epithelial barrier protein FLG have no important effect on IBD susceptibility (p>0.4), but contribute to the high prevalence of atopy, notably co-existent eczema and food allergy (p=0.0003 OR 3.3 (1.7–6.6) and p=0.0001 OR 4.5 (2.0–10.0), respectively). Conclusion: Childhood onset IBD is characterised by extensive intestinal involvement and progression of disease after diagnosis. Genetic association studies in childhood and adult IBD have provided evidence for a large number of new genomic loci. These loci encode genes involved in a number of homeostatic mechanisms: innate pattern recognition receptors, the differentiation of Th17-lymphocytes, autophagy, maintenance of epithelial barrier integrity and the orchestration of the secondary immune response.

The inflammatory bowel diseases (IBD), encompassing Crohn’s disease (CD) and ulcerative colitis (UC), are chronic inflammatory disorders of the gastrointestinal tract. Their aetiology is not fully understood but is thought to be a combination of the effect of environmental factors in a genetically susceptible person. The work presented is an examination of the phenotypic characteristics of CD in the Scottish population, and an investigation into genetic factors that may influence susceptibility and progression. An IBD cohort from Dundee was recruited (CD=367, UC=265), and extensive phenotypic information collected from these patients together with genomic DNA. Together with the Edinburgh CD cohort already established, the total CD population (n=1155) was examined for time to disease progression (stricturing and/or penetrating disease, according to the Montreal classification) and first resection; a multivariate analysis was performed for factors influencing these outcomes. In this Scottish CD population, the median time to disease progression and first resection was 14.2 years and 8.9 years respectively. The major factor influencing risk of resection and disease progression was disease location, with patients having pure ileal (L1) disease or ileocolonic (L3) disease being more susceptible than those with pure colonic (L2) disease. Compared with L2 disease, the hazards ratios (HR) for disease progression were 4.7 and 2.8, and risk of resection 5.2 and 2.6 for L1 and L3 disease respectively. Disease progression and risk of resection are surrogate markers of disease severity. To try to better understand the determinants of severe disease, a novel score for disease severity was developed and applied to the Dundee CD cohort. This composite score encompassed the variables of medical and surgical management, disease behaviour and location, nutritional status as well as hospitalisations, with a total score that could range from 1 to 16. A score of 7 or more was found to define the 50% of patients with the most severe disease. This cut-off was used to divide patients into less severe and more severe categories; phenotypic and genetic factors were examined for correlation with more severe disease. Genetic factors examined were the 32 most significant CD susceptibility single nucleotide polymorphisms (SNPs) uncovered by recent genome-wide association scans (GWAS). Factors correlated with more severe disease included disease location (L1, odds ratio (OR) 2.20, p=0.0025), age group at diagnosis (p=0.0004) and two CD susceptibility SNPs (rs9286879 and rs17582416; p=0.0085 and p=0.045 respectively). NOD2 was the first IBD susceptibility gene identified. In order to further define pathways involving NOD2, a yeast two-hybrid screen in our laboratory using NOD2 cDNA as the bait had already identified an interaction between NOD2 and UDP-Nacetyl- alpha-D-galactosamine:polypeptide N-acetylgalactosaminyltransferase (GALNT2). This enzyme is involved in O-glycosylation, important in the post translational modification of mucins. A GALNT2 genotype/phenotype analysis on the Edinburgh IBD population was completed, with the Dundee IBD population used as a replication cohort. In the Edinburgh IBD population, the GALNT2 tagging SNP rs7536663 was associated with CD susceptibility (OR 1.38, p=0.0008 vs controls), but replication was not achieved in the Dundee cohort (p=0.469). There was no association of any of the GALNT2 SNPs with UC. The GALNT2/NOD2 interaction was further investigated by completing coimmunoprecipitation between the two genes to characterise the level and type of interaction. An interaction between GALNT2 and NOD2 was confirmed in mammalian cells, with the interaction being at the N-terminal end of the NOD2 protein. GALNT2 expression in a cell line and biopsies was investigated by quantitative polymerase chain reaction and immunohistochemistry respectively. There were no statistically significant changes in GALNT2 or NOD2 mRNA expression in the LS174T cell line after stimulation with specific ligands for NOD2 and GALNT2. GALNT2 protein expression was characterised in intestinal biopsy samples to be predominantly in the lamina propria, with some expression in the enterocytes. To further define the contribution of mucin genes to IBD susceptibility, tagging SNPs across the MUC2, MUC3A and MUC19 genes were genotyped in the Edinburgh IBD cohort and examined for a link with IBD, CD and UC susceptibility, but associations were not found. In view of the strong association with CD susceptibility of a SNP near the MUC19 locus in a recent GWAS, tagging SNPs across the leucine rich repeat kinase-2 (LRRK2) gene, near the MUC19 gene, were also genotyped and examined in the Dundee cohort for an association with IBD, CD and UC susceptibility, but was also negative when corrected for multiple testing. The studies presented allow an improved understanding of the influence of phenotypic characteristics on disease progression, need for surgery and severity in CD. The role of disease location has been determined to be particularly critical, in keeping with other published studies. A detailed examination of the influence of specific genes on disease susceptibility has failed to definitely demonstrate an association between germline variation in GALNT2, MUC2, MUC3A, MUC19 or LRRK2 and IBD, CD or UC susceptibility. An interaction in mammalian cells between NOD2 and GALNT2 has been shown, but further work is required to demonstrate that this is a biologically relevant interaction.

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