Francesca Bredin

Gene expression profiling of CD8+ T cells predicts prognosis in patients with Crohn disease and ulcerative colitis

Crohn disease (CD) and ulcerative colitis (UC) are increasingly common, chronic forms of inflammatory bowel disease. The behavior of these diseases varies unpredictably among patients. Identification of reliable prognostic biomarkers would enable treatment to be personalized so that patients destined to experience aggressive disease could receive appropriately potent therapies from diagnosis, while those who will experience more indolent disease are not exposed to the risks and side effects of unnecessary immunosuppression. Using transcriptional profiling of circulating T cells isolated from patients with CD and UC, we identified analogous CD8+ T cell transcriptional signatures that divided patients into 2 otherwise indistinguishable subgroups. In both UC and CD, patients in these subgroups subsequently experienced very different disease courses. A substantially higher incidence of frequently relapsing disease was experienced by those patients in the subgroup defined by elevated expression of genes involved in antigen-dependent T cell responses, including signaling initiated by both IL-7 and TCR ligation - pathways previously associated with prognosis in unrelated autoimmune diseases. No equivalent correlation was observed with CD4+ T cell gene expression. This suggests that the course of otherwise distinct autoimmune and inflammatory conditions may be influenced by common pathways and identifies what we believe to be the first biomarker that can predict prognosis in both UC and CD from diagnosis, a major step toward personalized therapy.

Use of sirolimus (rapamycin) to treat refractory Crohn's disease

We present the case of a 37-year-old woman with severe refractory colonic and perianal Crohn’s disease who had lost response to second-line, steroid-sparing treatments azathioprine, methotrexate and infliximab. For many such patients extensive surgery has often been considered the only option. New insights provided by the results of genome-wide association scanning in Crohn’s disease highlight autophagy, a cellular process implicated in the clearance of intracellular bacteria, as a key process in Crohn’s disease pathogeneses. Sirolimus (rapamycin) is a drug used to upregulate autophagy in cell culture in the laboratory, and in clinical practice to prevent rejection following organ transplantation due to independent immunosuppressive action. Our patient was treated with sirolimus for 6 months at a dose that maintained serum trough levels of 5 ng/ml. There was marked and sustained improvement in Crohn’s disease symptoms with the Harvey–Bradshaw index falling from 13 to 3, in serum markers of inflammation (C-reactive protein fell from 79 to 2) and endoscopic appearance. This is the first reported case of the use of sirolimus to treat Crohn’s disease.

Contribution of TNFSF15 gene variants to Crohn's disease susceptibility confirmed in UK population

Background: Identification of Crohns disease (CD)‐associated genetic variants is key to understanding pathogenic pathways underlying disease susceptibility. Recent reports of an association between TNFSF15 variants and CD have been modestly replicated in European populations, suggesting heterogeneity at this locus with stronger CD association in Japanese than European populations. Methods: We investigated the association between variants in TNFSF15 and CD in 756 CD patients and 636 controls. Disease subphenotype associations were also investigated. Results: TNFSF15 single nucleotide polymorphism (SNP) variants were associated with CD in our panel with peak odds ratio (OR) 1.2 (95% confidence interval [CI] 1.01–1.41) P = 0.033. The presence of a risk haplotype was replicated for the first time in a European population (frequency 67% in cases and 61% in controls) OR = 1.44 (95% CI 1.23–1.68) P = 0.00012. This result mirrors the UK panel in the index study (Yamazaki et al [2005] Hum Mol Genet 14:3499–3506) but is less significant than that reported in Japanese populations. There was no evidence of association with any individual CD subphenotype. Conclusions: Variants in TNFSF15 contribute to overall CD susceptibility in European populations, although to a lesser extent than that seen in the Japanese. Further studies to define the precise disease‐causing variants as well as targeted functional studies are now required in human CD as TNFSF15 is a potential target for biological therapies.

Genetic variants in TNF‐α but not DLG5 are associated with inflammatory bowel disease in a large United Kingdom cohort

Background: Genetic variants in DLG5, which encodes a scaffolding protein on chromosome 10q23, and tumor necrosis factor (TNF)‐&agr;, encoding a proinflammatory cytokine on chromosome 6p, have recently been reported to be associated with inflammatory bowel disease (IBD). We studied these variants to seek evidence of association with IBD in a large independent dataset. Methods: We genotyped 1104 unrelated white IBD subjects‐496 with Crohns disease, 512 with ulcerative colitis, and 96 with indeterminate colitis from the Cambridge/Eastern (UK) panel‐and 760 healthy control subjects for DLG5_113G/A, DLG5_4136C/A, TNF‐857C/T, and TNF‐1031T/C polymorphisms. Known Crohns disease‐predisposing variants in CARD15/NOD2 were also genotyped to permit analysis for reported epistatic interactions. Results: TNF‐857 was shown to be associated with IBD overall (P = 0.0079). A formal interaction test showed that TNF‐857 is associated equally with ulcerative colitis and Crohns disease. Neither of the DLG5 alleles, however, was associated with IBD (P = 0.32 and 0.35). Subgroup analysis also failed to show evidence of association between either DLG5 allele or genotype frequencies and ulcerative colitis or Crohns disease. Stratification of TNF‐&agr; and DLG5 cases by CARD15 genotype made no significant difference in the strength of associations. Conclusions: We have confirmed an association between the TNF‐857 promoter polymorphism and IBD in a large independent UK dataset but were unable to replicate an association at the previously reported loci within DLG5. This may reflect heterogeneity between the populations, a smaller effect size than originally predicted, or possibly a false‐positive result in the original study. Further fine mapping studies of the TNF promoter region and studies assessing functional consequences of TNF promoter polymorphisms are now required in IBD.

Genetic association between NLRP3 variants and Crohn's disease does not replicate in a large UK panel

Background: NLRP3 (formerly known as CIAS1 or NALP3) encodes a key component of the inflammasome and is a strong candidate gene for Crohns disease (CD) susceptibility. A recent study reported significant and internally replicated association between CD and six single nucleotide polymorphisms (SNPs) in a regulatory region 5.3 kb downstream of NLRP3. Independent replication is required to verify these findings. Methods: In all, 1298 CD cases and 1244 healthy controls were genotyped for the six SNPs using Taqman. Single locus, haplotype, and subphenotype analyses were conducted using logistic regression‐based methods and PLINK, respectively. Results: No significant associations were found, either on single locus, subphenotype, or haplotype analysis. Conclusions: Given our high (>90%) power to replicate findings from the index study, our data suggest either a much smaller effect size for the association between NLRP3 and CD susceptibility than previously reported or the possibility of a false‐positive result in the index study. Further studies in other populations are required to determine what role, if any, NLRP3 variants play in CD susceptibility. (Inflamm Bowel Dis 2011;)

Complex insertion/deletion polymorphism in NOD1 (CARD4) is not associated with inflammatory bowel disease susceptibility in East Anglia panel

Background and Aims: Genetic association between inflammatory bowel disease (IBD) and NOD1 (CARD4) has recently been reported. This gene has structural similarity to NOD2 (CARD15), a confirmed susceptibility gene for Crohns disease (CD). The NOD1 association was strongest at novel complex indel ND1 + 32656. Our aim was to ascertain the contribution of ND1 + 32656 variants to IBD in a large independent United Kingdom dataset and to identify any subphenotype association within CD and ulcerative colitis (UC). Methods: The presence of the ND1 + 32656 variant in our panel was confirmed by direct resequencing in 96 cases. One thousand three hundred seventy unrelated white IBD subjects (671UC, 645 CD, 54 indeterminate) and 760 regionally matched controls were then genotyped for the ND1 + 32656 variant. Data were analyzed by logistic regression methods within STATA software. Results: There was no association between ND1 + 32656 and IBD in our panel. There was no heterogeneity between UC and CD, nor within the CD subgroup when conditioned by subphenotype or the presence of NOD2 variants. Conclusions: There was no overall evidence of association between IBD and the reported NOD1 susceptibility variant ND1 + 32656 in our panel. The discrepancy with the earlier report may reflect a smaller effect size than previously predicted, a false‐positive result in the index study, or population heterogeneity.

Assessing fatigue in inflammatory bowel disease: comparison of three fatigue scales.

Fatigue is commonly reported by patients with inflammatory bowel disease (IBD), both in quiescent and active disease. Few fatigue scales have been tested in IBD.

PTH-088 Assessing fatigue in inflammatory bowel disease comparison and validation of three fatigue scales: ibd-f, mfi and maf scales

Introduction Patients with inflammatory bowel disease (IBD) report fatigue in both quiescent (41%) and active disease (86%);1however, due to its subjective nature it is difficult to assess. Many different fatigue scales exist, although most have not been tested with IBD populations. Only one scale has been developed specifically for people with IBD.2We aimed to assess validity and reliability of three fatigue assessment scales in an IBD adult population and to determine factors correlated with fatigue. Method A cross-sectional study. Participants (n = 605) were randomly selected and completed questionnaires assessing fatigue, anxiety, depression, quality of life and IBD activity. A sub-group of responders (n = 70) were sent the same mailing 6 weeks later for test-retest. The fatigue scales used were: the Inflammatory Bowel Disease Fatigue (IBD-F), the Multidimensional Fatigue Inventory (MFI) and the Multidimensional Assessment Fatigue (MAF). Internal consistency was measured by Cronbach’s alpha and test-retest reliability by the intra-class correlation coefficient (ICC). Results 465 (77%) questionnaires were completed for the test and 69% for retest. All three scales are highly correlated (p < 0.001). Test-retest suggests good agreement for all scales’ total scores with ICC values of 0.74 and 0.83 (IBD-F Section 1 and 2), 0.74 (MAF) and 0.65–0.84 (MFI). Age, gender, bowel condition, anxiety, depression and IBDQ scores were significantly associated with level of fatigue (p < 0.001) for all three fatigue scales. Older patients had lower fatigue scores, females had higher scores than males, colitis patients had significantly lower scores than Crohn’s patients, patients with a higher level of anxiety and depression had higher fatigue scores and better IDBQ was associated with lower fatigue scores. Conclusion All three tested fatigue scales were found to be valid and reliable measures of IBD fatigue. Factors such as age, gender, bowel condition, quality of life, anxiety and depression are significantly associated with fatigue and should all be taken into account in the process of care delivery to people with IBD and fatigue. Disclosure of interest W. Czuber-Dochan Grant/ Research Support from: Big Lottery Fund in collaboration with Crohn’s and Colitis UK, Speaker Bureau of: Dr Falk Pharma UK, Ferring, C. Norton Grant/ Research Support from: Big Lottery Fund in collaboration with Crohn’s and Colitis UK, Speaker Bureau of: Ferring, Shire, P. Bassett: None Declared, S. Berliner Conflict with: Trustee for Crohn’s and Colitis UK, F. Bredin Grant/Research Support from: Service development awards from Shire and ferring, M. Darvell Employee of: Crohn’s and Colitis UK, A. Forbes Grant/ Research Support from: Big Lottery Fund in collaboration with Crohn’s and Colitis UK, Speaker Bureau of: Dr Falk UK, Warner-Chilcott, NPS, M. Gay Consultant for: Crohn’s and Colitis UK, Conflict with: Trustee for Crohn’s and Colitis UK, E. Ream: None Declared, H. Terry Employee of: Crohn’s and Colitis UK References Czuber-Dochan W, Ream E, Norton C. Review article: description and management of fatigue in inflammatory bowel disease. Alimentary Pharmacology & Therapeutics. 2013;37(5):505–516 Czuber-Dochan W, Norton C, Bassett P, Berliner S, Bredin F, Darvell M, Forbes A, Gay M, Nathan I, Ream E, Terry H. Development and psychometric testing of inflammatory bowel disease fatigue (IBD-F) patient self-assessment scale. Journal of Crohn’s & Colitis. 2014;8:1398–1406

PTU-064 Inflammatory bowel disease and fatigue: the effect of physical activity and/or omega 3 supplementation

Introduction Fatigue is frequently reported by patients with Inflammatory Bowel Disease (IBD), despite disease remission. However, no previous intervention trial has studied this symptom. We tested the effects on fatigue in IBD patients from (i) individual advice to increase physical activity (PA) and/or (ii) supplementation with omega-3 fatty acids. Method Design:a randomised controlled 2 × 2 factorial study compared change-from-baseline scores in intervention and control groups. Primary outcome: change in FACIT-F (Functional Assessment of Chronic Illness Therapy – Fatigue) score; main secondary outcomes: change in fatigue survey scores including IBD-fatigue (IBD-F); PA by monitors (Actigraph, Pensacola, US); adverse effects. Eligibility: IBD remission; ≤2 portions oily fish/week; ≤ 60 min moderate-vigorous PA/week; no comorbidities causing fatigue; no depression. Interventions: exercise advice (15 min consultation) and fish oil supplement (2.97 g per day omega-3, “Take Omega 3”©, Edinburgh, UK); Controls: dietary consultation and placebo supplement. All patients received follow-up support (email, telephone). Results Over 640 IBD outpatients were screened: 74 of those eligible consented to inclusion and randomisation, 60 commenced the intervention, and 52 completed the study according to protocol. At baseline the four groups did not differ significantly (gender, age, disease location or past IBD activity, level of PA, or FACIT-F score). The only effect on fatigue from the primary outcome – significant deterioration in FACIT-F score (95% CI:-8.6-(-0.7); p = 0.02) – was with omega-3 supplement. Fatigue was however significantly reduced in the exercise groups, measured by IBD-F score (95% CI:-3.8-(-0.2); p = 0.03). There were no significant interactions between effects of exercise and fish oil on fatigue, or consistent trends in fatigue or PA levels across the various measures between the four groups. Only 1 treatment-related adverse event was reported (in exercise group), suggesting that neither exercise nor fish oil were associated with likelihood of occurrence of an adverse effect, including gastrointestinal symptoms. Conclusion The apparent worsening of fatigue with fish oil is unexplained. Exercise and fish oil, singly or in combination, were shown to be safe and generally well-tolerated in IBD patients. There was no evidence of adverse exercise-related effects on gut-related symptoms, and some evidence of improvement in fatigue. Hence, regular moderate-vigorous exercise may provide self-management options in IBD-related fatigue. Disclosure of interest A. McNelly Grant/ Research Support from: Big Lottery Fund in collaboration with Crohn’s and Colitis UK, I. Nathan Grant/ Research Support from: Big Lottery Fund in collaboration with Crohn’s and Colitis UK, Speaker Bureau of: Dr Falk Pharma UK, M. Monte: None Declared, G. Grimble: None Declared, C. Norton Grant/ Research Support from: National Lottery in collaboration with Crohn’s and Colitis UK, Speaker Bureau of: Ferring; Shire, F. Bredin: None Declared, W. Czuber-Dochan Grant/ Research Support from: Big Lottery Fund in collaboration with Crohn’s and Colitis UK, Speaker Bureau of: Dr Falk Pharma UK; Ferring, S. Berliner Consultant for: Crohn’s and Colitis UK, M. Gay Consultant for: Crohn’s and Colitis UK, M. Darvell Employee of: Crohn’s and Colitis UK, H. Terry Employee of: Crohn’s and Colitis UK, A. Forbes Grant/ Research Support from: Big Lottery Fund in collaboration with Crohn’s and Colitis UK, Speaker Bureau of: Dr Falk Pharma UK; Warner-Chilcott; NPS.

PWE-120 What Do Healthcare Professionals Know About Fatigue In Patients With Ibd And How Do They Manage It?

Introduction Fatigue is one of the top complaints in inflammatory bowel disease (IBD) with 40% of patients in remission and 86% in active condition reporting fatigue.1 However patients report that their complaints of fatigue are often not addressed in clinical consultations.2 This study aimed to gain an understanding of healthcare practitioners’ (HCPs) perception of IBD fatigue as experienced by people with IBD. Methods Descriptive phenomenology with purposive sampling was used to identify a range of professionals (gastroenterologists, IBD nurses, general practitioners, dietitians, psychologists and pharmacists). In-depth semi-structured interviews were conducted with 20 HCPs who work with people with IBD (June–Dec 2012). Colazzi’s framework was used to analyse the data.3 Results Three main themes and several sub-themes were identified. The main themes were: the phenomenon of fatigue as perceived by HCPs; the impact of fatigue on patients’ lives; and the methods used by HCPs to deal with fatigue. Fatigue was identified as an important, but difficult and often frustrating, symptom to understand. The study participants perceived fatigue as ‘a complicated and complex thing’. HCPs reported that fatigue impacts on the emotional, private and public aspects of patients’ functioning, however there were very few methods suggested on how to assess and manage the fatigue in a systematic way. Many expressed a desire for better education about fatigue and better multi-disciplinary effort to manage fatigue. Conclusion Despite fatigue being one of the symptoms most frequently reported by IBD patients, it remains poorly understood by HCPs, who find fatigue challenging and frustrating. There is a need for a systematic and structured assessment and management of this distressing symptom and HCPs should communicate with each other about care for each individual patient. There is a need for an assessment framework and for intervention strategies to be tested. It is essential for multidisciplinary team members to be involved in planning and managing coordinated care of patients reporting fatigue in IBD. References Czuber-Dochan W, Ream E, Norton C, Review article: description and management of fatigue in inflammatory bowel disease. Alim Pharma and Therap 2013;37(5):505–16 Czuber-Dochan W, et al. The experience of fatigue in people with inflammatory bowel disease: an exploratory study. JAN 2013;69(9):1987–99 Colazzi P, Psychological research as a phenomenology views it. In Valle R, King M Eds. Existential Phenomenological Alternatives for Psychology. 1978;New York: New York University Press Disclosure of Interest W. Czuber-Dochan Grant/research support from: Big Lottery Fund managed by Crohn’s and Colitis UK, C. Norton Grant/research support from: Big Lottery Fund managed by Crohn’s and Colitis UK, S. Berliner Conflict with: Trustee Crohn’s and Colitis UK, F. Bredin Grant/research support from: Big Lottery Fund managed by Crohn’s and Colitis UK, M. Darvell Employee of: Crohn’s and Colitis UK, A. Forbes Grant/research support from: Big Lottery Fund managed by Crohn’s and Colitis UK, M. Gay Conflict with: Vice-Chair and Trustee Crohn’s and Colitis UK, I. Nathan Grant/research support from: Big Lottery Fund managed by Crohn’s and Colitis UK, E. Ream: None Declared, H. Terry Employee of: Crohn’s and Colitis UK.