To Örebro University

Background and Aims: An adaptive immunological response to microbial antigens has been observed in Crohn's disease (CD). Intriguingly, this serological response precedes the diagnosis in some patients and has also been observed in healthy relatives. We aimed to determine whether genetic factors are implicated in this response in a CD twin cohort.

Methods: In total, 82 twin pairs (Leuven n = 13, Maastricht n = 8, Örebro n = 61) took part: 81 pairs with CD (concordant monozygotic n = 16, discordant monozygotic n = 22, concordant dizygotic n = 3, discordant dizygotic n = 40) and 1 monozygotic pair with both CD and ulcerative colitis. Serology for Pseudomonas fluorescens-related protein (anti-I2), Escherichia coli outer membrane porin C (anti-OmpC), CBir1flagellin (anti-CBir1) and antibodies to oligomannan (anti-Saccharomyces cerevisiae antibody [ASCA]) was determined by standardized enzyme-linked immunoassay.

Results: All markers were more often present in CD twins than in their healthy twin siblings. Using the intraclass correlation coefficient (ICC), agreements in concentrations of anti-OmpC and anti-I2 were observed in discordant monozygotic but not in discordant dizygotic twin pairs with CD (anti-OmpC, ICC 0.80 and -0.02, respectively) and (anti-I2, ICC 0.56 and 0.05, respectively). In contrast, no agreements were found in anti-CBir, immunoglobulin (Ig) G ASCA and ASCA IgA.

Conclusions: We show that anti-I2 and anti-CBir1 statuses have specificity for CD and confirm previous reported specificities for anti-OmpC and ASCA. Based on quantitative analyses and observed ICCs, genetics seems to predispose to the anti-OmpC and anti-I2 response but less to ASCA and anti-CBir1 responses.

BACKGROUND: Inflammatory bowel disease (IBD) has been linked to an increased risk of colorectal neoplasia. However, the types and risks of specific polyp types in IBD are less clear.

METHODS: We identified 41,880 individuals with IBD [Crohn's disease (CD: n=12,850); Ulcerative colitis (UC): n=29,030)] from Sweden matched with 41,880 reference individuals. Using Cox regression, we calculated adjusted hazard ratios (aHRs) for neoplastic colorectal polyps (Tubular, Serrated/Sessile, Advanced and Villous) defined by histopathology codes.

RESULTS: During follow-up, 1648 (3.9%) IBD patients and 1143 (2.7%) reference individuals had an incident neoplastic colorectal polyp, corresponding to an incidence rate of 46.1 and 34.2 per 10,000 person-years, respectively. This correlated to an aHR of 1.23 (95% CI 1.12-1.35) with the highest HRs seen for sessile serrated polyps (8.50, 95% CI 1.10-65.90) and traditional serrated adenomas (1.72, 95% CI 1.02-2.91). aHRs for colorectal polyps were particularly elevated in those diagnosed with IBD at a young age and after 10 years after diagnosis. Both absolute and relative risks of colorectal polyps were higher in UC than in CD (aHRs 1.31 vs. 1.06, respectively), with a 20-year cumulative risk differences of 4.4% in UC and 1.5% in CD, corresponding to one extra polyp in 23 patients with UC and one in 67 CD patients during the first 20 years after IBD diagnosis.

CONCLUSIONS: In this nationwide population-based study, there was an increased risk of neoplastic colorectal polyps in IBD patients. Colonoscopic surveillance in IBD appears important, especially in UC and after 10 years of disease.

Background and Aims: The association between microscopic colitis [MC] and cancer risk is unclear. Large, population-based studies are lacking.

Methods: We conducted a nationwide cohort study of 11 758 patients with incident MC [diagnosed 1990-2016 in Sweden], 50 828 matched reference individuals, and 11 614 siblings to MC patients. Data were obtained through Sweden's pathology departments and from the Swedish Cancer Register. Adjusted hazard ratios [aHRs] were calculated using Cox proportional hazards models.

Results: At the end of follow-up [mean: 6.7 years], 1239 [10.5%] of MC patients had received a cancer diagnosis, compared with 4815 [9.5%] of reference individuals (aHR 1.08 [95% confidence interval1.02-1.16]). The risk of cancer was highest during the first year of follow up. The absolute excess risks for cancer at 5, 10, and 20 years after MC diagnosis were + 1.0% (95% confidence interval [C1]0.4%-1.6%), +1.5% [0.4%-2.6%], and + 3.7% [-2.3-9.6%], respectively, equivalent to one extra cancer event in every 55 individuals with MC followed for 10 years. MC was associated with an increased risk of lymphoma (aHR 1.43 [1.06-1.92]) and lung cancer (aHR 1.32 [1.04-1.68]) but with decreased risks of colorectal (aHR 0.52 [0.40-0.66]) and gastrointestinal cancers (aHR 0.72 [0.60-0.85]). We found no association with breast or bladder cancer. Using siblings as reference group to minimise the impact of shared genetic and early environmental factors, patients with MC were still at an increased risk of cancer (HR 1.20 [1.06-1.36]).

Conclusions: This nationwide cohort study demonstrated an 8% increased risk of cancer in MC patients. The risk was highest during the first year of follow-up.

Background: Studies from mainly before the wide use of targeted therapies and guidelines for thromboprophylaxis indicate that patients with inflammatory bowel disease (IBD) are at a doubled risk of venous thromboembolism (VTE). We studied the risk of VTE in a modern-day cohort of patients with IBD, overall and in subgroups of disease characteristics.

Methods: Using Swedish healthcare registers, we identified a nationwide population-based cohort of 55,252 patients with incident IBD between 2007 and 2021 with a median follow-up time of 6.5 years. Patients were matched by age, sex, calendar year and county of residence with up to ten reference individuals from the general population (N=536,067). The primary outcome was VTE, including pulmonary embolism and deep vein thrombosis. Incidence rates per 1,000 person-years and hazard ratios (HR) were calculated for IBD in general and according to disease subtype, sex, age and disease characteristics at diagnosis. HRs stratified by matching variables (model 1) and additionally adjusted for comorbidities and socioeconomic factors (model 2) were estimated by using Cox regression.

Results: The incidence rate of VTE among patients with IBD was 5.03 per 1,000 person-years compared with 2.34 per 1,000 person-years among reference individuals (Table 1). This corresponded to a doubled incidence of VTE (HR=2.18, 95% confidence interval (CI)=2.07-2.29, model 1). Adjusting further for covariates in model 2 had only minor effects on the HR. The HR was consistent across IBD subtypes and sex. The relative risk was higher for those with younger age (18-39 years) at IBD diagnosis (HR 2.52, 95% CI: 2.22-2.83) with a risk difference of 1.25 per 1,000 person-years. The IR, 10.64 per 1,000 person-years, and risk difference, 5.42 per 1,000 person-years, was the highest for those with elderly onset (≥60 years) IBD. There was a stronger association for those with extensive ulcerative colitis (E3), primary sclerosing cholangitis, extraintestinal manifestations and perianal disease. HRs for VTE were persistently elevated across follow-up time, but was higher during the first year of follow-up (Figure 1).

Conclusion: The risk of VTE was doubled in these modern-day data and remained elevated across follow-up time. Disease characteristics associated with higher inflammatory burden at diagnosis and older age are markers of increased risk. This underscores the importance of continuous vigilance and individual assessment of risk factors for VTE in patients with IBD.

Background and Aims: The incidence of inflammatory bowel disease (IBD) is increasing in Eastern Europe possibly due to changes in environmental factors towards a more "westernised" standard of Living. The aim of this study was to investigate differences in exposure to environmental factors prior to diagnosis in Eastern and Western European IBD patients.

Methods: The EpiCom cohort is a population-based, prospective inception cohort of 1560 unselected IBD patients from 31 European countries covering a background population of 10.1 million. At the time of diagnosis patients were asked to complete an 87-item questionnaire concerning environmental factors.

Results: A total of 1182 patients (76%) answered the questionnaire, 444 (38%) had Crohn's disease (CD), 627 (53%) ulcerative colitis (UC), and 111 (9%) IBD unclassified. No geographic differences regarding smoking status, caffeine intake, use of oral contraceptives, or number of first-degree relatives with IBD were found. Sugar intake was higher in CD and UC patients from Eastern Europe than in Western Europe while fibre intake was lower (p < 0.01). Daily consumption of fast food as well as appendectomy before the age of 20 was more frequent in Eastern European than in Western European UC patients (p < 0.01). Eastern European CD and UC patients had received more vaccinations and experienced fewer childhood infections than Western European patients (p < 0.01).

Conclusions: In this European population-based inception cohort of unselected IBD patients, Eastern and Western European patients differed in environmental factors prior to diagnosis. Eastern European patients exhibited higher occurrences of suspected risk factors for IBD included in the Western lifestyle. (C) 2013 European Crohn's and Colitis Organisation. Published by Elsevier B.V. All rights reserved.

Background and Aims: The EpiCom study and inception cohort was initiated in 2010 in 31 centers from 14 Western and 8 Eastern European countries, covering a 10.1 million person background population. Our aim was to investigate whether there is a difference between Eastern and Western Europe in health care and education of patients with inflammatory bowel disease (IBD).

Methods: A quality of care (QoC) questionnaire was developed in the EpiCom group consisting of 16 questions covering 5 items: time interval between the onset of symptoms and diagnosis, information, education, empathy and access to health care providers.

Results: Of 1,515 patients, 947 (217 east/730 west) answered the QoC questionnaire. Only 23% of all patients had knowledge about IBD before diagnosis. In Eastern Europe, significantly more patients searched out information about IBD themselves (77% vs. 68%, p < 0.05), the main source was the Internet (92% vs. 88% p = 0.23). In Western Europe, significantly more patients were educated by nurses (19% vs. 1%, p < 0.05), while in Eastern Europe, gastroenterologists were easier to contact (80% vs. 68%, p < 0.05).

Conclusion: Health care differed significantly between Eastern and Western Europe in all items, but satisfaction rates were high in both geographic regions. Because of the low awareness and the rising incidence of IBD, general information should be the focus of patient organizations and medical societies. In Western Europe IBD nurses play a very important role in reducing the burden of patient management. (c) 2014 European Crohn's and Colitis Organisation. Published by Elsevier B.V. All rights reserved.

Background & Aims: Health-related quality of life (HRQoL) is impaired in patients with Inflammatory Bowel Disease (IBD). The aim was prospectively to assess and validate the pattern of HRQoL in an unselected, population-based inception cohort of IBD patients from Eastern and Western Europe.

Methods: The EpiCom inception cohort consists of 1560 IBD patients from 31 European centres covering a background population of approximately 10.1 million. Patients answered the disease specific Short Inflammatory Bowel Disease Questionnaire (SIBDQ) and generic Short Form 12 (SF-12) questionnaire at diagnosis and after one year of follow-up.

Results: In total, 1079 patients were included in this study. Crohn's disease (CD) patients mean SIBDQ scores improved from 45.3 to 55.3 in Eastern Europe and from 44.9 to 53.6 in Western Europe. SIBDQ scores for ulcerative colitis (UC) patients improved from 44.9 to 57.4 and from 48.8 to 55.7, respectively. UC patients needing surgery or biologicals had lower SIBDQ scores before and after compared to the rest, while biological therapy improved SIBDQ scores in CD. CD and UC patients in both regions improved all SF-12 scores. Only Eastern European UC patients achieved SF-12 summary scores equal to or above the normal population.

Conclusion: Medical and surgical treatment improved HRQoL during the first year of disease. The majority of IBD patients in both Eastern and Western Europe reported a positive perception of disease-specific but not generic HRQoL. Biological therapy improved HRQoL in CD patients, while UC patients in need of surgery or biological therapy experienced lower perceptions of HRQoL than the rest.

BACKGROUND: The EpiCom-study investigates a possible East-West-gradient in Europe in the incidence of IBD and the association with environmental factors. A secured web-based database is used to facilitate and centralize data registration.

AIM: To construct and validate a web-based inception cohort database available in both English and Russian language.

METHOD: The EpiCom database has been constructed in collaboration with all 34 participating centers. The database was translated into Russian using forward translation, patient questionnaires were translated by simplified forward-backward translation. Data insertion implies fulfillment of international diagnostic criteria, disease activity, medical therapy, quality of life, work productivity and activity impairment, outcome of pregnancy, surgery, cancer and death. Data is secured by the WinLog3 System, developed in cooperation with the Danish Data Protection Agency. Validation of the database has been performed in two consecutive rounds, each followed by corrections in accordance with comments.

RESULTS: The EpiCom database fulfills the requirements of the participating countries' local data security agencies by being stored at a single location. The database was found overall to be "good" or "very good" by 81% of the participants after the second validation round and the general applicability of the database was evaluated as "good" or "very good" by 77%. In the inclusion period January 1st -December 31st 2010 1336 IBD patients have been included in the database.

CONCLUSION: A user-friendly, tailor-made and secure web-based inception cohort database has been successfully constructed, facilitating remote data input. The incidence of IBD in 23 European countries can be found at www.epicom-ecco.eu.

Background and Aims: Few population-based cohort studies have assessed the disease course of ulcerative colitis [UC] in the era of biological therapy and widespread use of immunomodulators. The aim of this study was to assess the 5-year outcome and disease course of patients with UC in the Epi-IBD cohort.

Methods: In a prospective, population-based inception cohort of unselected patients with UC, patients were followed up from the time of their diagnosis, which included the collection of their clinical data, demographics, disease activity, medical therapy, and rates of surgery, cancers, and deaths. Associations between outcomes and multiple covariates were analysed by Cox regression analysis.

Results: A total of 717 patients were included in the study. During follow-up, 43 [6%] patients underwent a colectomy and 163 [23%] patients were hospitalised. Of patients with limited colitis [distal to the left flexure], 90 [21%] progressed to extensive colitis. In addition, 92 [27%] patients with extensive colitis experienced a regression in disease extent, which was associated with a reduced risk of hospitalisation (hazard ratio [HR]: 0.5 95% CI: 0.3-0.8]. Overall, patients were treated similarly in both geographical regions; 80 [11%] patients needed biological therapy and 210 [29%] patients received immunomodulators. Treatment with immunomodulators was found to reduce the risk of hospitalisation [HR: 0.5 95% CI: 0.3-0.8].

Conclusions: Although patients in this population-based cohort were treated more aggressively with immunomodulators and biological therapy than in cohorts from the previous two decades, their disease outcomes, including colectomy rates, were no different. However, treatment with immunomodulators was found to reduce the risk of hospitalisation.

Background and aims: Anaemia is an important complication of inflammatory bowel disease (IBD). The aim of this study was to determine the prevalence of anaemia and the practice of anaemia screening during the first year following diagnosis in a European prospective population-based inception cohort.

Methods: Newly diagnosed IBD patients were included and followed prospectively for one year in 29 European and 1 Australian centre. Clinical data including demographics, medical therapy, surgery and blood samples were collected. Anaemia was defined according to the World Health Organization.

Results: A total of 1,871 patients (CD: 686, 88%; UC: 1,021, 87%; IBDU 164. 81%) were included in the study. The prevalence of anaemia was higher in CD than in UC patients and overall, 49% of CD and 39% of UC patients had at least one instance of anaemia during the first 12 months after diagnosis. UC patients with more extensive disease and those from Eastern European countries, and CD patients with penetrating disease or colonic disease location, had higher risks of anaemia. CD and UC patients in need of none or only mild anti-inflammatory treatment had a lower risk of anaemia. In a significant proportion of patients, anaemia was not assessed until several months after diagnosis, and in almost half of all cases of anaemia a thorough work-up was not performed.

Conclusions: Overall, 42% of patients had at least one instance of anaemia during the first year following diagnosis. Most patients were assessed for anaemia regularly; however, a full anaemia work-up was frequently neglected in this community setting.

Introduction: Long-term data on the influence of smoking on risk of microscopic colitis are limited. We therefore sought to examine and characterize the association between smoking and risk of incident microscopic colitis in two large prospective cohorts of women.

Methods: We conducted a prospective study of 231,015 women enrolled in the Nurses' Health Study (NHS) and NHSII. Information regarding smoking, other lifestyle factors, and medications were collected biennially from 1976 to 2012 in NHS and 1989 to 2013 in NHSII. Incident cases of microscopic colitis were confirmed through physician medical record review. We used Cox proportional hazards modeling to examine the association between smoking and risk of microscopic colitis.

Results: We documented 166 incident cases of microscopic colitis over 6,122,779 person-years of follow up. Compared to non-smokers, the multivariable-adjusted hazard ratio (HR) for microscopic colitis was 2.52 (95% CI 1.59 - 4.00) amongst current smokers and 1.54 (95% CI 1.09 - 2.17) amongst past smokers. The risk increased with higher pack-years of smoking (Ptrend = 0.001) and diminished following smoking cessation (Ptrend = 0.017). Current smoking appeared to be more strongly associated with risk of collagenous colitis (3.68; 95% CI 1.94 - 6.97) than lymphocytic colitis (HR 1.71; 95% CI 0.83 - 3.53).

Conclusion: In two large prospective cohort studies, we observed an association between current smoking and risk of microscopic colitis. Risk of microscopic colitis appeared to increase with higher pack-years and diminish following smoking cessation. Future studies focused on characterizing the biologic mechanisms underlying these associations are warranted.

Background & aims: Inflammatory bowel disease has considerable effects on work-related outcomes and leads to high societal costs due to sick leave and disability pension. The aims of this study were to systematically review evidence on work-related outcomes that are relevant to productivity losses and to evaluate whether medical or surgical interventions have a positive impact on patients work ability.

Methods: A systematic literature search in PubMed was conducted in June 2013. Abstracts were screened by two independent reviewers, and full-text articles describing the frequency of work-related outcomes were retrieved. Two independent reviewers extracted data according to the PRISMA Statement for Reporting Systematic Reviews and Meta-Analyses. Findings were organized by study design (non-interventional/interventional). Non-interventional studies were structured according to whether they presented data in comparison to control groups or not and interventional studies were summarized according to type of intervention.

Results: This review included 30 non-interventional (15 with comparison groups and 15 without comparison group) and 17 interventional studies (9 surgical and 8 medical). The majority of the studies reported a high burden of work:related outcomes among inflammatory bowel disease patients regardless of the methodology used. While biologic agents showed positive effect on work absenteeism and presenteeism in randomized clinical trials, the impact of surgical interventions needs further evaluation.

Conclusions: Inflammatory bowel disease patients experience a high burden in work-related outcomes. Additional data on productivity losses and the long-term impact of interventions is needed to help inform decision-makers about treatment options and their benefits in reducing productivity losses in inflammatory bowel disease patients. (C) 2014 European Crohn's and Colitis Organisation. Published by Elsevier B.V. All rights reserved.

BACKGROUND AND AIMS: Systemic inflammation is well-recognized to be associated with ulcerative colitis (UC), but whether these effects are causal or consequential remains unclear. We aimed to define potential causal relationship of cytokine dysregulation with different tiers of evidence.

METHODS: We firstly synthesized serum proteomic profiling data from two multi-centered observational studies, in which a panel of systemic inflammatory proteins was analyzed to examine their associations with UC risk. To further dissect observed associations, we then performed a bidirectional two-sample Mendelian randomization (TSMR) analysis from both forward and reverse directions using five genome-wide association study (GWAS) summary level data for serum proteomic profiles and the largest GWAS of 28,738 European-ancestry individuals for UC risk.

RESULTS: Pooled analysis of serum proteomic data identified 14 proteins to be associated with the risk of UC. Forward MR analysis using only cis-acting protein quantitative trait loci (cis-pQTLs) or trans-pQTLs further validated causal associations of two chemokines and the increased risk of UC: C-X-C motif chemokine ligand 9 (CXCL9) (OR, 1.45, 95% CI, 1.08-1.95, P=.012) and C-C motif chemokine ligand 11 (CCL11) (OR, 1.14, 95%CI: 1.09-1.18, P=3.89×10  -10). Using both cis- and trans-acting pQTLs, an association of caspase-8 (CASP8) (OR, 1.04, 95% CI, 1.03-1.05, P= 7.63×10  -19) was additionally identified. Reverse MR did not find any influence of genetic predisposition to UC on any of these three inflammation proteins.

CONCLUSIONS: Pre-existing elevated levels of CXCL9, CCL11 and CASP8 may play a role in the pathogenesis of UC.

BACKGROUND/AIM: Patients with inflammatory bowel disease (IBD) have more work disability than the general population. We aimed to estimate the monetary cost of IBD for the individual through assessment of earnings in relation to diagnosis.

METHODS: Through linkage of national registers we identified patients aged 30-55 years at first IBD diagnosis in Sweden 2002-2011, and same-sex IBD-free siblings. We estimated taxable earnings and disposable income from 5 years before to 5 years after diagnosis.

RESULTS: The 5,961 patients (27% Crohn's disease, 68% ulcerative colitis, 4.3% IBD unclassified) had similar taxable earnings as their 7,810 siblings until the year of diagnosis, when earnings decreased and remained lower than in siblings during follow-up. The adjusted difference in earnings over the entire 5-year period after diagnosis was -5% (-8,212€; 95%CI: -11,458 to-4,967). The difference was larger in women than in men, and larger in Crohn's disease than in ulcerative colitis. When stratifying for sex and IBD subtype and comparing earnings during each year of follow-up, the median annual earnings were lower in women with Crohn's disease and ulcerative colitis than in their sisters during all years of follow-up, whereas the men had similar annual taxable earnings as their brothers. The disposable income was similar between patients and siblings during the investigated time period.

CONCLUSION: From the year of diagnosis and at least 5 years onwards, patients with IBD had 5% lower earnings than siblings, mainly explained by differences between women with IBD and their sisters. However, there were no differences in disposable income.

Background and Aims: Crohn's disease may affect the ability to work and lead to permanent disability. We aimed to investigate work loss in prevalent patients.

Methods: We identified patients with Crohn's disease and general population comparators matched by sex, birth year, healthcare region and education. We assessed days of sick leave and disability pension retrieved from the Swedish Social Insurance Agency and estimated the absolute and relative risk of receiving disability pension [minimum 25% work impairment].

Results: In 2014, the 20638 Crohn's disease patients [median age 44 years] had more than twice as many mean lost workdays [disability pension: 44; sick leave: 19] as the 102038 comparators [disability pension: 20; sick leave: 8], mean difference 35 days [95% confidence interval 33-37]. However, the majority had no lost workdays [68% of patients and 85% of comparators]. The proportion of patients receiving disability pension was 15% (6.5% in the comparators, risk ratio 2.34 [2.25-2.43]) and was higher in all subgroups, especially in female patients [28% vs 13% in the comparators], in those with ≤9 years of education [41% vs 23%] and in ages 60-64 years [46% vs 25%]. The relative risk of disability pension within the patient cohort [adjusted for age, sex, region and education] was higher in patients with complicated disease behaviour, extraintestinal manifestations, need of surgery or treatment with biologics. The differences between patients and comparators remained when comparing other calendar years [2006-2013].

Conclusion: Work loss was found in approximately one-third of patients. The mean number of lost workdays was twice as high as in the comparators.

Background: We aimed to identify protein signatures predictive of a future diagnosis of inflammatory bowel disease (IBD).

Methods: We conducted a case-control study, nested within large population-based cohorts with biorepositories. Samples were obtained from individuals who later in life were diagnosed with IBD (preclinical cases) and compared with age and sex-matched individuals who remained free from IBD during follow-up (controls). Using proximity extension assays (Olink, Uppsala), we measured 176 proteins. We applied regularized logistic regression to identify protein signatures of preclinical disease in serum from the discovery cohort (n=312). Their performance was validated in an external preclinical cohort (n=222). The biological relevance of identified proteins was further assessed in an inception cohort (n=144). Finally, we used an IBD twin cohort (n=327) to examine the impact of genetic and shared environmental factors on identified proteins.

Results: We identified 34 proteins associated with preclinical Crohn’s disease (CD) in the discovery cohort (Pfalse discovery rate <0.10), with 9 confirmed in the validation cohort (Pfalse discovery rate <0.05). For preclinical ulcerative colitis (UC), 45 proteins were identified and 12 validated (Fig. 1A-B). In the discovery cohort, a signature of 29 proteins differentiated preclinical CD cases from controls with an AUC of 0.85 (Fig. 1G). Its performance was confirmed when applied to the preclinical validation cohort (AUC=0.84, Fig. 1H). Moreover, the signature had excellent capacity to differentiate newly diagnosed CD from healthy controls in the inception cohort (AUC = 0.99, Fig. 1I). The preclinical UC signature had a significant, but albeit lower, predictive capacity in the discovery (AUC=0.77), validation (AUC=0.67) and inception cohort (AUC=0.90, Fig. 1G-I).15 of 17 proteins associated with preclinical IBD demonstrated significantly higher intra-pair correlation coefficients in healthy monozygotic- compared to dizygotic twin pairs, indicating an influence from genetic factors on the regulation of these protein markers. The preclinical signature for CD demonstrated an AUC of 0.87 when comparing twins with preclinical CD (n=10) to matched external healthy twins. However, its predictive capacity was lower when comparing preclinical CD twins with their healthy twin siblings (AUC=0.58), i.e., when accounting for genetic and shared environmental factors. The difference in AUC estimates in the twin cohort was not significant (P=0.07).

Background and Aims: Nephrotoxicity is a rare idiosyncratic reaction to 5-aminosalicylate (5-ASA) therapies. The aims of this study were to describe the clinical features of this complication and identify clinically useful genetic markers so that these drugs can be avoided or so that monitoring can be intensified in high-risk patients.

Methods: Inflammatory bowel disease patients were recruited from 89 sites around the world. Inclusion criteria included normal renal function prior to commencing 5-ASA, >= 50% rise in creatinine any time after starting 5-ASA, and physician opinion implicating 5-ASA strong enough to justify drug withdrawal. An adjudication panel identified definite and probable cases from structured case report forms. A genome-wide association study was then undertaken with these cases and 4109 disease controls.

Results: After adjudication, 151 cases of 5-ASA-induced nephrotoxicity were identified. Sixty-eight percent of cases were males, with nephrotoxicity occurring at a median age of 39.4 years (range 6-79 years). The median time for development of renal injury after commencing 5-ASA was 3.0 years (95% confidence interval [CI] 2.3-3.7). Only 30% of cases recovered completely after drug withdrawal, with 15 patients requiring permanent renal replacement therapy. A genome-wide association study identified a suggestive association in the HLA region (p = 1 x 10(-7)) with 5-ASA-induced nephrotoxicity. A sub-group analysis of patients who had a renal biopsy demonstrating interstitial nephritis (n = 55) significantly strengthened this association (p = 4 x 10(-9), odds ratio 3.1).

Conclusions: This is the largest and most detailed study of 5-ASA-induced nephrotoxicity to date. It highlights the morbidity associated with this condition and identifies for the first time a significant genetic predisposition to drug-induced renal injury.

Background: MiRNAs represent a class of small non-coding RNAs which are involved in regulation of protein-coding gene expression. Being implicated in various processes such as development and regu-latory circuits of cells, miRNAs also play an important role in the etiology of a variety of diseases. Imbalance of the regulatory pro-cesses within immune system development and response may lead to disturbed production of pro-inflammatory cytokines and over-reactivity of the immune cells, thus causing relapsing inflamma-tion, a characteristic feature of inflammatory bowel disease (IBD). Recent studies of colonic miRNAs employed NGS for the distinction between CD, UC and healthy controls, or among different CD sub-types. However, NGS-based profiles of blood-circulating miRNAs have thus far not been investigated in the context of IBD together with other immune-mediated diseases, including ankylosing spon-dylitis, psoriasis, systemic lupus erythematosus, rheumatoid arthritis and sarcoidosis, as well as non-immune hemolytic-uremic syndrome.

Methods: Study participants were recruited in Germany and Sweden, where peripheral blood samples (PAXgene) as well as phenotypical and clinical information (such as treatment status, dis-ease activity and location) was collected. Small RNA transcriptomes of 680 individuals (Figure 1) were sequenced using Illumina NGS platform. Small RNA-seq data preprocessing and quantification were performed using cutadapt and miraligner (ref. miRBase v22), respectively. Differential expression analysis (DESeq2) and correla-tion (Spearman) analysis have been performed to identify disease activity-, trait- and treatment-specific miRNA signatures. These sig-natures were then utilized in a machine-learning approach to build classification models for IBD diagnostics.

Results: The results of multiple pairwise differential expression anal-yses among different immune-mediated inflammatory conditions and healthy controls revealed inflammation-specific as well and dis-ease-specific deregulation of miRNAs. Correlation analysis identified miRNAs positively and negatively correlated with IBD activity. The preliminary results of machine learning classifiers based on miRNA profiles showed that median Matthews correlation coefficient for all model types showed remarkable predictive performance estimated as being 1.00 (median over main diagnoses), as well as ranging from 0.68 to 0.76 (median over CD location) and from 0.69 to 0.77 (median over UC extent).

Conclusions: Immune-mediated inflammatory diseases share com-mon and distinct differentially expressed miRNAs, which have a potential to be used in the diagnostics of IBD, including the evalua-tion of the disease activity.

BACKGROUND AND AIMS: Inflammatory bowel disease (IBD) is a chronic relapsing disorder of the gastrointestinal tract, which generally manifests as Crohn's disease (CD) or ulcerative colitis (UC). These subtypes are heterogeneous in terms of disease location and histological features, while sharing common clinical presentation, genetic associations and thus, common immune regulatory pathways.

METHODS: Using miRNA and mRNA coupled transcriptome profiling and systems biology approaches, we report a comprehensive analysis of blood transcriptomes from treatment-naïve (n=110) and treatment-exposed (n=177) IBD patients as well as symptomatic- (n=65) and healthy controls (n=95).

RESULTS: Broadly, the peripheral blood transcriptomes of CD and UC patients were similar. However, there was an extensive gene deregulation in the blood of IBD patients, while only a slight deregulation in symptomatic controls, when compared with healthy controls. The deregulated mRNAs and miRNAs are mainly involved in the innate immunity and are especially enriched in neutrophil activation-related pathways. Oxidative phosphorylation and neutrophil activation-related modules were found to be differentially co-expressed among treatment-naïve IBD as compared to healthy controls. In the deregulated neutrophil activation-related co-expression module, the IL1B was identified as the central gene. The co-expression levels among IL1B and chemosensing receptor (CXCR1/2 and FPR1/2) genes were reduced in the blood of IBD patients when compared with healthy controls.

CONCLUSIONS: Immune dysregulation seen in peripheral blood transcriptomes of treatment-naïve IBD patients is mainly driven by neutrophil activation.

BACKGROUND: Success in personalised medicine in complex disease is critically dependent on biomarker discovery. We profiled serum proteins using a novel proximity extension assay (PEA) to identify diagnostic and prognostic biomarkers in inflammatory bowel disease (IBD).

METHODS: We conducted a prospective case-control study in an inception cohort of 552 patients (328 IBD, 224 non-IBD), profiling proteins recruited across 6 centres. Treatment escalation was characterised by the need for biological agents or surgery after initial disease remission. Nested leave-one-out cross validation was used to examine the performance of diagnostic and prognostic proteins.

RESULTS: A total of 66 serum proteins differentiated IBD from symptomatic non-IBD controls including MMP-12 (Holm adjusted p=4.1×10 -23 ) and OSM (p=3.7×10 -16). Nine of these proteins associate with cis- germline variation (59 independent SNPs). Fifteen proteins, all members of TNF independent pathways including IL-1 and OSM predicted escalation, over a median follow-up of 518 (IQR 224-756) days. Nested cross-validation of the entire data set allows characterisation of 5-protein-models (96% comprising five core proteins ITGAV, EpCAM, IL18, SLAMF7, and IL8) which define a high-risk subgroup in IBD (HR 3.90, CI: 2.43-6.26), or allows distinct 2, and 3 protein models for UC and CD respectively.

CONCLUSION: We have characterised a simple oligo-protein panel that has the potential to identify IBD from symptomatic controls and to predict future disease course. Further prospective work is required to validate our findings.

BACKGROUND: Epigenetic alterations may provide valuable insights into gene-environment interactions play in the pathogenesis of Inflammatory Bowel Disease (IBD).

METHODS: Genome-wide methylation was measured from peripheral blood using the Illumina 450k platform in a case-control study in an inception cohort (295 controls, 154 CD, 161 UC, 28 IBD-U) with covariates of age, sex, and cell counts, deconvoluted by the Houseman method. Genotyping was performed using Illumina HumanOmniExpressExome-8 BeadChips and gene expression using Ion AmpliSeq Human Gene Expression Core Panel. Treatment escalation was characterised by the need for biological agents or surgery after initial disease remission.

RESULTS: A total of 137 differentially methylated positions (DMP) were identified in IBD, including VMP1/MIR21 (p=9.11×10 -15) and RPS6KA2 (6.43×10 -13); with consistency seen across Scandinavia and UK. Dysregulated loci demonstrate strong genetic influence, notably VMP1 (p=1.53×10 -15). Age acceleration is seen in IBD (coefficient 0.94, p<2.2x10 -16). Several immuno-active genes demonstrated highly significant correlations between methylation and gene expression in IBD, in particular OSM: IBD r -0.32, p 3.64×10 -7 vs. non-IBD r -0.14, p=0.77). Multi-omic integration of methylome, genome and transcriptome also implicate specific pathways that associate with immune activation, response and regulation at disease inception. At follow up, a signature of 3 DMPs (TAP1, TESPA1, RPTOR) associated with treatment escalation to biological agents or surgery (hazard ratio of 5.19 (CI:2.14-12.56, logrank p=9.70×10 -4).

CONCLUSION: These data demonstrate consistent epigenetic alterations at diagnosis in European patients with IBD, providing insights into the pathogenetic importance and translational potential of epigenetic mapping in complex disease.

BACKGROUND: MicroRNAs (miRNAs) are cell-specific small non-coding RNAs that can regulate gene expression and have been implicated in Inflammatory Bowel Disease (IBD) pathogenesis. In our study, we define the cell-specific miRNA profiles and investigate its biomarker potential in IBD.

METHODS: In a 2-stage prospective multi-centre case control study, Next Generation sequencing was performed on a discovery cohort of immunomagnetically separated leucocytes from 32 patients (9 CD, 14 UC, 8 healthy controls) and differentially expressed signals were validated in whole blood in 294 patients (97 UC, 98 CD, 98 non-IBD) using quantitative PCR. Correlations were analysed with phenotype, including need for early treatment escalation as a marker of progressive disease using Cox proportional hazards.

RESULTS: In stage 1, each leucocyte subset (CD4+ and CD8+ T-cells and CD14+ monocytes) was analysed in IBD and controls. Three specific miRNAs differentiated IBD from controls in CD4+ T-cells, including miR-1307-3p (p=0.01), miR-3615 (p=0.02) and miR-4792 (p=0.01). In the extension cohort, in stage 2, miR-1307-3p was able to predict disease progression in IBD (HR 1.98, IQR:1.20-3.27;logrank p=1.80×10-3), in particular CD (HR 2.81; IQR: 1.11-3.53, p=6.50×10-4). Using blood-based multimarker miRNA models, the estimated chance of escalation in CD was 83% if 2 or more criteria were met and 90% for UC if 3 or more criteria are met.

INTERPRETATION: We have identified and validated unique CD4+ T-cell miRNAs that are differentially regulated in IBD. These miRNAs may be able to predict treatment escalation and have the potential for clinical translation; further prospective evaluation is now indicated.