UK IBD Twin Registry: Concordance and Environmental Risk Factors of Twins with IBD.

BACKGROUND AND AIMS: Twin studies have long been used to infer heritability. Within the 'omics era, twin cohorts have even greater research potential. This study describes the formation of the UK IBD Twin Registry and analysis of concordance and environmental factors. METHOD: Twin pairs with IBD were recruited by advertising via IBD charities and social media, re-tracing a dormant IBD database and clinician referral. Details of zygosity, concordance, disease history and environmental factors were assessed. Pair concordance was calculated, and environmental factors were analysed with logistic regression models adjusted for zygosity and concordance. RESULTS: Ninety-one twin pairs were included in the analysis; forty-two with CD and forty-nine with UC. More MZ twin pairs with CD were concordant compared with DZ pairs, thus inferring heritability (Chi-sq. 15.6. P < 0.001). In UC, MZ concordance was also numerically greater. Cigarette smoking was predictive of CD (OR 2.66, 95% CI 1.16 to 6.07 P = 0.02); there may be an independent association with cannabis smoking (OR 2.59 95% CI 0.89 to 7.55 P = 0.08). Breastfeeding was protective against UC (OR 0.48, 95% CI 0.25-0.93, P = 0.03), but not CD. Self-reports of less occurrences of gastroenteritis than peers were protective against future UC onset (OR 0.33 95% CI 0.15 to 0.74, P = 0.01). Method of delivery, parental attitudes towards hygiene and recall of diet did not impact future IBD concordance. CONCLUSIONS: This study supports the heritability of IBD. Twin study analysis was able to elucidate environmental factors associated with IBD.

Cancer Risk in 2621 Chinese Patients with Inflammatory Bowel Disease: A Population-based Cohort Study.

BACKGROUND: Studies on cancer risk in inflammatory bowel disease (IBD) have yielded inconsistent results. We conducted a population-based study to determine the risk of cancer in patients with Crohn's disease (CD) and ulcerative colitis (UC). METHODS: Using a territory-wide IBD registry in Hong Kong, we identified 2621 patients with IBD and no history of cancer from 1990 to 2016. We followed them from diagnosis until either September 2016, cancer development, proctocolectomy, or death. Standardized incidence ratios (SIRs) of overall cancer and site-specific cancers were calculated. RESULTS: Of 2621 patients with IBD (1108 CD; 1603 UC; median age, 49 yr; 59.5% men) followed for 26,234 person-years, 88 patients developed cancer after IBD diagnosis. Patients with CD had an increased risk of anorectal cancers (SIR 4.11; 95% confidence interval (CI), 1.84-9.14) and hematological cancers (SIR 3.86, 95% CI, 1.61-9.27) including leukemia (SIR 5.98; 95% CI, 1.93-18.54). Nonmelanoma skin cancer was significantly increased in both CD and UC (CD: SIR 13.88; 95% CI, 1.95-98.51; UC: SIR 9.05; 95% CI, 2.26-36.19). Patients with CD had a higher risk of renal-cell carcinoma (SIR 6.89; 95% CI, 2.22-21.37), and patients with UC had a higher risk of prostate cancer (SIR 2.47; 95% CI, 1.24-4.95). CONCLUSIONS: In a population-based study, Chinese patients with CD are at an increased risk of anorectal cancers and hematological cancers compared with the general population. A higher risk of nonmelanoma skin cancer was also observed in CD and UC. Cancer surveillance should be considered.

European Crohn's and Colitis Organisation Topical Review on Transitional Care in Inflammatory Bowel Disease.

BACKGROUND: This European Crohn's and Colitis Organisation [ECCO] topical review focuses on the transition of adolescents with inflammatory bowel disease [IBD] from child-centred to adult-oriented care. The aim was to provide evidence-supported, expert consensus for health professionals taking part in the transition. METHODS: An online survey determined the areas of importance for health professionals involved in the transition of adolescents with IBD. Thereafter an expert panel of nine paediatric and five adult gastroenterologists was formed to identify the critical elements of the transition programme, and to prepare core messages defined as 'current practice points'. There is limited literature about transition, therefore this review is mainly based on expert opinion and consensus, rather than on specific evidence. RESULTS: A total of 21 practice points were generated before the first [online] voting round. Practice points that reached >80% agreement were accepted, while those that did not reach 80% agreement were refined during a consensus meeting and subjected to voting. Ultimately, 14 practice points were retained by this review. CONCLUSION: We present a consensus-based framework for transitional care in IBD that provides a guidance for clinical practice.

3rd European Evidence-based Consensus on the Diagnosis and Management of Crohn's Disease 2016: Part 1: Diagnosis and Medical Management.

This paper is the first in a series of two publications relating to the European Crohn's and Colitis Organisation [ECCO] evidence-based consensus on the diagnosis and management of Crohn's disease and concerns the methodology of the consensus process, and the classification, diagnosis and medical management of active and quiescent Crohn's disease. Surgical management as well as special situations including management of perianal Crohn's disease of this ECCO Consensus are covered in a subsequent second paper [Gionchetti et al JCC 2016].

Epidemiology of Inflammatory Bowel Disease from 1981 to 2014: Results from a Territory-Wide Population-Based Registry in Hong Kong.

BACKGROUND: Incidence of inflammatory bowel disease (IBD) is increasing in Asia, but population-based prevalence data are limited. This study examined IBD incidence and prevalence based on results of a territory-wide IBD registry in Hong Kong. METHODS: We collected data on 2575 patients with IBD (1541 ulcerative colitis [UC], 983 Crohn's disease [CD], 51 IBD unclassified) from 1981 to 2014 using hospital and territory-wide administrative coding system. Prevalence and incidence, disease phenotype, surgery, and mortality were analyzed. RESULTS: Adjusted prevalence of IBD, UC, CD, and IBD unclassified per 100,000 individuals in 2014 were 44.0, 24.5, 18.6, and 0.9, respectively. Age-adjusted incidence of IBD per 100,000 individuals increased from 0.10 (95% confidence interval, 0.06-0.16) in 1985 to 3.12 (95% confidence interval, 2.88-3.38) in 2014. UC:CD incidence ratio reduced from 8.9 to 1.0 over 30 years (P < 0.001). A family history of IBD was reported in 3.0% of patients. Stricturing or penetrating disease was found in 41% and perianal disease in 25% of patients with CD. 5-aminosalicylate use was common in UC (96%) and CD (89%). Cumulative rates of surgery for CD were 20.3% at 1 year and 25.7% at 5 years, and the corresponding rates for UC were 1.8% and 2.1%, respectively. Mortality for CD and UC was not significantly different from the general population. CONCLUSIONS: In a population-based study in Hong Kong, prevalence of IBD is lower than in the west although comparable to that of other East Asian countries. Complicated CD is common. Overall mortality remains low in Asians with IBD.

Low-dose azathioprine is effective in maintaining remission in steroid-dependent ulcerative colitis: results from a territory-wide Chinese population-based IBD registry.

BACKGROUND: Whether low-dose azathioprine (AZA) is effective in maintaining remission in patients with steroid-dependent ulcerative colitis (UC) remains unclear. We assessed the efficacy and safety of low-dose AZA in a Chinese population with UC. METHODS: We identified steroid-dependent UC patients in clinical remission on AZA maintenance therapy from a territory-wide IBD Registry. Standard- and low-dose AZA were defined as at least 2 mg/kg/day and less than 2 mg/kg/day, respectively. Relapse rates were analyzed by Kaplan-Meier analysis and compared using log-rank test. RESULTS: Among 1226 UC patients, 128 (53% male, median duration on AZA 44 months) were included. Median maintenance AZA dose was 1.3 mg/kg/day. 97.7% of the patients were on concomitant oral 5-aminosalicylic acid. Cumulative relapse-free rates in patients on standard-dose and low-dose AZA were 71.2%, 52.8% and 45.2%, and 71.8%, 55.3% and 46.2% at 12, 24 and 36 months, respectively (p = 0.871). Relapse rate within 12 months was higher in patients who withdrew compared with those who maintained on AZA (52.6% versus 29.4%; p = 0.045). Mean corpuscular volume increased after AZA therapy in both of the low-dose [median (interquartile range, IQR): 88.2 (81.4-92.2) versus 95.1 (90.1-100.9) fl, p < 0.001] and standard-dose subgroups [median (IQR) 86.8 (76.9-89.9) versus 94.7 (85.9-99.7) fl, p < 0.001]. Leukopenia occurred in 21.1% of the patients. Patients on standard dose had a higher risk for leukopenia than those on low-dose AZA [odds ratio (OR) 3.9, 95% CI 1.9-8.2, p < 0.001]. CONCLUSIONS: In the Chinese population, low-dose AZA is effective for maintaining remission in steroid-dependent UC patients. Standard-dose AZA was associated with more than threefold increased risk of leukopenia.

A Systematic Review Assessing Medical Treatment for Rectovaginal and Enterovesical Fistulae in Crohn's Disease.

BACKGROUND: Rectovaginal and enterovesical fistulae are difficult to treat in patients with Crohn's disease. Currently, there is no consensus regarding their appropriate management. AIM OF THE STUDY: The aim of the study was to review the literature on the medical management of rectovaginal and enterovesical fistulae in Crohn's disease and to assess their response to treatment. METHOD: A literature search of MEDLINE, EMBASE, Science Citation Index Expanded, and Cochrane was performed. RESULTS: Twenty-three studies were identified, reporting on 137 rectovaginal and 44 enterovesical fistulae. The overall response rates of rectovaginal fistulae to medical therapy were: 38.3% complete response (fistula closure), 22.3% partial response, and 39.4% no response. For enterovesical fistulae the response rates to medical therapy were: 65.9% complete response, 20.5% partial response, and 13.6% no response. Specifically, response to anti-tumor necrosis factor therapy of 78 rectovaginal fistulae was: 41.0% complete response, 21.8% partial response, and 37.2% no response. Response of 14 enterovesical fistulae to anti-tumor necrosis factor therapy was: 57.1% complete response, 35.7% partial response, and 7.1% no response. The response to a combination of medical and surgical therapy in 43 rectovaginal fistulae was: 44.2% complete response, 20.9% partial response, and 34.9% no response. CONCLUSIONS: Medical therapy, alone or in combination with surgery, appears to benefit some patients with rectovaginal or enterovesical fistula. However, given the small size and low quality of the published studies, it is still difficult to draw conclusions regarding treatment. Larger, better quality studies are required to assess response to medical treatment and evaluate indications for surgery.

Danish cohort of monozygotic inflammatory bowel disease twins: Clinical characteristics and inflammatory activity.

AIM: To describe the establishment of a Danish inflammatory bowel diseases (IBD) twin cohort with focus on concordance of treatment and inflammatory markers. METHODS: We identified MZ twins, likely to be discordant or concordant for IBD, by merging information from the Danish Twin Register and the National Patient Register. The twins were asked to provide biological samples, questionnaires, and data access to patient files and public registries. Biological samples were collected via a mobile laboratory, which allowed for immediate centrifugation, fractionation, and storage of samples. The mean time from collection of samples to storage in the -80 °C mobile freezer was less than one hour. The diagnoses where validated using the Copenhagen diagnostic criteria. RESULTS: We identified 159 MZ IBD twin pairs, in a total of 62 (39%) pairs both twins agreed to participate. Of the supposed 62 IBD pairs, the IBD diagnosis could be confirmed in 54 pairs. The cohort included 10 concordant pairs, whereof some were discordant for either treatment or surgery. The 10 concordant pairs, where both pairs suffered from IBD, included eight CD/CD pairs, one UC/UC pair and one UC/IBDU pair. The discordant pairs comprised 31 UC, 5 IBDU (IBD unclassified), and 8 CD discordant pairs. In the co-twins not affected by IBD, calprotectin was above 100 µg/g in 2 participants, and above 50 µg/g in a further 5 participants. CONCLUSION: The presented IBD twin cohorts are an excellent resource for bioinformatics studies with proper adjustment for disease-associated exposures including medication and inflammatory activity in the co-twins.

Dysregulated Lysine Acetyltransferase 2B Promotes Inflammatory Bowel Disease Pathogenesis Through Transcriptional Repression of Interleukin-10.

BACKGROUND AND AIMS: Accumulating evidence supports epigenetic modifications in mediating intestinal immunity in inflammatory bowel disease [IBD] pathogenesis. This study aimed to identify key dysregulated epigenetic modulators and the molecular downstream pathways in IBD. METHODS: Expression of 116 well-defined epigenetic modulators was profiled and validated in 96 intestinal tissues from patients with Crohn's disease [CD], ulcerative colitis [UC], and healthy controls using quantitative reverse transcriptase polymerase chain reaction [QRT-PCR], western blot, and immunohistochemistry. Dysregulation of histone modifications and IBD-related cytokines were examined by chromatin immunoprecipitation, luciferase activity, and gene expression analyses in normal colonic epithelial cell line, NCM460, upon small-molecule inhibition or RNA interference, followed by validation in primary colonic tissues. RESULTS: Targeted expression profiling uncovered seven differentially expressed epigenetic modulators, of which the down-regulation of lysine acetyltransferase 2B [KAT2B] mRNA and protein was the most significant and was consequently validated in inflamed CD and UC compared with healthy colonic tissues. KAT2B protein localised abundantly in nuclei of normal colonic epithelium but diminished in paired inflamed CD and UC tissues. Pharmacological inhibition of KAT2B by anacardic acid in NCM460 cells reduced the levels of histone H4 lysine 5 acetylation [H4K5ac] and interleukin-10 [IL-10] in a dose-dependent manner. Knockdown of KAT2B reduced the IL-10 promoter occupancy of KAT2B and H4K5ac, resulting in transcriptional silencing. IL-10 level was also diminished in inflamed IBD tissues. CONCLUSIONS: Our findings demonstrated a novel epigenetic mechanism of IL-10 dysregulation in IBD. Down-regulation of KAT2B may disrupt the innate and adaptive inflammatory responses due to the suppression of this crucial anti-inflammatory cytokine.

Natural History of Elderly-onset Ulcerative Colitis: Results from a Territory-wide Inflammatory Bowel Disease Registry.

BACKGROUND AND AIMS: Data on the natural history of elderly-onset ulcerative colitis [UC] are limited. We aimed to investigate clinical features and outcomes of patients with elderly-onset UC. METHODS: Patients with a confirmed diagnosis of UC between 1981 and 2013, from 13 hospitals within a territory-wide Hong Kong Inflammatory Bowel Disease Registry, were included. Clinical features and outcomes of elderly-onset patients, defined as age ≥ 60 years at diagnosis, were compared with those of non-elderly-onset disease [< 60 years at diagnosis]. RESULTS: We identified 1225 patients, of whom 12.8% [157/1225; 56.1% male] had elderly-onset UC. Median duration of follow-up was 11 years [interquartile range, 6-16 years]. Age-specific incidence of elderly-onset UC increased from 0.1 per 100000 persons before 1991 to 1.3 per 100000 persons after 2010. There were more ex-smokers [32.2% vs. 12.2%, p < 0.001] and higher proportion of comorbidities [p < 0.001] in elderly-onset than non-elderly-onset patients. Disease extent, corticosteroids, immunosuppressants use, and colectomy rates were similar between the two groups. Elderly-onset disease was an independent risk factor for cytomegalovirus infection [odds ratio 2.9, 95% confidence interval 1.6-5.2, p < 0.001]. More elderly-onset patients had Clostridium difficile infection [11.0% vs. 5.4%, p = 0.007], hospitalisation for UC exacerbation [50.6% vs. 41.8%, p = 0.037], colorectal cancer [3.2% vs. 0.9%, p = 0.033], all-cause mortality [7.0% vs. 1.0%, p < 0.001], and UC-related mortality [1.9% vs. 0.2%, p = 0.017] than non-elderly-onset patients. CONCLUSIONS: Elderly-onset UC patients are increasing in number. These patients have higher risk of opportunistic infections, hospitalisation, colorectal cancer, and mortality than non-elderly-onset patients. Management and therapeutic strategies in this special group need careful attention.

Why I don't want to continue practising general medicine and delivering the acute 'take'.

Unscheduled admissions to hospital are usually coordinated by the acute assessment unit (AAU), often led in rotation by physicians from range of specialties, together with specialists in acute medicine. This hybrid model is a vestige since before the specialty of acute medicine was developed. The increasing elderly population means this needs to change, enabling elderly care physicians to work in parallel with acute physicians as the needs of patients in the AAU are largely served by these two disciplines. Specialties, including elderly care, should provide support by looking after patients with diseases in which they are expert, and by ensuring that the same specialist team looks after patients in the AAU and on downstream specialty wards. A major expansion in elderly care, and new ways of teamworking are required. A model of care is proposed.

Heritability in inflammatory bowel disease: from the first twin study to genome-wide association studies.

Since Tysk et al's pioneering analysis of the Swedish twin registry, twin and family studies continue to support a strong genetic basis of the inflammatory bowel diseases. The coefficient of heritability for siblings of inflammatory bowel disease probands is 25 to 42 for Crohn's disease and 4 to 15 for ulcerative colitis. Heritability estimates for Crohn's disease and ulcerative colitis from pooled twin studies are 0.75 and 0.67, respectively. However, this is at odds with the much lower heritability estimates from Genome-Wide Association Studies (GWAS). This "missing heritability" is likely due to shortfalls in both family studies and GWAS. The coefficient of heritability fails to account for familial shared environment. Heritability calculations from twin data are based on Falconer's method, with premises that are increasingly understood to be flawed. GWAS based heritability estimates may underestimate heritability due to incomplete linkage disequilibrium, and because some single nucleotide polypeptides (SNPs) do not reach a level of significance to allow detection. SNPs missed by GWAS include common SNPs with low penetrance and rare SNPs with high penetrance. All methods of heritability estimation regard genetic and environmental variance as separate entities, although it is now understood that there is a complex multidirectional interplay between genetic are environmental factors mediated by the microbiota, the epigenome, and the innate and acquired immune systems. Due to the limitations of heritability estimates, it is unlikely that a true value for heritability will be reached. Further work aimed at quantifying the variance explained across GWAS, epigenome-wide, and microbiota-wide association studies will help to define factors leading to inflammatory bowel disease.

Non-colorectal intestinal tract carcinomas in inflammatory bowel disease: results of the 3rd ECCO Pathogenesis Scientific Workshop (II).

Patients with inflammatory bowel diseases (IBD) have an excess risk of certain gastrointestinal cancers. Much work has focused on colon cancer in IBD patients, but comparatively less is known about other more rare cancers. The European Crohn's and Colitis Organization established a pathogenesis workshop to review what is known about these cancers and formulate proposals for future studies to address the most important knowledge gaps. This article reviews the current state of knowledge about small bowel adenocarcinoma, ileo-anal pouch and rectal cuff cancer, and anal/perianal fistula cancers in IBD patients.