Richard B. Gearry

Genome-wide meta-analysis increases to 71 the number of confirmed Crohn's disease susceptibility loci

We undertook a meta-analysis of six Crohns disease genome-wide association studies (GWAS) comprising 6,333 affected individuals (cases) and 15,056 controls and followed up the top association signals in 15,694 cases, 14,026 controls and 414 parent-offspring trios. We identified 30 new susceptibility loci meeting genome-wide significance (P < 5 × 10−8). A series of in silico analyses highlighted particular genes within these loci and, together with manual curation, implicated functionally interesting candidate genes including SMAD3, ERAP2, IL10, IL2RA, TYK2, FUT2, DNMT3A, DENND1B, BACH2 and TAGAP. Combined with previously confirmed loci, these results identify 71 distinct loci with genome-wide significant evidence for association with Crohns disease.

Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE): Determining Therapeutic Goals for Treat-to-Target.

OBJECTIVES:The Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE) program was initiated by the International Organization for the Study of Inflammatory Bowel Diseases (IOIBD). It examined potential treatment targets for inflammatory bowel disease (IBD) to be used for a “treat-to-target” clinical management strategy using an evidence-based expert consensus process.METHODS:A Steering Committee of 28 IBD specialists developed recommendations based on a systematic literature review and expert opinion. Consensus was gained if ≥75% of participants scored the recommendation as 7–10 on a 10-point rating scale (where 10=agree completely).RESULTS:The group agreed upon 12 recommendations for ulcerative colitis (UC) and Crohn’s disease (CD). The agreed target for UC was clinical/patient-reported outcome (PRO) remission (defined as resolution of rectal bleeding and diarrhea/altered bowel habit) and endoscopic remission (defined as a Mayo endoscopic subscore of 0–1). Histological remission was considered as an adjunctive goal. Clinical/PRO remission was also agreed upon as a target for CD and defined as resolution of abdominal pain and diarrhea/altered bowel habit; and endoscopic remission, defined as resolution of ulceration at ileocolonoscopy, or resolution of findings of inflammation on cross-sectional imaging in patients who cannot be adequately assessed with ileocolonoscopy. Biomarker remission (normal C-reactive protein (CRP) and calprotectin) was considered as an adjunctive target.CONCLUSIONS:Evidence- and consensus-based recommendations for selecting the goals for treat-to-target strategies in patients with IBD are made available. Prospective studies are needed to determine how these targets will change disease course and patients’ quality of life.

World Gastroenterology Organization Practice Guidelines for the Diagnosis and Management of IBD in 2010

Inflammatory bowel disease (IBD) represents a group of idiopathic, chronic, inflammatory intestinal conditions. Its two main disease categories are: Crohns disease (CD) and ulcerative colitis (UC), which feature both overlapping and distinct clinical and pathological features. While these diseases have, in the past, been most evident in the developed world, their prevalence in the developing world has been gradually increasing in recent decades. This poses unique issues in diagnosis and management which have been scarcely addressed in the literature or in extant guidelines. Depending on the nature of the complaints, investigations to diagnose either form of IBD or to assess disease activity will vary and will also be influenced by geographic variations in other conditions that might mimic IBD. Similarly, therapy varies depending on the phenotype of the disease being treated and available resources. The World Gastroenterology Organization has, accordingly, developed guidelines for diagnosing and treating IBD using a cascade approach to account for variability in resources in countries around the world.

High incidence of Crohn's disease in Canterbury, New Zealand: Results of an epidemiologic study

Background: Inflammatory bowel disease (IBD) has increased exponentially in industrialized nations over the last 50 years. Previous New Zealand studies have shown that IBD is less common than in other countries; however, clinical observations suggested a high incidence and prevalence of IBD in Canterbury, particularly Crohns disease (CD). Aim: This study aimed to determine the descriptive epidemiology of IBD in Canterbury. Methods: Canterbury IBD patients, recruited using multiple strategies, gave informed consent, permission for clinical record review, completed a questionnaire, and were bled for DNA extraction as part of the Canterbury IBD Project. Cases were confirmed using standard criteria, and completeness of recruitment was validated using capture‐recapture methods. Demographic and phenotypic data were extracted from case notes. One thousand four hundred twenty patients (715 CD, 668 ulcerative colitis [UC]) were recruited (>91% of Canterbury IBD patients). Results: In 2004, age‐standardized (World Health Organization World Standard Population) IBD, CD, and UC incidence rates were 25.2, 16.5, and 7.6/100,000/year, respectively. The IBD, CD, and UC point prevalences on 1 June, 2005 were 308.3, 155.2, and 145.0/100,000, respectively. CD patients were more likely than UC patients to be female (61.4% vs. 47.1%) and to be younger (median age, 39.9 years vs. 43.7 years). The percent of IBD patients who were white was 97.5%. Conclusion: IBD is at least as common in Canterbury as in other western regions. CD incidence and prevalence are amongst the highest ever reported and are higher than for UC. IBD population characteristics are otherwise similar to other countries. The Canterbury IBD Project will be a valuable tool for future population‐based IBD epidemiology and genetics research.

Dietary poorly absorbed, short‐chain carbohydrates increase delivery of water and fermentable substrates to the proximal colon

Background  Functional gut symptoms are induced by inclusion and reduced by dietary restriction of poorly absorbed short‐chain carbohydrates (FODMAPs), but the mechanisms of action remain untested.

Crohn's disease management after intestinal resection: a randomised trial.

BACKGROUND Most patients with Crohns disease need an intestinal resection, but a majority will subsequently experience disease recurrence and require further surgery. This study aimed to identify the optimal strategy to prevent postoperative disease recurrence. METHODS In this randomised trial, consecutive patients from 17 centres in Australia and New Zealand undergoing intestinal resection of all macroscopic Crohns disease, with an endoscopically accessible anastomosis, received 3 months of metronidazole therapy. Patients at high risk of recurrence also received a thiopurine, or adalimumab if they were intolerant to thiopurines. Patients were randomly assigned to parallel groups: colonoscopy at 6 months (active care) or no colonoscopy (standard care). We used computer-generated block randomisation to allocate patients in each centre to active or standard care in a 2:1 ratio. For endoscopic recurrence (Rutgeerts score ≥i2) at 6 months, patients stepped-up to thiopurine, fortnightly adalimumab with thiopurine, or weekly adalimumab. The primary endpoint was endoscopic recurrence at 18 months. Patients and treating physicians were aware of the patients study group and treatment, but central reading of the endoscopic findings was undertaken blind to the study group and treatment. Analysis included all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, number NCT00989560. FINDINGS Between Oct 13, 2009, and Sept 28, 2011, 174 (83% high risk across both active and standard care groups) patients were enrolled and received at least one dose of study drug. Of 122 patients in the active care group, 47 (39%) stepped-up treatment. At 18 months, endoscopic recurrence occurred in 60 (49%) patients in the active care group and 35 (67%) patients in the standard care group (p=0.03). Complete mucosal normality was maintained in 27 (22%) of 122 patients in the active care group versus four (8%) in the standard care group (p=0.03). In the active care arm, of those with 6 months recurrence who stepped up treatment, 18 (38%) of 47 patients were in remission 12 months later; conversely, of those in remission at 6 months who did not change therapy recurrence occurred in 31 (41%) of 75 patients 12 months later. Smoking (odds ratio [OR] 2.4, 95% CI 1.2-4.8, p=0.02) and the presence of two or more clinical risk factors including smoking (OR 2.8, 95% CI 1.01-7.7, p=0.05) increased the risk of endoscopic recurrence. The incidence and type of adverse and severe adverse events did not differ significantly between patients in the active care and standard care groups (100 [82%] of 122 vs 45 [87%] of 52; p=0.51) and (33 [27%] of 122 vs 18 [35%] of 52; p=0.36), respectively. INTERPRETATION Treatment according to clinical risk of recurrence, with early colonoscopy and treatment step-up for recurrence, is better than conventional drug therapy alone for prevention of postoperative Crohns disease recurrence. Selective immune suppression, adjusted for early recurrence, rather than routine use, leads to disease control in most patients. Clinical risk factors predict recurrence, but patients at low risk also need monitoring. Early remission does not preclude the need for ongoing monitoring. FUNDING AbbVie, Gutsy Group, Gandel Philanthropy, Angior Foundation, Crohns Colitis Australia, and the National Health and Medical Research Council.

Inherited determinants of Crohn's disease and ulcerative colitis phenotypes: a genetic association study

Summary Background Crohns disease and ulcerative colitis are the two major forms of inflammatory bowel disease; treatment strategies have historically been determined by this binary categorisation. Genetic studies have identified 163 susceptibility loci for inflammatory bowel disease, mostly shared between Crohns disease and ulcerative colitis. We undertook the largest genotype association study, to date, in widely used clinical subphenotypes of inflammatory bowel disease with the goal of further understanding the biological relations between diseases. Methods This study included patients from 49 centres in 16 countries in Europe, North America, and Australasia. We applied the Montreal classification system of inflammatory bowel disease subphenotypes to 34 819 patients (19 713 with Crohns disease, 14 683 with ulcerative colitis) genotyped on the Immunochip array. We tested for genotype–phenotype associations across 156 154 genetic variants. We generated genetic risk scores by combining information from all known inflammatory bowel disease associations to summarise the total load of genetic risk for a particular phenotype. We used these risk scores to test the hypothesis that colonic Crohns disease, ileal Crohns disease, and ulcerative colitis are all genetically distinct from each other, and to attempt to identify patients with a mismatch between clinical diagnosis and genetic risk profile. Findings After quality control, the primary analysis included 29 838 patients (16 902 with Crohns disease, 12 597 with ulcerative colitis). Three loci (NOD2, MHC, and MST1 3p21) were associated with subphenotypes of inflammatory bowel disease, mainly disease location (essentially fixed over time; median follow-up of 10·5 years). Little or no genetic association with disease behaviour (which changed dramatically over time) remained after conditioning on disease location and age at onset. The genetic risk score representing all known risk alleles for inflammatory bowel disease showed strong association with disease subphenotype (p=1·65 × 10−78), even after exclusion of NOD2, MHC, and 3p21 (p=9·23 × 10−18). Predictive models based on the genetic risk score strongly distinguished colonic from ileal Crohns disease. Our genetic risk score could also identify a small number of patients with discrepant genetic risk profiles who were significantly more likely to have a revised diagnosis after follow-up (p=6·8 × 10−4). Interpretation Our data support a continuum of disorders within inflammatory bowel disease, much better explained by three groups (ileal Crohns disease, colonic Crohns disease, and ulcerative colitis) than by Crohns disease and ulcerative colitis as currently defined. Disease location is an intrinsic aspect of a patients disease, in part genetically determined, and the major driver to changes in disease behaviour over time. Funding International Inflammatory Bowel Disease Genetics Consortium members funding sources (see Acknowledgments for full list).

The low FODMAP diet improves gastrointestinal symptoms in patients with irritable bowel syndrome: a prospective study.

Current treatment for irritable bowel syndrome (IBS) is suboptimal. Fermentable oligo‐, di‐, mono‐saccharides and polyols (FODMAPs) may trigger gastrointestinal symptoms in IBS patients. Our aim was to determine whether a low FODMAP diet improves symptoms in IBS patients.

Reduction of dietary poorly absorbed short-chain carbohydrates (FODMAPs) improves abdominal symptoms in patients with inflammatory bowel disease—a pilot study

OBJECTIVE Functional gut symptoms are common in patients with inflammatory bowel disease (IBD). Since poorly absorbed, short-chain carbohydrates (FODMAPs) appear to play an important role in the induction of functional gut symptoms, we aimed to determine the effect of their dietary restriction on abdominal symptoms in patients with stable IBD and to examine factors associated with success of and adherence to the diet. MATERIAL AND METHOD 52 consecutive patients with Crohns disease and 20 with ulcerative colitis who received dietary advice at least 3 months prior at a gastrointestinal dietetic service in Victoria, Australia, underwent a retrospective telephone questionnaire. Information gathered included patient demographics, recall of dietary advice, dietary adherence, and change in gastrointestinal symptoms. RESULTS Up to 70% of patients were adherent to the diet. Approximately one in two patients responded (defined as improvement of at least 5 out of 10 in overall symptoms). Overall abdominal symptoms, abdominal pain, bloating, wind and diarrhoea improved in patients with Crohns disease and ulcerative colitis (p<0.02 for all), but constipation did not. For Crohns disease, efficacy was associated with dietary adherence (p= 0.033) and inefficacy with non-adherence (p=0.013). Sustained response was associated with post-secondary education and working 35 h per week or less (p<0.03). CONCLUSIONS These data suggest that reduction of FODMAP intake offers an efficacious strategy for patients with IBD who have concurrent functional gut symptoms. A controlled dietary intervention trial is indicated.

Azathioprine and 6‐mercaptopurine pharmacogenetics and metabolite monitoring in inflammatory bowel disease

Abstract The thiopurine drugs azathioprine and 6‐mercaptopurine (6‐MP) are well‐established in the treatment of inflammatory bowel disease (IBD). However, there is a wide inter‐ and intra‐patient variation in the concentrations of active and toxic metabolites due to their complex metabolism and genetic polymorphisms in metabolizing enzymes. Serious drug toxicity leads to cessation of therapy in 9–25% of patients, and there is failure to achieve efficacy in approximately 15% of cases. Advances in the understanding of thiopurine drug metabolism have led to new genetic and metabolite tests to help clinicians optimize thiopurine use. Thiopurine methyltransferase (TPMT) enzyme activity can predict life‐threatening myelotoxicity in the one in 300 patients who are TPMT‐deficient. However, myelotoxicity can also occur in the presence of normal TPMT activity so blood count monitoring should remain standard practice. TPMT testing may also aid in dose individualization. 6‐Thioguanine nucleotides (6‐TGN) are thought to be the predominant active metabolites of the thiopurines. 6‐Thioguanine nucleotide concentration is correlated with bone marrow toxicity and may also correlate with efficacy in IBD. Measurement of 6‐TGN and 6‐methylmercaptopurine (6‐MMP) concentration is most useful in determining why a patient is not responding to a standard dose of a thiopurine drug and may help in avoiding myelosuppression. The ratio of these metabolites can help distinguish non‐compliance, under‐dosing, thiopurine‐resistant and thiopurine‐refractory disease. Some of these investigations are entering routine clinical practice but more research is required to determine their optimal use in patients with IBD.