Ian C. Lawrance

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.

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).

Continuous Therapy With Certolizumab Pegol Maintains Remission of Patients With Crohn's Disease for up to 18 Months

BACKGROUND & AIMS The safety and efficacy of maintenance therapy with the anti-tumor necrosis factor certolizumab pegol has not been reported beyond 6 months. We assessed the long-term efficacy, safety, and immunogenicity of continuous versus interrupted maintenance therapy with subcutaneous certolizumab pegol in patients with Crohns disease. METHODS Patients who responded to induction therapy at week 6 of the PEGylated Antibody Fragment Evaluation in Crohns Disease: Safety and Efficacy (PRECiSE) 2 trial were assigned randomly to groups given certolizumab pegol (continuous) or placebo (drug-interruption) during weeks 6 to 26. Patients who completed PRECiSE 2 were eligible to enter PRECiSE 3, an ongoing, prospective, open-label extension trial in which patients have received certolizumab pegol (400 mg) every 4 weeks for 54 weeks to date, and were not offered the option to increase their dose. Disease activity was measured by the Harvey-Bradshaw Index. RESULTS Harvey-Bradshaw Index responses at week 26 for the continuous and drug-interruption groups were 56.3% and 37.6%, respectively; corresponding remission rates were 47.9% and 32.4%, respectively. Of patients responding at week 26, response rates at week 80 after the start of PRECiSE 2 in the continuous and drug-interruption groups were 66.1% and 63.3%, respectively; among patients in remission at week 26, week 80 remission rates were 62.1% and 63.2%, respectively. More patients in the drug-interruption group developed antibodies against certolizumab pegol (and had lower plasma concentrations of certolizumab pegol) than the continuously treated group. CONCLUSIONS Certolizumab pegol effectively maintains remission of Crohns disease for up to 18 months. Continuous therapy is more effective than interrupted therapy.

Randomised clinical trial: certolizumab pegol for fistulas in Crohn?s disease ? subgroup results from a placebo-controlled study

Aliment Pharmacol Ther 2011; 33: 185–193

HLA-DQA1-HLA-DRB1 variants confer susceptibility to pancreatitis induced by thiopurine immunosuppressants

Pancreatitis occurs in approximately 4% of patients treated with the thiopurines azathioprine or mercaptopurine. Its development is unpredictable and almost always leads to drug withdrawal. We identified patients with inflammatory bowel disease (IBD) who had developed pancreatitis within 3 months of starting these drugs from 168 sites around the world. After detailed case adjudication, we performed a genome-wide association study on 172 cases and 2,035 controls with IBD. We identified strong evidence of association within the class II HLA region, with the most significant association identified at rs2647087 (odds ratio 2.59, 95% confidence interval 2.07–3.26, P = 2 × 10−16). We replicated these findings in an independent set of 78 cases and 472 controls with IBD matched for drug exposure. Fine mapping of the HLA region identified association with the HLA-DQA1*02:01–HLA-DRB1*07:01 haplotype. Patients heterozygous at rs2647087 have a 9% risk of developing pancreatitis after administration of a thiopurine, whereas homozygotes have a 17% risk.

Results of the 4th scientific workshop of the ECCO (I): Pathophysiology of intestinal fibrosis in IBD

The fourth scientific workshop of the European Crohns and Colitis Organization (ECCO) focused on the relevance of intestinal fibrosis in the disease course of inflammatory bowel disease (IBD). The objective was to better understand the pathophysiological mechanisms of intestinal fibrosis, to identify useful markers and imaging modalities of fibrosis in order to assess its presence and progression, and, finally, to point out possible approaches for the prevention and the treatment of fibrosis. The results of this workshop are presented in three separate manuscripts. This first section describes the most important mechanisms that contribute to the initiation and progression of intestinal fibrosis in IBD including the cellular and molecular mediators, the extracellular matrix molecules and matrix metalloproteinases/tissue inhibitors of metalloproteinases-system, the microbiota products, the role of fat, genetic and epigenetic factors, as well as the currently available experimental models. Furthermore, it identifies unanswered questions in the field of intestinal fibrosis and provides a framework for future research.

A Prospective Comparative Study of ASCA and pANCA in Chinese and Caucasian IBD Patients

BACKGROUND:Inflammatory bowel disease manifests throughout all ethnic groups. Antisaccharomyces cerevisiae (ASCA) and antineutrophil cytoplasmic antibodies (pANCA) can aid in the differentiation between Crohns disease (CD) and ulcerative colitis (UC), but their sensitivity may vary between races.OBJECTIVES:This study compared the sensitivity, specificity, and positive and negative predictive values (PPV, NPV) of pANCA and ASCA between Chinese and Caucasian IBD populations and identified disease subtype associations.RESULTS:Three hundred patients were prospectively recruited from Caucasian and Chinese populations (CD, n = 50, UC, n = 50, controls, n = 50 each). pANCA detection was greater in Caucasian than Chinese UC patients (p = 0.046). ASCA IgG detection was similar, but IgA was lower in Chinese CD patients (p < 0.001). Differentiation between UC and CD (+ve pANCA/−ve ASCA) demonstrated a PPV of 92% in isolated colonic disease. Logistic regression in CD identified positive pANCA had a lower association with ileal (OR = 6.8, p = 0.0067) and complicated disease (OR = 5.5, p = 0.015). Caucasian CD patients with positive ASCA IgA/IgG had a greater association with ileal (OR = 6.7, p = 0.022) or complicated disease (OR = 9.4, p = 0.0073) and in Chinese CD patients positive ASCA IgA/IgG was associated with isolated ileal disease (OR = 16.8, p = 0.032). Linear regression demonstrated that higher ASCA titers predicted complicated CD and isolated ileal disease.CONCLUSIONS:This study identified that pANCA is more sensitive in Caucasian than Chinese UC and that ASCA IgA has a low yield in Chinese CD. pANCA and ASCA are useful for differentiating between UC and CD in both populations, and ASCA IgG and IgA titers have potential use in determining the risk of developing complicated CD.

Serious infections in patients with inflammatory bowel disease receiving anti‐tumor‐necrosis‐factor‐alpha therapy: An Australian and New Zealand experience

Background and Aim:  Anti‐tumor‐necrosis‐factor‐alpha (anti‐TNF‐α) medications are effective in inflammatory bowel disease (IBD), but have an increased risk of tuberculosis (TB) and serious infections. The aim of this study was to examine the Australian/New Zealand experience of serious infections and TB in IBD patients receiving anti‐TNF‐α therapy from 1999–2009.

Rectal tacrolimus in the treatment of resistant ulcerative proctitis

Background  Resistant ulcerative proctitis can be extremely difficult to manage. Oral tacrolimus can be effective, but may have numerous adverse effects. Topically administered tacrolimus, however, may also be effective in proctitis.