Timothy R. Orchard

The second European evidence-based Consensus on the diagnosis and management of Crohn's disease: Definitions and diagnosis.

Crohns disease is a lifelong disease arising from an interaction between genetic and environmental factors, but observed predominantly in developed countries of the world. The precise aetiology is unknown and therefore a causal therapy is not yet available. Within Europe there is a distinct North–South gradient, but the incidence appears to have increased in Southern countries in recent years.1 Many patients live with a considerable symptom burden despite medical treatment in the hope that the aetiology of the disease will shortly be revealed and curative therapies emerge. Since it is uncertain that the precise pathogenesis of Crohns disease will be revealed anytime soon, clinicians have to advise patients on the basis of information available today rather than an unknown future. Despite a multiplicity of randomised trials there will always be many questions that can only be answered by the exercise of judgement and opinion. This leads to differences in practice between clinicians, which may be brought into sharp relief by differences in emphasis between countries. The Consensus endeavours to address these differences. The Consensus is not meant to supersede the guidelines of different countries (such as those from the UK,2 Germany,3 or France), which reach broadly the same conclusions since they are, after all, based on the same evidence. Rather, the aim of the Consensus is to promote a European perspective on the management of Crohns disease and its dilemmas. Since the development of guidelines is an expensive and time-consuming process, it may help to avoid duplication of effort in the future. A Consensus is also considered important because an increasing number of therapeutic trials are based in Europe, especially in eastern European countries where practice guidelines have yet to be published. This document is based on the European consensus on the diagnosis and management of Crohns …

Guidelines for the management of inflammatory bowel disease in adults

The management of inflammatory bowel disease represents a key component of clinical practice for members of the British Society of Gastroenterology (BSG). There has been considerable progress in management strategies affecting all aspects of clinical care since the publication of previous BSG guidelines in 2004, necessitating the present revision. Key components of the present document worthy of attention as having been subject to re-assessment, and revision, and having direct impact on practice include: The data generated by the nationwide audits of inflammatory bowel disease (IBD) management in the UK in 2006, and 2008. The publication of ‘Quality Care: service standards for the healthcare of people with IBD’ in 2009. The introduction of the Montreal classification for Crohns disease and ulcerative colitis. The revision of recommendations for the use of immunosuppressive therapy. The detailed analysis, guidelines and recommendations for the safe and appropriate use of biological therapies in Crohns disease and ulcerative colitis. The reassessment of the role of surgery in disease management, with emphasis on the importance of multi-disciplinary decision-making in complex cases. The availablity of new data on the role of reconstructive surgery in ulcerative colitis. The cross-referencing to revised guidelines for colonoscopic surveillance, for the management of metabolic bone disease, and for the care of children with inflammatory bowel disease. Use of the BSG discussion forum available on the BSG website to enable ongoing feedback on the published document http://www.bsg.org.uk/forum (accessed Oct 2010). The present document is intended primarily for the use of clinicians in the United Kingdom, and serves to replace the previous BSG guidelines in IBD, while complementing recent consensus statements published by the European Crohns and Colitis Organisation (ECCO) https://www.ecco-ibd.eu/index.php (accessed Oct 2010).

The efficacy of azathioprine for the treatment of inflammatory bowel disease: a 30 year review

Background: There are limited data on factors predicting response to azathioprine and uncertainty regarding the optimal duration of treatment. Patients and methods: The notes of patients attending the Oxford IBD clinic from 1968 to 1999 were reviewed. Remission was defined as no need for oral steroids for at least three months and relapse was defined as active disease requiring steroids. Results: A total of 622 of 2205 patients were treated with azathioprine (272 Crohns disease, 346 ulcerative colitis, and four indeterminate colitis). Mean duration of the initial course of treatment was 634 days. The overall remission rates were 45% for Crohns disease and 58% for ulcerative colitis. For the 424 patients who received more than six months of treatment, remission rates were 64% and 87%, respectively. Factors favouring remission were ulcerative colitis (p=0.0001), lower white blood cell (WBC) or neutrophil count (p=0.0001), higher mean cell volume (p=0.0001), and older age (p=0.05). For Crohns disease, colonic disease favoured remission (p=0.03). Factors that were not significant were age, sex, lymphocyte count, and dose (mg/kg). The proportion of patients remaining in remission at one, three, and five years was 0.95, 0.69, and 0.55, respectively. The chance of remaining in remission was higher if WBC was less than 5×109 (p=0.03) and in male patients (p=0.01; Crohns disease only). There was no difference in relapse rates between Crohns disease and ulcerative colitis. After stopping azathioprine, the proportion of patients remaining in remission at one, three, and five years was 0.63, 0.44, and 0.35 (222 patients). Duration of azathioprine treatment did not affect the relapse rate after stopping treatment (p=0.68). Conclusions: Azathioprine is effective treatment for ulcerative colitis and Crohns disease. The efficacy of azathioprine is reasonably well sustained over five years.

Association analyses identify 38 susceptibility loci for inflammatory bowel disease and highlight shared genetic risk across populations

Ulcerative colitis and Crohns disease are the two main forms of inflammatory bowel disease (IBD). Here we report the first trans-ancestry association study of IBD, with genome-wide or Immunochip genotype data from an extended cohort of 86,640 European individuals and Immunochip data from 9,846 individuals of East Asian, Indian or Iranian descent. We implicate 38 loci in IBD risk for the first time. For the majority of the IBD risk loci, the direction and magnitude of effect are consistent in European and non-European cohorts. Nevertheless, we observe genetic heterogeneity between divergent populations at several established risk loci driven by differences in allele frequency (NOD2) or effect size (TNFSF15 and ATG16L1) or a combination of these factors (IL23R and IRGM). Our results provide biological insights into the pathogenesis of IBD and demonstrate the usefulness of trans-ancestry association studies for mapping loci associated with complex diseases and understanding genetic architecture across diverse populations.

Peripheral arthropathies in inflammatory bowel disease: their articular distribution and natural history

Background—Peripheral arthropathy is a well-recognised complication of inflammatory bowel disease (IBD). Little is known of its natural history, but a variety of joint involvement has been described, from large joint pauciarticular arthropathy to a rheumatoid pattern polyarthropathy. Aims—To classify the peripheral arthropathies according to pattern of articular involvement, and study their natural history and clinical associations. Methods—The case notes of all patients attending the Oxford IBD clinic were reviewed, and information on general disease characteristics, extraintestinal features, and arthropathy extracted. This was confirmed by direct patient interview using questionnaires at routine follow up. Patients with recorded joint swelling or effusion were classified as type 1 (pauciarticular) if less than five joints were involved and type 2 (polyarticular) if five or more were involved. Patients without evidence of swelling were classified as arthralgia. Results—In total, 976 patients with ulcerative colitis (UC) and 483 with Crohn’s disease (CD) were reviewed. Type 1 occurred in 3.6% of patients with UC (83% acute and self-limiting) and in 6.0% of those with CD (79% self-limiting); 83% and 76%, respectively, were associated with relapsing IBD. Type 2 occurred in 2.5% of patients with UC and 4.0% of those with CD; 87% and 89%, respectively, caused persistent symptoms whereas only 29% and 42%, respectively, were associated with relapsing IBD. Conclusion—Enteropathic peripheral arthropathy without axial involvement can be subdivided into a pauciarticular, large joint arthropathy, and a bilateral symmetrical polyarthropathy, each being distinguished by its articular distribution and natural history.

Clinical phenotype is related to HLA genotype in the peripheral arthropathies of inflammatory bowel disease

BACKGROUND & AIMS The detection of phenotype-determining genes as opposed to disease susceptibility genes requires precise phenotypic characterization of patients. Peripheral arthropathies in inflammatory bowel disease (IBD) are well recognized and are classified with the HLA-B*27-related spondyloarthropathies by the European Spondyloarthropathy Study Group. However, previous HLA studies in IBD have only shown this association with axial disease rather than peripheral arthropathy. We recently reported a clinical classification that describes 2 types of peripheral arthropathy, distinguished by their natural history and articular distribution. We now report the results of immunogenetic studies in these patients and compare them with other spondyloarthropathies. METHODS IBD patients with type 1 (n = 57) and type 2 (n = 45) peripheral arthropathy were identified by case note review and questionnaire. Patients and 603 controls from Oxfordshire were assigned HLA-A, -B, -C, -DR, and -DQ genotypes by sequence-specific primer polymerase chain reaction. Patient results were compared with controls (corrected for multiple comparisons), then with each other in light of existing hypotheses. The results were compared with those of a cohort of 30 patients with postenteric reactive arthritis (ReA) and 16 patients with IBD-associated ankylosing spondylitis (IBD-AS). RESULTS Type 1 arthropathy was associated with HLA-DRB1*0103 (DR103; a rare subtype of DR1) in 33% (P < 0.0001; relative risk [RR], 12.1), B*35 in 30% (P = 0.01; RR, 2.2), and B*27 in 26% (P = 0. 001; RR, 4.0). In contrast, type 2 was associated with HLA-B*44 in 62% (P = 0.01; RR, 2.1). Similar significant associations to type 1 arthropathy were found in ReA, except that the HLA-B*27 association was significantly stronger and an association was found with DRB1*0101 (DR1) in 43% (P = 0.001; RR, 2.2). IBD-AS was associated only with HLA-B*27 and DRB1*0101. CONCLUSIONS These data suggest that the clinical classification into type 1 and type 2 arthropathies describes immunogenetically distinct entities and establish that in polygenic disorders, genes may determine clinical phenotype without conferring overall disease susceptibility (in this case, HLA genes). Type 1 arthropathy is clinically and immunogenetically similar to the spondyloarthropathies, but different HLA associations may define phenotypically distinct groups. Type 2 arthropathy has different HLA associations and may have a different etiology. Further studies are now required to confirm these associations and to elucidate the different pathogenetic mechanisms.

Long-term risk of malignancy after treatment of inflammatory bowel disease with azathioprine

Background and aim : Data from renal transplant and rheumatoid arthritis patients suggest that there is an increased risk of malignancy after treatment with azathioprine. Whether this is true for patients with inflammatory bowel disease remains uncertain.

Genotype-phenotype analysis of the Crohn’s disease susceptibility haplotype on chromosome 5q31

Background and aims: Recent molecular data suggest that genetic factors may underlie the disease heterogeneity observed in both ulcerative colitis (UC) and Crohn’s disease (CD). A locus on chromosome 5q has been implicated in susceptibility to CD, and recently refined by linkage disequilibrium mapping to a conserved 250 kb haplotype (5q31). No data regarding the contribution of this locus to clinical phenotype exist. In this case control study, we investigated the contribution of this haplotype to both susceptibility and phenotype of CD and UC. Patients and methods: We studied 330 Caucasian CD and 457 UC patients recruited from a single UK centre. Association with disease susceptibility and phenotype was analysed with haplotypes reconstructed from three single nucleotide polymorphisms chosen to span this susceptibility region. Evidence for possible genetic epistasis between IBD5 and NOD2/CARD15 was sought. Results: Linkage disequilibrium across this region was confirmed, with two haplotypes comprising 88% of all chromosomes. Susceptibility to CD, but not to UC, was associated with homozygosity for a common haplotype, H2 (pc=0.002; relative risk (RR) 2.0). Genotype-phenotype analyses demonstrated that this association was particularly strong in patients with perianal disease (pc=0.0005; RR 1.7), especially in individuals homozygous for this haplotype (pc=0.0005; RR 3.0). Importantly, no association with H2 was found in 186 patients without perianal disease. No evidence of epistasis between IBD5 and NOD2/CARD15 was demonstrated. Conclusions: The IBD5 risk haplotype is associated with CD only. Genotype-phenotype analysis reveals that the strongest association is observed in patients with perianal CD. While the precise gene involved is unclear, these data provide further molecular evidence for a genetic basis of the clinical heterogeneity of CD.

Diagnostic precision of anti-Saccharomyces cerevisiae antibodies and perinuclear antineutrophil cytoplasmic antibodies in inflammatory bowel disease

AIMS:The aim of this study was to assess the diagnostic precision of antiSaccharomyces cerevisiae (ASCA) and perinuclear antineutrophil cytoplasmic antibodies (pANCA) in inflammatory bowel disease (IBD) and evaluate their discriminative ability between ulcerative colitis (UC) and Crohns disease (CD).METHODS:Meta-analysis of studies reporting on ASCA and pANCA in IBD was performed. Sensitivity, specificity, and likelihood ratios (LR+, LR–) were calculated for different test combinations for CD, UC, and for IBD compared with controls. Meta-regression was used to analyze the effect of age, DNAse, colonic CD, and assay type.RESULTS:Sixty studies comprising 3,841 UC and 4,019 CD patients were included. The ASCA+ with pANCA– test offered the best sensitivity for CD (54.6%) with 92.8% specificity and an area under the ROC (receiver operating characteristic) curve (AUC) of 0.85 (LR+ = 6.5, LR– = 0.5). Sensitivity and specificity of pANCA+ tests for UC were 55.3% and 88.5%, respectively (AUC of 0.82; LR+ = 4.5, LR– = 0.5). Sensitivity and specificity were improved to 70.3% and 93.4% in a pediatric subgroup when combined with an ASCA– test. Meta-regression analysis showed decreased diagnostic precision of ASCA for isolated colonic CD (RDOR = 0.3).CONCLUSIONS:ASCA and pANCA testing are specific but not sensitive for CD and UC. It may be particularly useful for differentiating between CD and UC in the pediatric population.

Characterization of Inflammatory Bowel Disease With Urinary Metabolic Profiling

OBJECTIVES:Distinguishing between the inflammatory bowel disease (IBD), Crohns disease (CD), and ulcerative colitis (UC) is important for both management and prognostic reasons. Discrimination using noninvasive techniques could be an adjunct to conventional diagnostics. Differences have been shown between the intestinal microbiota of CD and UC patients and controls; the gut bacteria influence specific urinary metabolites that are quantifiable using proton high-resolution nuclear magnetic resonance (NMR) spectroscopy. This study tested the hypothesis that such metabolites differ between IBD and control cohorts, and that using multivariate pattern-recognition analysis, the cohorts could be distinguished by urine NMR spectroscopy.METHODS:NMR spectra were acquired from urine samples of 206 Caucasian subjects (86 CD patients, 60 UC patients, and 60 healthy controls). Longitudinal samples were collected from 75 individuals. NMR resonances specific for metabolites influenced by the gut microbes were studied, including hippurate, formate, and 4-cresol sulfate. Multivariate analysis of all urinary metabolites involved principal components analysis (PCA) and partial least squares discriminant analysis (PLS-DA).RESULTS:Hippurate levels were lowest in CD patients and differed significantly between the three cohorts (P<0.0001). Formate levels were higher and 4-cresol sulfate levels lower in CD patients than in UC patients or controls (P=0.0005 and P=0.0002, respectively). PCA revealed clustering of the groups; PLS-DA modeling was able to distinguish the cohorts. These results were independent of medication and diet and were reproducible in the longitudinal cohort.CONCLUSIONS:Specific urinary metabolites related to gut microbial metabolism differ between CD patients, UC patients, and controls. The emerging technique of urinary metabolic profiling with multivariate analysis was able to distinguish these cohorts.