Derek P. Jewell

Genome-wide association defines more than 30 distinct susceptibility loci for Crohn's disease

Several risk factors for Crohns disease have been identified in recent genome-wide association studies. To advance gene discovery further, we combined data from three studies on Crohns disease (a total of 3,230 cases and 4,829 controls) and carried out replication in 3,664 independent cases with a mixture of population-based and family-based controls. The results strongly confirm 11 previously reported loci and provide genome-wide significant evidence for 21 additional loci, including the regions containing STAT3, JAK2, ICOSLG, CDKAL1 and ITLN1. The expanded molecular understanding of the basis of this disease offers promise for informed therapeutic development.

Toward an Integrated Clinical, Molecular and Serological Classification of Inflammatory Bowel Disease: Report of a Working Party of the 2005 Montreal World Congress of Gastroenterology

The discovery of a series of genetic and serological markers associated with disease susceptibility and phenotype in inflammatory bowel disease has led to the prospect of an integrated classification system involving clinical, serological and genetic parameters. The Working Party has reviewed current clinical classification systems in Crohns disease, ulcerative colitis and indeterminate colitis, and provided recommendations for clinical classification in practice. Progress with respect to integrating serological and genetic markers has been examined in detail, and the implications are discussed. While an integrated system is not proposed for clinical use at present, the introduction of a widely acceptable clinical subclassification is strongly advocated, which would allow detailed correlations among serotype, genotype and clinical phenotype to be examined and confirmed in independent cohorts of patients and, thereby, provide a vital foundation for future work.

A Simple Classification of Crohn's Disease: Report of the Working Party for the World Congresses of Gastroenterology, Vienna 1998

Summary: Crohns disease is a heterogeneous entity. Previous attempts of classification have been based primarily on anatomic location and behavior of disease. However, no uniform definition of patient subgroups has yet achieved broad acceptance. The aim of this international Working Party was to develop a simple classification of Crohns disease based on objective variables. Eight outcome‐related variables relevant to Crohns disease were identified and stepwise evaluated in 413 consecutive cases, a database survey, and by clinical considerations. Allocation of variables was conducted with well‐defined Crohns disease populations from Europe and North America. Cross‐table analyses were performed by chi‐square testing. Three variables were finally elected: Age at Diagnosis [below 40 years (A1), equal to or above 40 years (A2)], Location [terminal ileum (L1), colon (L2), ileocolon (L3), upper gastrointestinal (L4)], and Behavior [nonstricturing nonpenetrating (B1), stricturing (B2), penetrating (B3)]. The allocation of patients to these 24 subgroups proved feasible and resulted in specific disease clusters. Cross‐table analyses revealed associations between Age at Diagnosis and Location, and between Behavior and Location (all p < 0.001). The Vienna classification of Crohns disease provides distinct definitions to categorize Crohns patients into 24 subgroups. Operational guidelines should be used for the characterization of patients in clinical trials as well as for correlation of particular phenotypes with putative biologic markers or environmental factors.

Sequence variants in the autophagy gene IRGM and multiple other replicating loci contribute to Crohn's disease susceptibility.

A genome-wide association scan in individuals with Crohns disease by the Wellcome Trust Case Control Consortium detected strong association at four novel loci. We tested 37 SNPs from these and other loci for association in an independent case-control sample. We obtained replication for the autophagy-inducing IRGM gene on chromosome 5q33.1 (replication P = 6.6 × 10−4, combined P = 2.1 × 10−10) and for nine other loci, including NKX2-3, PTPN2 and gene deserts on chromosomes 1q and 5p13.

NOD2 stimulation induces autophagy in dendritic cells influencing bacterial handling and antigen presentation

Nucleotide-binding oligomerization domain–containing-2 (NOD2) acts as a bacterial sensor in dendritic cells (DCs), but it is not clear how bacterial recognition links with antigen presentation after NOD2 stimulation. NOD2 variants are associated with Crohns disease, where breakdown in self-recognition of commensal bacteria leads to gastrointestinal inflammation. Here we show NOD2 triggering by muramyldipeptide induces autophagy in DCs. This effect requires receptor-interacting serine-threonine kinase-2 (RIPK-2), autophagy-related protein-5 (ATG5), ATG7 and ATG16L1 but not NLR family, pyrin domain containing-3 (NALP3).We show that NOD2-mediated autophagy is required for both bacterial handling and generation of major histocompatibility complex (MHC) class II antigen-specific CD4+ T cell responses in DCs. DCs from individuals with Crohns disease expressing Crohns disease—associated NOD2 or ATG16L1 risk variants are defective in autophagy induction, bacterial trafficking and antigen presentation. Our findings link two Crohns disease–associated susceptibility genes in a single functional pathway and reveal defects in this pathway in Crohns disease DCs that could lead to bacterial persistence via impaired lysosomal destruction and immune mediated clearance.

A comparison of budesonide with prednisolone for active Crohn's disease

BACKGROUND Patients with active Crohns disease are often treated with corticosteroids, but the treatment has many side effects. Budesonide is a potent, well-absorbed corticosteroid, but because of a high rate of first-pass metabolism in the liver, its systemic bioavailability is low. METHODS We conducted a randomized, double-blind, 10-week trial comparing the efficacy and safety of an oral controlled-release form of budesonide with the efficacy and safety of prednisolone in 176 patients with active ileal or ileocecal Crohns disease (88 patients in each treatment group). The dose of budesonide was 9 mg per day for eight weeks and then 6 mg per day for two weeks. The dose of prednisolone was 40 mg per day for two weeks, after which it was gradually reduced to 5 mg per day during the last week. RESULTS At 10 weeks, 53 percent of the patients treated with budesonide were in remission (defined as a score < or = 150 on the Crohns disease activity index), as compared with 66 percent of those treated with prednisolone (P = 0.12). The mean score on the Crohns disease activity index decreased from 275 to 175 in the budesonide group and from 279 to 136 in the prednisolone group (P = 0.001). Corticosteroid-associated side effects were significantly less common in the budesonide group (29 vs. 48 patients, P = 0.003). Two patients in the prednisolone group had serious complications (one had intestinal perforation and one an abdominal-wall fistula). The mean morning plasma cortisol concentration was significantly lower in the prednisolone group than in the budesonide group after 4 weeks (P < 0.001) and 8 weeks (P = 0.02) of therapy, but not after 10 weeks. CONCLUSIONS Among patients with active Crohns disease, both controlled-release budesonide and prednisolone are effective in inducing remission. In this trial, prednisolone reduced scores on the Crohns disease activity index more, whereas with budesonide there were fewer glucocorticoid-associated side effects and less suppression of pituitary-adrenal function.

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.

In vivo antigen challenge in celiac disease identifies a single transglutaminase-modified peptide as the dominant A- gliadin T-cell epitope

Celiac disease (CD) is an increasingly diagnosed enteropathy (prevalence, 1:200–1:300) that is induced by dietary exposure to wheat gliadins (as well as related proteins in rye and barley) and is strongly associated with HLA-DQ2 (α1*0501, β1*0201), which is present in over 90% of CD patients. Because a variety of gliadin peptides have been identified as epitopes for gliadin-specific T-cell clones and as bioactive sequences in feeding studies and in ex vivo CD intestinal biopsy challenge, it has been unclear whether a ‘dominant’ T-cell epitope is associated with CD. Here, we used fresh peripheral blood lymphocytes from individual subjects undergoing short-term antigen challenge and tissue transglutaminase-treated, overlapping synthetic peptides spanning A-gliadin to demonstrate a transient, disease-specific, DQ2-restricted, CD4 T-cell response to a single dominant epitope. Optimal gamma interferon release in an ELISPOT assay was elicited by a 17-amino-acid peptide corresponding to the partially deamidated peptide of A-gliadin amino acids 57–73 (Q65E). Consistent with earlier reports indicating that host tissue transglutaminase modification of gliadin enhances gliadin-specific CD T-cell responses, tissue transglutaminase specifically deamidated Q65 in the peptide of A-gliadin amino acids 56–75. Discovery of this dominant epitope may allow development of antigen-specific immunotherapy for CD.

Colorectal cancer in ulcerative colitis: a cohort study of primary referrals from three centres.

A retrospective cohort of 823 patients with ulcerative colitis who resided at the time of diagnosis in one of three defined geographical areas (West Midlands region, Oxford region, England and Stockholm County, Sweden) was assembled. The patients were first seen at named hospitals in these areas and the diagnosis of ulcerative colitis established within five years of onset of symptoms between 1945-1965. All patients were 15 years of age or more at onset of disease and were followed for a minimum of 17 years and a maximum of 38 years. Ninety seven per cent completeness of follow up was achieved. Examining the colorectal cancer risk in the series relative to the risk in the general population by standardised morbidity ratios, there was an eight fold increased risk of cancer in the series as a whole. Dividing the series by extent of colitis, extensive colitis patients showed a 19 fold increase in risk. A four fold increased risk was shown in the remainder of the series (left sided colitis, proctitis and extent unknown). Life table analyses in extensive colitis gave cumulative risks of 7.2% (CI 3.6-10.8) at 20 years from onset of disease and 16.5% (CI 9.0-24.0) at 30 years from onset. No significant effect of age at onset, sex or referral centre could be detected. Examination of the data by interval from onset to cancer and by actual age at development of cancer suggests that patients who develop colorectal cancer will do so in a distribution around 50 years of age independent of duration of disease in adult onset ulcerative colitis (greater than 15 years at onset of disease). An inverse relationship was shown between age at onset of disease and interval from onset of disease to cancer. Further age specific rates for cancer increased up to 50 years and decreased thereafter. These results suggest that extensive colitis patients have a genetic predisposition to colorectal cancer and that longstanding inflammation is not of primary importance in the initiation/promotion of cancer in this disease.

INTENSIVE INTRAVENOUS REGIMEN FOR SEVERE ATTACKS OF ULCERATIVE COLITIS

Abstract A 5-day intensive intravenous regimen for the treatment of severe attacks of ulcerative colitis has been developed, and the results in forty-nine patients treated in this way in a 5-year period are described. Thirty-six patients were in complete remission at the end of the 5-day course. Four showed clinical improvement without remission, and they all required urgent surgery within the next 6 weeks. The remainder were unchanged by the intravenous regimen and required emergency surgery. This regimen gives a higher remission-rate than has been recorded previously, and failure to respond provides a simple and straightforward indication for surgery without further delay. When used in the treatment of first attacks of the disease, the regimen gives a considerable chance of a prolonged remission. Two-thirds of the first-attack patients who went into remission remained symptom-free during the period of follow-up, which averaged more than 3 years.