register interest

Emeritus Professor Derek P Jewell

Research Area: Genetics and Genomics
Keywords: Crohn's disease, ulcerative colitis, genes and autophagy

Derek Jewell leads the research into genetic susceptibility of inflammatory bowel disease and on T cell epitopes of gliadin responsible for coeliac disease.
However, he has now retired from clinical work and has only part-time employment with the University. Two research fellows are being co-supervised with Professor Alison Simmons in WIMM.

Name Department Institution Country
Professor Alison Simmons Experimental Medicine Division Oxford University, Weatherall Institute of Molecular Medicine United Kingdom
Tariq Ahmad Peninsula Medical School United Kingdom
Miquel Sans University Clinic of Barcelona Spain
Guo C, Ahmad T, Beckly J, Cummings JRF, Hancock L, Geremia A, Cooney R, Pathan S, Jewell DP. 2011. Association of caspase-9 and RUNX3 with inflammatory bowel disease. Tissue Antigens, 77 (1), pp. 23-29. | Show Abstract | Read more

Previous linkage studies have identified a region at 1p36 as the susceptibility locus (IBD7) of inflammatory bowel disease (IBD). The objective of this study was to investigate whether polymorphisms of caspase-9 (CASP9) gene and RUNX3 are associated with IBD susceptibility and clinical phenotypes. We studied 555 Crohn's disease (CD) and 651 ulcerative colitis (UC) patients recruited from a single UK center. A total of 964 healthy Caucasian subjects were recruited as controls from general practitioner well person clinics in Oxfordshire. Fourteen single nucleotide polymorphisms (SNPs) of CASP9 and 11 SNPs of RUNX3 were genotyped using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) (homogenous MassEXTEND, hME, Sequenom™, Sequenom Inc., San Diego, CA). Linkage disequilibrium (LD) and haplotype association analysis were performed using 2ld and phase v2.0 software. No association of individual SNPs of CASP9 or RUNX3 with UC or CD was identified. The rs1052571 of CASP9 was associated with severe UC [P = 0.0034, odds ratio (OR) = 1.957, 95% confidence interval (CI) = 1.240-3.088]. Significant haplotype associations between CASP9 and IBD were identified, while no association of RUNX3 haplotypes with either UC or CD was found. Our findings suggested that CASP9 gene might be another IBD susceptibility gene.

Cummings JRF, Cooney RM, Clarke G, Beckly J, Geremia A, Pathan S, Hancock L, Guo C, Cardon LR, Jewell DP. 2010. The genetics of NOD-like receptors in Crohn's disease. Tissue Antigens, 76 (1), pp. 48-56. | Show Abstract | Read more

The first Crohn's disease (CD) susceptibility gene identified was CARD15, which is a member of the emerging NOD-like receptor (NLR) family. These function as intracellular cystosolic pattern recognition receptors (PRRs) and play a central role in the innate immune response. We studied other members of the NLR family using a gene-wide haplotype tagging approach in a well-characterised collection of 547 CD patients and 465 controls. Four single nucleotide polymorphisms (SNPs) in NLRP3 had P values < 0.05 and are in high linkage disequilibrium (LD) with each other (r(2) > 0.90 for all four SNPs). rs4925648 and rs10925019 were the most strongly associated with CD susceptibility (P = 0.001, odds ratio (OR) 1.62, 95% CI 1.2-2.18; and P = 6.5 x 10(-4), OR 1.65, 95% CI 1.23-2.19, respectively). rs1363758 located in NLRP11 was associated with CD susceptibility [P = 0.002 (1.64, 1.19-2.25)], which was weakly confirmed in an independent case-cohort collection on joint analysis [P = 0.05, (1.28, 1-1.64)]. On sub-phenotype analysis, an interesting association between NLRP1 and skin extra-intestinal manifestations and colonic, inflammatory CD was identified. None of these results was replicated in the Wellcome Trust Case Control Consortium study and therefore need replication in a further large cohort.

Wellcome Trust Case Control Consortium, Craddock N, Hurles ME, Cardin N, Pearson RD, Plagnol V, Robson S, Vukcevic D, Barnes C, Conrad DF et al. 2010. Genome-wide association study of CNVs in 16,000 cases of eight common diseases and 3,000 shared controls. Nature, 464 (7289), pp. 713-720. | Show Abstract | Read more

Copy number variants (CNVs) account for a major proportion of human genetic polymorphism and have been predicted to have an important role in genetic susceptibility to common disease. To address this we undertook a large, direct genome-wide study of association between CNVs and eight common human diseases. Using a purpose-designed array we typed approximately 19,000 individuals into distinct copy-number classes at 3,432 polymorphic CNVs, including an estimated approximately 50% of all common CNVs larger than 500 base pairs. We identified several biological artefacts that lead to false-positive associations, including systematic CNV differences between DNAs derived from blood and cell lines. Association testing and follow-up replication analyses confirmed three loci where CNVs were associated with disease-IRGM for Crohn's disease, HLA for Crohn's disease, rheumatoid arthritis and type 1 diabetes, and TSPAN8 for type 2 diabetes-although in each case the locus had previously been identified in single nucleotide polymorphism (SNP)-based studies, reflecting our observation that most common CNVs that are well-typed on our array are well tagged by SNPs and so have been indirectly explored through SNP studies. We conclude that common CNVs that can be typed on existing platforms are unlikely to contribute greatly to the genetic basis of common human diseases.

Tye-Din JA, Stewart JA, Dromey JA, Beissbarth T, van Heel DA, Tatham A, Henderson K, Mannering SI, Gianfrani C, Jewell DP et al. 2010. Comprehensive, quantitative mapping of T cell epitopes in gluten in celiac disease. Sci Transl Med, 2 (41), pp. 41ra51. | Show Abstract | Read more

Celiac disease is a genetic condition that results in a debilitating immune reaction in the gut to antigens in grain. The antigenic peptides recognized by the T cells that cause this disease are incompletely defined. Our understanding of the epitopes of pathogenic CD4(+ )T cells is based primarily on responses shown by intestinal T-cells in vitro to hydrolysates or polypeptides of gluten, the causative antigen. A protease-resistant 33-amino acid peptide from wheat alpha-gliadin is the immunodominant antigen, but little is known about the spectrum of T cell epitopes in rye and barley or the hierarchy of immunodominance and consistency of recognition of T-cell epitopes in vivo. We induced polyclonal gluten-specific T cells in the peripheral blood of celiac patients by feeding them cereal and performed a comprehensive, unbiased analysis of responses to all celiac toxic prolamins, a class of plant storage protein. The peptides that stimulated T cells were the same among patients who ate the same cereal, but were different after wheat, barley and rye ingestion. Unexpectedly, a sequence from omega-gliadin (wheat) and C-hordein (barley) but not alpha-gliadin was immunodominant regardless of the grain consumed. Furthermore, T cells specific for just three peptides accounted for the majority of gluten-specific T cells, and their recognition of gluten peptides was highly redundant. Our findings show that pathogenic T cells in celiac disease show limited diversity, and therefore suggest that peptide-based therapeutics for this disease and potentially other strongly HLA-restricted immune diseases should be possible.

UK IBD Genetics Consortium, Barrett JC, Lee JC, Lees CW, Prescott NJ, Anderson CA, Phillips A, Wesley E, Parnell K, Zhang H et al. 2009. Genome-wide association study of ulcerative colitis identifies three new susceptibility loci, including the HNF4A region. Nat Genet, 41 (12), pp. 1330-1334. | Show Abstract | Read more

Ulcerative colitis is a common form of inflammatory bowel disease with a complex etiology. As part of the Wellcome Trust Case Control Consortium 2, we performed a genome-wide association scan for ulcerative colitis in 2,361 cases and 5,417 controls. Loci showing evidence of association at P < 1 x 10(-5) were followed up by genotyping in an independent set of 2,321 cases and 4,818 controls. We find genome-wide significant evidence of association at three new loci, each containing at least one biologically relevant candidate gene, on chromosomes 20q13 (HNF4A; P = 3.2 x 10(-17)), 16q22 (CDH1 and CDH3; P = 2.8 x 10(-8)) and 7q31 (LAMB1; P = 3.0 x 10(-8)). Of note, CDH1 has recently been associated with susceptibility to colorectal cancer, an established complication of longstanding ulcerative colitis. The new associations suggest that changes in the integrity of the intestinal epithelial barrier may contribute to the pathogenesis of ulcerative colitis.

Pathan S, Gowdy RE, Cooney R, Beckly JB, Hancock L, Guo C, Barrett JC, Morris A, Jewell DP. 2009. Confirmation of the novel association at the BTNL2 locus with ulcerative colitis. Tissue Antigens, 74 (4), pp. 322-329. | Show Abstract | Read more

Linkage in families and association in population case-control investigations have clearly shown that genes within the major histocompatibility complex region on chromosome 6p are relevant to the susceptibility and pathogenesis of ulcerative colitis (UC) and Crohn's disease. However, identifying the causative variants by fine mapping has not been conclusive. In this study using 58 single nucleotide polymorphisms (SNPs) with 616 UC cases, there was significant association with SNP rs2294881 of the (butyrophilin-like 2) BTNL2 gene with odds ratio (OR) = 2.80, confidence interval (CI) = 1.62-4.84 and P = 5.69 x 10(-4) (P(Bonferroni) = 3.3 x 10(-2)) and replication of SNP rs9268480. The missense SNP rs2076523 (K196E) showed novel association with a subset of UC cases with colectomy (n = 126), OR = 0.25, CI = 0.11-0.58 and P = 4.42 x 10(-4) (P(Bonferroni) = 2.56 x 10(-2)). These three associated variants within the BTNL2 gene were neither in linkage disequilibrium with each other nor correlated with the SNPs tagging the human leukocyte antigen (HLA)-DRB1*1502 and HLA-DRB1*0301 alleles.

Cooney R, Cummings JRF, Pathan S, Beckly J, Geremia A, Hancock L, Guo C, Morris A, Jewell DP. 2009. Association between genetic variants in myosin IXB and Crohn's disease. Inflamm Bowel Dis, 15 (7), pp. 1014-1021. | Show Abstract | Read more

BACKGROUND: Genetic variation in myosin IXB (MYO9B) was found to be associated with ulcerative colitis (UC) in a recent collaborative study. A nonsynonymous single nucleotide polymorphism (SNP) rs1545620 at the 3' end of the gene was found to be significantly associated with UC and weakly associated with Crohn's disease (CD). The aim of our current study was to replicate these findings in an independent UC cohort and to investigate association with CD. We also investigated subphenotype association and interactions with CARD15, IL23R, ATG16L1, and the IBD5 risk haplotype. METHODS: In all, 652 CD patients, 650 UC patients, and 1190 controls were genotyped for 8 MYO9B SNPs. Haplotype testing, epistasis testing with known polymorphisms, and subphenotype analysis were performed. RESULTS: An intronic SNP rs2305767 in the MYO9B gene was associated with inflammatory bowel disease (IBD) overall (corrected P-value 0.002, odds ratio [OR] 0.76, 95% confidence interval [CI] 0.67-0.86). On individual disease analysis an association was found with CD (corrected P-value 0.001, OR 0.62, 95% CI 0.53-0.73) but not with UC. Analysis of the common MYO9B haplotypes showed significant association for CD and UC alone and IBD overall. No subphenotypic association was found. These data support an association between CD and SNPs in MYO9B independent of the established effects of SNPs in CARD15, IL23R, ATG16L1, and the IBD5 haplotype. There was no evidence of epistasis between SNPs in MYO9B and these established genes. CONCLUSIONS: MYO9B variants may be involved in IBD pathogenesis.

Bojic D, Radojicic Z, Nedeljkovic-Protic M, Al-Ali M, Jewell DP, Travis SPL. 2009. Long-term outcome after admission for acute severe ulcerative colitis in Oxford: the 1992-1993 cohort. Inflamm Bowel Dis, 15 (6), pp. 823-828. | Show Abstract | Read more

BACKGROUND: To determine the long-term outcome of patients admitted with acute severe colitis (ASC) who avoided colectomy on the index admission, a retrospective cohort study was performed. METHODS: Patients admitted for intensive treatment of ASC in 1992-1993 previously described for a predictive index of short-term outcome in severe ulcerative colitis (UC) were followed for a median 122 months (range 3-144). Complete responders (CR) to intensive therapy had <3 nonbloody stools/day on day 7 of the index admission; incomplete responders (IR) were all others who avoided colectomy on that admission. Main outcome measures were colectomy-free survival, time to colectomy, and duration of steroid-free remission. RESULTS: In all, 6/19 CR (32%) came to colectomy compared to 10/13 IR (P = 0.016; relative risk 3.33, 95% confidence interval [CI] 1.12-9.9). The median +/- interquartile range time to colectomy was 28 +/- 47 months (range 6-99) for CR who came to colectomy versus 7.5 +/- 32 (3-72) months for IR (P = 0.118). Among the IR, 7/13 came to colectomy within 12 months, and all within 6 years from the index admission. The longest period of steroid-free remission was 42 +/- 48 (0-120) months for CR, but 9 +/- 20 (1-35) months for IR (P = 0.011). CONCLUSIONS: One week after admission with ASC in the prebiologic era, IRs had a 50% chance of colectomy within a year and 70% within 5 years, despite cyclosporin and azathioprine where appropriate. The maximum duration of remission in CRs was almost 5 times longer than IRs. It is unknown whether biologics change the long-term outcome.

Williams HRT, Cox IJ, Walker DG, North BV, Patel VM, Marshall SE, Jewell DP, Ghosh S, Thomas HJW, Teare JP et al. 2009. Characterization of inflammatory bowel disease with urinary metabolic profiling. Am J Gastroenterol, 104 (6), pp. 1435-1444. | Show Abstract | Read more

OBJECTIVES: Distinguishing between the inflammatory bowel disease (IBD), Crohn's 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.

Banerjee S, Oneda B, Yap LM, Jewell DP, Matters GL, Fitzpatrick LR, Seibold F, Sterchi EE, Ahmad T, Lottaz D, Bond JS. 2009. MEP1A allele for meprin A metalloprotease is a susceptibility gene for inflammatory bowel disease. Mucosal Immunol, 2 (3), pp. 220-231. | Show Abstract | Read more

The MEP1A gene, located on human chromosome 6p (mouse chromosome 17) in a susceptibility region for inflammatory bowel disease (IBD), encodes the alpha-subunit of metalloproteinase meprin A, which is expressed in the intestinal epithelium. This study shows a genetic association of MEP1A with IBD in a cohort of ulcerative colitis (UC) patients. There were four single-nucleotide polymorphisms in the coding region (P=0.0012-0.04), and one in the 3'-untranslated region (P=2 x 10(-7)) that displayed associations with UC. Moreover, meprin-alpha mRNA was decreased in inflamed mucosa of IBD patients. Meprin-alpha knockout mice exhibited a more severe intestinal injury and inflammation than their wild-type counterparts following oral administration of dextran sulfate sodium. Collectively, the data implicate MEP1A as a UC susceptibility gene and indicate that decreased meprin-alpha expression is associated with intestinal inflammation in IBD patients and in a mouse experimental model of IBD.

Anderson CA, Massey DCO, Barrett JC, Prescott NJ, Tremelling M, Fisher SA, Gwilliam R, Jacob J, Nimmo ER, Drummond H et al. 2009. Investigation of Crohn's disease risk loci in ulcerative colitis further defines their molecular relationship. Gastroenterology, 136 (2), pp. 523-9.e3. | Show Abstract | Read more

BACKGROUND & AIMS: Identifying shared and disease-specific susceptibility loci for Crohn's disease (CD) and ulcerative colitis (UC) would help define the biologic relationship between the inflammatory bowel diseases. More than 30 CD susceptibility loci have been identified. These represent important candidate susceptibility loci for UC. Loci discovered by the index genome scans in CD have previously been tested for association with UC, but those identified in the recent meta-analysis await such investigation. Furthermore, the recently identified UC locus at ECM1 requires formal testing for association with CD. METHODS: We analyzed 45 single nucleotide polymorphisms, tagging 29 of the loci recently associated with CD in 2527 UC cases and 4070 population controls. We also genotyped the UC-associated ECM1 variant rs11205387 in 1560 CD patients and 3028 controls. RESULTS: Nine regions showed association with UC at a threshold corrected for the 29 loci tested (P < .0017). The strongest association (P = 4.13 x 10(-8); odds ratio = 1.27) was identified with a 170-kilobase region on chromosome 1q32 that contains 3 genes. We also found association with JAK2 and replicated a recently reported association with STAT3, further implicating the role of this signaling pathway in inflammatory bowel disease. Additional novel UC susceptibility genes were LYRM4 and CDKAL1. Twenty of the loci were not associated with UC, and several appear to be specific to CD. ECM1 variation was not associated with CD. CONCLUSIONS: Collectively, these data help define the genetic relationship between CD and UC and characterize common, as well as disease-specific mechanisms of pathogenesis.

Orchard TR, Holt H, Bradbury L, Hammersma J, McNally E, Jewell DP, Wordsworth BP. 2009. The prevalence, clinical features and association of HLA-B27 in sacroiliitis associated with established Crohn's disease. Aliment Pharmacol Ther, 29 (2), pp. 193-197. | Show Abstract | Read more

BACKGROUND: Sacroiliitis is a recognized complication of Crohn's disease and may occur distinct from progressive ankylosing spondylitis (AS). AIM: To estimate prospectively the prevalence of sacroiliitis in patients with established Crohn's disease, to characterize the clinical features and to correlate these with the presence of HLA-B27. METHODS: All Crohn's disease patients under active follow-up of between 5 and 12 years duration were invited to participate. Patients underwent a clinical evaluation including symptom questionnaire, rheumatological examination and underwent HLA genotyping. Patients then underwent magnetic resonance imaging (MRI) of the sacroiliac joints. The clinical and radiological factors were correlated with HLA-B27 status. RESULTS: 56 patients underwent initial assessment and 44 had MRI scans. Seventeen of 44 (39%) patients had MRI evidence of sacroiliitis, of whom 5 fulfilled the criteria for AS. Symptoms of low back pain were elicited in a majority of these patients--11/17 (65%) compared to 3 of 27 (11%) patients with normal scans (P = 0.003). There were no differences in functional indices with the exception of patients with AS. HLA-B27 was present in seven patients, and all seven had MRI evidence of sacroiliitis, five had AS. CONCLUSIONS: Sacroiliitis is common in patients with established Crohn's disease and in the majority of cases, patients have symptoms of inflammatory low back pain if questioned carefully. HLA-B27 is not associated with isolated sacroiliitis, but is associated with AS. However, possession of HLA-B27 appears to convey a very high risk of developing axial inflammation in Crohn's disease.

Thomas HJ, Ahmad T, Rajaguru C, Barnardo M, Warren BF, Jewell DP. 2009. Contribution of histological, serological, and genetic factors to the clinical heterogeneity of adult-onset coeliac disease. Scand J Gastroenterol, 44 (9), pp. 1076-1083. | Show Abstract | Read more

OBJECTIVE: Although the factors predisposing to coeliac disease (CD) are largely understood, it remains unclear what determines the clinical heterogeneity of the disease. The aim of this study was to explore the contribution of histological, serological, and genetic factors to disease presentation. MATERIAL AND METHODS: The study was designed as a retrospective chart review of 384 unrelated Caucasian patients diagnosed with CD after the age of 16 at a single UK centre. RESULTS: We found that 8.8% of IgA-competent CD patients were endomysial antibody (EMA)-negative. Compared with the EMA-positive group, EMA-negative CD patients had a lower prevalence of iron deficiency (52.0% versus 72.6%, p=0.03) and Marsh IIIb-c lesions (66.7% versus 85.3%, p=0.03). Histological severity at diagnosis correlated with anaemia (p<0.01), folate deficiency (p<0.01), and iron deficiency (p=0.05), but no other laboratory or clinical features. Compared with human leucocyte antigen (HLA)-DQ2.5-positive patients, those carrying HLA-DQ2.2 were similar in terms of all the characteristics we considered, whereas those carrying HLA-DQ8 had a lower frequency of EMA positivity (62.5% versus 92.6%, p<0.01). The proportion of EMA-positive patients increased with frequency of the HLA-DQB1*0201 allele (76.7% versus 92.3% versus 96.4% for 0 versus 1 versus 2 alleles, p<0.01); no other evidence of a gene-dose effect of HLA-DQB1*0201 was observed. CONCLUSIONS: Histological severity at diagnosis of CD is associated with anaemia and some micronutrient deficiencies, but no other clinical features. The proportion of EMA-positive patients is higher amongst those carrying HLA-DQ2 than in those carrying HLA-DQ8, and is highest in HLA-DQ2 homozygotes. We found no correlation between frequency of the HLA-DQ alleles encoding HLA-DQ2.5 and CD severity.

de Silva HJ, de Silva NR, de Silva AP, Jewell DP. 2008. Emergence of inflammatory bowel disease 'beyond the West': do prosperity and improved hygiene have a role? Trans R Soc Trop Med Hyg, 102 (9), pp. 857-860. | Show Abstract | Read more

Inflammatory bowel disease (IBD) is increasing in many countries 'beyond the West'. This increase may be due to an increased rate of diagnosis but might also represent a true increase in incidence. Economic development, leading to improved hygiene and other changes in lifestyle, may play a role in the increase in IBD. However, the marked difference in prevalence between ethnic groups suggests that the genetic background of populations may also be relevant and supports the current hypothesis that IBD represents an interaction between environmental factors and a genetically susceptible host. Investigating the early stages of IBD as it emerges in new populations may provide new clues to its pathophysiology.

Thomas HJ, Wotton CJ, Yeates D, Ahmad T, Jewell DP, Goldacre MJ. 2008. Pneumococcal infection in patients with coeliac disease. Eur J Gastroenterol Hepatol, 20 (7), pp. 624-628. | Show Abstract | Read more

OBJECTIVES: Some patients with coeliac disease are hyposplenic. Splenectomy is a risk factor for pneumococcal infection. Our objective was to determine the risk of invasive pneumococcal disease - septicaemia, pneumonia or meningitis - in patients with coeliac disease. METHODS: We analysed routinely collected, linked statistical records of hospital admission to study the risk of pneumococcal infection in patients with coeliac disease, in patients who underwent splenectomy and in a comparison cohort. The main outcome measure was the rate ratio for pneumococcal infection in the coeliac and splenectomized cohorts, compared with the comparison cohort. We undertook the study using linked records in two temporally and geographically distinct populations: the Oxford region (1963-1999) and the whole of England (1998-2003). RESULTS: The rate ratio of pneumococcal infection in patients with coeliac disease was 2.06 (95% confidence interval, 1.27-3.15) in the Oxford population and 1.61 (1.36-1.90) in England as a whole. As a comparison, the rate ratios in splenectomized patients were 3.40 (2.44-4.60) and 3.32 (2.80-3.90) in the Oxford and England populations, respectively. The increased rate ratio in coeliac patients persisted beyond the first year after diagnosis of the coeliac disease. The period covered by the Oxford study was mainly before the widespread availability of pneumococcal vaccination; but the availability of pneumococcal vaccine was widespread during the time of the English study. CONCLUSION: Some patients with coeliac disease have an elevated risk of invasive pneumococcal disease.

Geboes K, Colombel J-F, Greenstein A, Jewell DP, Sandborn WJ, Vatn MH, Warren B, Riddell RH, Pathology Task Force of the International Organization of Inflammatory Bowel Diseases. 2008. Indeterminate colitis: a review of the concept--what's in a name? Inflamm Bowel Dis, 14 (6), pp. 850-857. | Show Abstract | Read more

The precise diagnosis of colitis cannot always be established with the available diagnostic tools. The subgroup of patients with an uncertain diagnosis has been classified as "indeterminate colitis" (IC). The definition of "indeterminate," however, has changed over the years. Originally, IC was proposed by pathologists for colectomy specimens, usually from patients operated on for severe colitis, showing overlapping features of ulcerative colitis (UC) and Crohn's disease (CD). Later, the same terminology was used for patients showing no clear clinical, endoscopic, histologic, and other features allowing a diagnosis of either UC or CD. Therefore, it is difficult to compare different studies. An International Organization of Inflammatory Bowel Diseases (IOIBD) working party confirmed 1) the ambiguous nature of the term, and 2) proposes an updated classification for the category of patients with an unclear diagnosis. According to this, the term IBD unclassified (IBDU) is confirmed, as suggested by the Montreal Working Party 2005 for patients with clinically chronic colitis, that clearly have IBD but when definitive features of CD or UC are absent. In resected specimens the term "colitis of uncertain type or etiology" (CUTE) is preferred. It is accepted that most of the time this may have a prefix, such as severe, chronic. The classification of IBD varies when based only on biopsies rather than on a colectomy specimen. The vast majority of these have severe colitis. For those that cannot bear to abandon the highly ambiguous term IC, if it is used at all, this is where it can be used parenthetically.

Fisher SA, Tremelling M, Anderson CA, Gwilliam R, Bumpstead S, Prescott NJ, Nimmo ER, Massey D, Berzuini C, Johnson C et al. 2008. Genetic determinants of ulcerative colitis include the ECM1 locus and five loci implicated in Crohn's disease. Nat Genet, 40 (6), pp. 710-712. | Show Abstract | Read more

We report results of a nonsynonymous SNP scan for ulcerative colitis and identify a previously unknown susceptibility locus at ECM1. We also show that several risk loci are common to ulcerative colitis and Crohn's disease (IL23R, IL12B, HLA, NKX2-3 and MST1), whereas autophagy genes ATG16L1 and IRGM, along with NOD2 (also known as CARD15), are specific for Crohn's disease. These data provide the first detailed illustration of the genetic relationship between these common inflammatory bowel diseases.

Beckly JB, Hancock L, Geremia A, Cummings JRF, Morris A, Cooney R, Pathan S, Guo C, Jewell DP. 2008. Two-stage candidate gene study of chromosome 3p demonstrates an association between nonsynonymous variants in the MST1R gene and Crohn's disease. Inflamm Bowel Dis, 14 (4), pp. 500-507. | Show Abstract | Read more

BACKGROUND: Genomewide linkage studies identified chromosome 3p21 as an IBD locus. Genomewide association studies have supported this locus and the Wellcome Trust Case Control Consortium (WTCCC) study narrowed it to a 0.6 Mb region. Our objectives were to perform a 2-stage candidate gene association study of the 3p locus and to identify linkage disequilibrium (LD) between significant single-nucleotide polymorphisms (SNPs) and an Oxfordshire subset (n = 282) of the WTCCC as well as the HapMap SNPs. METHODS: A total of 197 SNPs in 53 genes from the 3p locus were genotyped on the Illumina platform in a screening cohort of 469 Crohn's disease (CD) patients and 461 controls. Significant associations were then genotyped on the iPLEX platform in the original as well as a second cohort of 139 CD patients, 670 ulcerative colitis (UC) patients, and 1131 controls. All cases and controls were Caucasian and from the Oxfordshire region of the UK. RESULTS: An intronic SNP rs1128535 in the TRAIP gene was associated with CD in the screening and validation cohorts (combined [n = 608] P = 0.0004 [corrected 0.002], odds ratio [OR] 0.77, 95% confidence interval [CI], 0.67-0.89]). No association was seen for UC. Epistasis was seen with the common CARD15 mutations (P = 0.00003 [corrected 0.0006], OR 0.48, 95% CI, 0.34-0.68). No LD was demonstrated with the WTCCC SNPs. Strong LD was demonstrated with 2 nonsynonymous HapMap SNPs in the MST1R gene in an adjacent LD block to the peak WTCCC association, suggesting a distinct association signal. CONCLUSIONS: The LD with these functional MST1R variants implicate this gene as having a possible role in CD pathogenesis.

Jewell DPA, Gheduzzi S, Mitchell MS, Miles AW. 2008. Locking plates increase the strength of dynamic hip screws. Injury, 39 (2), pp. 209-212. | Show Abstract | Read more

INTRODUCTION: Failure of a dynamic hip screw (DHS) fixation leads to decreased mobility of the patient and frequently to a decrease in general health. The most common mode of failure of a DHS is cut out of the lag screw from the femoral head. The second most common mode of failure is lift-off of the plate from the femur. The aim of this laboratory-based experimental study was to determine whether a DHS secured to an osteoporotic femur with a locking screw plate would provide a stronger construct than the standard DHS plate. METHOD: The standard DHS design was compared to a DHS with fixed angle locking screws holding the DHS plate to the femur. Standard dynamic compression plates (DCP) and locking compression plates (LCP) were attached to synthetic, osteoporotic bone. A load was applied to replicate the forces occurring following the fixation of unstable, intertrochanteric hip fractures. A bracket on the proximal end of the plate replicated the lag screw in the femoral head. The constructs were cyclically loaded by a screw-driven material-testing machine and the number of cycles before failure occurred was determined. RESULTS: The mean number of cycles to failure for the locking plate construct was 2.6 times greater than for the standard screw construct (285 versus 108 cycles, respectively p=0.016). CONCLUSION: A dynamic hip screw with fixed angle locking screws would reduce the risk of DHS failure. A locking screw DHS would be particularly useful in patients with osteoporotic bone, and in patients with less stable fracture configurations.

Wellcome Trust Case Control Consortium, Australo-Anglo-American Spondylitis Consortium (TASC), Burton PR, Clayton DG, Cardon LR, Craddock N, Deloukas P, Duncanson A, Kwiatkowski DP, McCarthy MI et al. 2007. Association scan of 14,500 nonsynonymous SNPs in four diseases identifies autoimmunity variants. Nat Genet, 39 (11), pp. 1329-1337. | Show Abstract | Read more

We have genotyped 14,436 nonsynonymous SNPs (nsSNPs) and 897 major histocompatibility complex (MHC) tag SNPs from 1,000 independent cases of ankylosing spondylitis (AS), autoimmune thyroid disease (AITD), multiple sclerosis (MS) and breast cancer (BC). Comparing these data against a common control dataset derived from 1,500 randomly selected healthy British individuals, we report initial association and independent replication in a North American sample of two new loci related to ankylosing spondylitis, ARTS1 and IL23R, and confirmation of the previously reported association of AITD with TSHR and FCRL3. These findings, enabled in part by increased statistical power resulting from the expansion of the control reference group to include individuals from the other disease groups, highlight notable new possibilities for autoimmune regulation and suggest that IL23R may be a common susceptibility factor for the major 'seronegative' diseases.

Cummings JRF, Ahmad T, Geremia A, Beckly J, Cooney R, Hancock L, Pathan S, Guo C, Cardon LR, Jewell DP. 2007. Contribution of the novel inflammatory bowel disease gene IL23R to disease susceptibility and phenotype. Inflamm Bowel Dis, 13 (9), pp. 1063-1068. | Show Abstract | Read more

BACKGROUND: A North American genome-wide single nucleotide polymorphism (SNP) association study identified IL23R as a novel inflammatory bowel disease (IBD) susceptibility gene. Association was reported with multiple risk variants in the centromeric portion of IL23R in 3 large independent cohorts. The aims of this study were to replicate the association of IL23R with Crohn's disease (CD), examine subphenotype relationships, and look for evidence of epistasis with the known CD susceptibility gene CARD15 and susceptibility haplotype IBD5 in a large collection of CD patients. We further investigated the relationship between IL23R and ulcerative colitis (UC). METHODS: In all, 604 CD and 647 UC patients who had been rigorously phenotyped and who had been recruited from a single UK center were used in this study. Controls were either spouses of patients (141) or were recruited from well-person clinics (993). Eight SNPs were genotyped using MassArray (Sequenom). All 8 SNPs genotyped were significantly associated with CD. RESULTS: The association with the nonsynonymous SNP rs11209026 was confirmed (P=6.65x10(-6), odds ratio [OR], 0.43, 95% confidence interval [CI]: 0.29-0.64). The most significant SNP in our study was rs7517847 (P=4.9x10(-9), OR 0.65, 0.56-0.75), which is statistically independent of rs11209026. Preliminary evidence suggests an epistatic interaction with the IBD5 risk haplotype. The effects of mutations in this IL23R appear weaker in UC (P=0.008, OR 0.63, 0.45-0.89 and 0.005 OR, 0.81, 0.71-0.94, respectively). No subphenotype associations were identified. CONCLUSIONS: We confirmed the findings that IL23R is a susceptibility gene for IBD with suggestive epistasis with the IBD5 locus in the CD population.

Cummings JRF, Cooney R, Pathan S, Anderson CA, Barrett JC, Beckly J, Geremia A, Hancock L, Guo C, Ahmad T et al. 2007. Confirmation of the role of ATG16L1 as a Crohn's disease susceptibility gene. Inflamm Bowel Dis, 13 (8), pp. 941-946. | Show Abstract | Read more

BACKGROUND: A German genome-wide nonsynonymous single nucleotide polymorphism (nsSNP) association study identified ATG16L1 as a Crohn's disease (CD) susceptibility gene. The association appeared to be confined to the nsSNP rs2,241,880 and was confirmed in 2 German independent case-control collections (combined P = 4.0 x 10(-8), odds ratio [OR] 1.45; 95% confidence interval [CI]: 1.21-1.74), a CD transmission disequilibrium test (TDT) collection, and an independent UK cohort. A weak statistical interaction with CARD15 was demonstrated. No association with ulcerative colitis (UC) was demonstrated. The aims of the study were to replicate the association with CD, examine subphenotype associations and statistical interactions with CARD15, IL23R, and the IBD5 risk haplotype, as well as explore the association with UC. METHODS: The study included 645 CD and 676 UC rigorously phenotyped patients recruited from a single UK center. Unaffected controls comprised either spouses of patients (141) or individuals recruited from well-person clinics (1,049). The nsSNP rs2,241,880 was genotyped using MassArray (Sequenom). RESULTS: A strong association with CD was demonstrated (P = 2.33 x 10(-7), OR 1.45 [1.25-1.67]), but no significant association was demonstrated with any subphenotype. We failed to replicate the reported interaction between rs2,241,880 and the CARD15 low-risk haplotypes dd and Dd. No significant statistical interaction with the 3 known CD susceptibility genes was seen. No association with UC susceptibility (P = 0.37, OR 1.06 [0.93-1.22]), or any UC subphenotype was identified. CONCLUSIONS: We confirmed the findings that ATG16L1 is a CD susceptibility gene and found no evidence of interaction with CARD15, IL23R, or IBD5.

Parkes M, Barrett JC, Prescott NJ, Tremelling M, Anderson CA, Fisher SA, Roberts RG, Nimmo ER, Cummings FR, Soars D et al. 2007. Sequence variants in the autophagy gene IRGM and multiple other replicating loci contribute to Crohn's disease susceptibility. Nat Genet, 39 (7), pp. 830-832. | Show Abstract | Read more

A genome-wide association scan in individuals with Crohn's 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 x 10(-4), combined P = 2.1 x 10(-10)) and for nine other loci, including NKX2-3, PTPN2 and gene deserts on chromosomes 1q and 5p13.

Wellcome Trust Case Control Consortium. 2007. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature, 447 (7145), pp. 661-678. | Show Abstract | Read more

There is increasing evidence that genome-wide association (GWA) studies represent a powerful approach to the identification of genes involved in common human diseases. We describe a joint GWA study (using the Affymetrix GeneChip 500K Mapping Array Set) undertaken in the British population, which has examined approximately 2,000 individuals for each of 7 major diseases and a shared set of approximately 3,000 controls. Case-control comparisons identified 24 independent association signals at P < 5 x 10(-7): 1 in bipolar disorder, 1 in coronary artery disease, 9 in Crohn's disease, 3 in rheumatoid arthritis, 7 in type 1 diabetes and 3 in type 2 diabetes. On the basis of prior findings and replication studies thus-far completed, almost all of these signals reflect genuine susceptibility effects. We observed association at many previously identified loci, and found compelling evidence that some loci confer risk for more than one of the diseases studied. Across all diseases, we identified a large number of further signals (including 58 loci with single-point P values between 10(-5) and 5 x 10(-7)) likely to yield additional susceptibility loci. The importance of appropriately large samples was confirmed by the modest effect sizes observed at most loci identified. This study thus represents a thorough validation of the GWA approach. It has also demonstrated that careful use of a shared control group represents a safe and effective approach to GWA analyses of multiple disease phenotypes; has generated a genome-wide genotype database for future studies of common diseases in the British population; and shown that, provided individuals with non-European ancestry are excluded, the extent of population stratification in the British population is generally modest. Our findings offer new avenues for exploring the pathophysiology of these important disorders. We anticipate that our data, results and software, which will be widely available to other investigators, will provide a powerful resource for human genetics research.

Hugot J-P, Zaccaria I, Cavanaugh J, Yang H, Vermeire S, Lappalainen M, Schreiber S, Annese V, Jewell DP, Fowler EV et al. 2007. Prevalence of CARD15/NOD2 mutations in Caucasian healthy people. Am J Gastroenterol, 102 (6), pp. 1259-1267. | Show Abstract | Read more

BACKGROUND: Crohn's disease (CD) has been associated with CARD15/NOD2 mutations in Caucasians. The R702W, G908R, and 1007fs mutations represent 82% of the mutated chromosomes. The relative risk of developing CD in homozygous or compound heterozygous people has been estimated as between 10 and 40 times that of the general population. This high risk may support the opinion that CARD15/NOD2 variants are strong CD risk factors at the individual and population levels. SUBJECTS AND METHODS: The allele and genotype frequencies were calculated for the R702W, G908R, and 1007fs mutations in 3,575 Caucasian healthy controls recruited by 15 groups distributed on three continents. Geographic homogeneity was tested and the observed proportion of double mutants was compared with the expected value using chi2 tests. RESULTS: The allele frequencies of the R702W, G908R, and 1007fs mutations were 4.3% (3.6-4.9), 1.2% (0.8-1.6), and 2.3% (1.8-2.8), respectively, with large geographic fluctuations of the G908R, 1007fs, and wild-type alleles (P<0.0001). At the population level, no simple relationship was observed between mutation frequencies and the disease incidences in the studied populations. At the individual level, no significant deficit of double-dose mutation carriers among healthy controls was found, providing strong evidence that the penetrances of the most at-risk genotypes are low. CONCLUSION: Altogether, these data confirm that CARD15/NOD2 acts in interaction with other unknown risk cofactors.

Jakobovits SL, Jewell DP, Travis SPL. 2007. Infliximab for the treatment of ulcerative colitis: outcomes in Oxford from 2000 to 2006. Aliment Pharmacol Ther, 25 (9), pp. 1055-1060. | Show Abstract | Read more

BACKGROUND: Infliximab has been shown to be of benefit in the treatment of ulcerative colitis but long-term colectomy rates remain unknown. AIMS: To review the rate of colectomy after infliximab for ulcerative colitis and to identify factors that might predict the need for colectomy. METHODS: We conducted a retrospective cohort study of patients with active ulcerative colitis treated with infliximab between 2000 and 2006. The primary outcome was colectomy-free survival. Disease and treatment characteristics and complications were documented. RESULTS: Thirty patients were treated with infliximab for refractory ulcerative colitis. Sixteen (53%) came to colectomy a median of 140 days after their first infusion (range 4-607). There was no difference in colectomy between those receiving infliximab for acute severe ulcerative colitis failing intravenous steroids (8/14) and out-patients with steroid-refractory ulcerative colitis (8/16). Only 17% (5/30) achieved a steroid-free remission after a median follow-up of 13 months (range 2-72). Univariate analysis showed that a younger age at diagnosis of colitis was significantly associated with an increased rate of colectomy (27.5 years vs. 38.7 years, P = 0.016). CONCLUSION: Over half the patients studied came to colectomy. Of those avoiding colectomy, only five (17%) sustained a steroid-free remission.

Hyder SA, Travis SPL, Jewell DP, McC Mortensen NJ, George BD. 2006. Fistulating anal Crohn's disease: results of combined surgical and infliximab treatment. Dis Colon Rectum, 49 (12), pp. 1837-1841. | Show Abstract | Read more

INTRODUCTION: Infliximab is a monoclonal antibody against tumor necrosis factor-alpha, which has been shown to be effective in fistulating Crohn's disease. The safety of infliximab in patients with potential perianal sepsis is uncertain. This study was designed to assess the safety and outcome of infliximab therapy combined with surgery for patients with fistulating anal Crohn's disease. METHODS: All patients receiving infliximab for fistulating anal Crohn's disease between 2000 and 2004 were studied. Patients' demographics, clinical findings, magnetic resonance imaging, and examination under anesthesia were recorded. Perianal Crohn's disease activity index before and 8 to 12 weeks after three infusions of infliximab (5 mg/kg) were recorded. Routine policy was to insert drainage seton sutures at the time of preinfliximab examination under anesthesia and then remove it after the second infusion. Complications of treatment and outcome at the last clinic follow-up were recorded. RESULTS: Twenty-two patients underwent infliximab treatment (6 males; median age, 35 (range, 16-60) years). Twenty-one patients had preinfliximab examination under anesthesia: 12 required abscess drainage; 17 had at least one drainage seton suture inserted. Fourteen patients underwent pretreatment magnetic resonance imaging to identify clinically occult collections. All but one patient were established on immunomodulator therapy before infliximab treatment. Perianal Crohn's disease activity index improved significantly after infliximab infusion (preinfusion: median, 11, range, 8-17; postinfusion: median, 8, range, 5-16; P<0.001). There were no serious complications of infliximab treatment. At median follow-up of 21 (range, 4-31) months, only four patients achieved sustained fistula healing. Five patients have required defunctioning or proctectomy. Four patients have required repeated infusions of infliximab. CONCLUSIONS: Infliximab therapy in combination with examination under anesthesia/seton drainage is a safe and effective short-term treatment for fistulating anal Crohn's disease. Long-term fistula healing rates are low.

Herrlinger KR, Jewell DP. 2006. Review article: interactions between genotype and response to therapy in inflammatory bowel diseases. Aliment Pharmacol Ther, 24 (10), pp. 1403-1412. | Show Abstract | Read more

BACKGROUND: More than half of the patients with inflammatory bowel diseases are candidates for immunosuppressive therapy. However, even the most effective drugs used in inflammatory bowel disease are only successful in about two-thirds of patients. Adverse events limit their use in a further substantial proportion of patients. Recent research has focussed on the possibility of predicting a drugs' efficacy and/or toxicity by identifying polymorphic variants in the genes encoding enzymes involved in metabolic pathways. AIM: To highlight recent advances and limitations in the field of pharmacogenetics in inflammatory bowel disease. RESULTS: Recent pharmacogenetic studies have mainly focussed on immunosuppressive agents including corticosteroids, azathioprine, methotrexate and infliximab. Several polymorphic genes encoding enzymes involved in the metabolism of these drugs have been identified including the inosine triphosphate pyrophosphatase in thiopurine therapy, the methylene tetrahydrofolate reductase in methotrexate therapy and polymorphisms in apoptosis genes in infliximab therapy. However, at the present time, genotyping for the variants of the thiopurine methyltransferase gene, an enzyme important for the metabolism of the thiopurine drugs, is the only useful test in clinical practice. CONCLUSIONS: Although the field of pharmacogenetics in inflammatory bowel disease is promising most new targets have so far failed to translate into clinical practice. Future pharmaceutical trials should include pharmacogenetic research to test appropriate candidate genes in a prospective manner.

McGovern DPB, Butler H, Ahmad T, Paolucci M, van Heel DA, Negoro K, Hysi P, Ragoussis J, Travis SPL, Cardon LR, Jewell DP. 2006. TUCAN (CARD8) genetic variants and inflammatory bowel disease. Gastroenterology, 131 (4), pp. 1190-1196. | Show Abstract | Read more

BACKGROUND & AIMS: The identification of the association between Crohn's disease (CD) and NOD2 (CARD15) confirmed both the heritability of CD and highlighted the role of the nuclear factor kappaB (NFkappaB) pathway in disease pathogenesis. Other susceptibility loci exist. TUCAN (CARD8) is located beneath a CD peak of linkage on chromosome 19q. TUCAN is expressed in the gut and is a negative regulator of NFkappaB, making it an excellent candidate gene for gastrointestinal inflammation. METHODS: Ten single nucleotide polymorphisms (SNP) across TUCAN were genotyped in 365 controls, 372 patients with CD, and 373 patients with ulcerative colitis. A diagnostic panel for CD was constructed using smoking status and TUCAN, NOD2, IBD5, NOD1, and TNFSF15 data. RESULTS: We demonstrate significant association between a TUCAN SNP and CD (OR 1.35, P = .0083). The association was more pronounced with disease affecting sites other than the colon (odds ratio, 1.52) and NOD2-negative CD (odds ratio, 1.50). Combination of these data with smoking and NOD2, IBD5, NOD1, and TNFSF15 status demonstrated very strong associations with CD and high sensitivities (96.3%), specificities (99.4%), and likelihood ratios (12.8) for CD, although further work will be needed before this model can be translated into direct clinical utility. CONCLUSIONS: We have shown an association between a likely functional polymorphism in TUCAN and CD. The combination of these data in a genetic panel suggests that clinicians may soon be able to translate genetic advances into direct benefits for patients.

Jones DC, Edgar RS, Ahmad T, Cummings JRF, Jewell DP, Trowsdale J, Young NT. 2006. Killer Ig-like receptor (KIR) genotype and HLA ligand combinations in ulcerative colitis susceptibility. Genes Immun, 7 (7), pp. 576-582. | Show Abstract | Read more

Killer immunoglobulin-like receptors (KIRs) are expressed on natural killer cells and some T-cell subsets and produce either activation or inhibitory signals upon binding with the appropriate human leucocyte antigen (HLA) ligand on target cells. Recent genetic association studies have implicated KIR genotype in the development of several inflammatory conditions. Ulcerative colitis (UC) is an inflammatory disorder of the colonic mucosa that results from an inappropriate activation of the immune system driven by host bacterial flora. We developed a polymerase chain reaction-sequence specific primer (SSP)-based assay to genotype 194 UC patients and 216 control individuals for 14 KIR genes, the HLA-Cw ligand epitopes of the KIR2D receptors and a polymorphism of the lectin-like-activating receptor NKG2D. Initial analysis found the phenotype frequency of KIR2DL2 and -2DS2 to be significantly increased in the UC cohort (P=0.030 and 0.038, respectively). Logistic regression analysis revealed a protective effect conferred by KIR2DL3 in the presence of its ligand HLA-Cw group 1 (P=0.019). These results suggest that KIR genotype and HLA ligand interaction may contribute to the genetic susceptibility of UC.

Boyton RJ, Reynolds C, Wahid FN, Jones MG, Ozerovitch L, Ahmad T, Chaudhry A, Jewell DP, Kon OM, Smith J et al. 2006. IFN gamma and CXCR-1 gene polymorphisms in idiopathic bronchiectasis. Tissue Antigens, 68 (4), pp. 325-330. | Show Abstract | Read more

Idiopathic bronchiectasis is a disease of chronic, bacterial lung infection, unresolving inflammation and progressive lung damage. Bronchiectasis can be associated with autoimmune diseases including ulcerative colitis. Defects of both innate and adaptive immunity have been proposed. The airway inflammation is characterized by interleukin-8 (IL-8) expression and infiltration by neutrophils and T cells. Here we investigated two candidate gene polymorphisms that may contribute to disease susceptibility: a CXCR-1 (+2607 G/C) gene polymorphism that is implicated in IL-8 binding and neutrophil trafficking as well as the interferon-gamma (IFNgamma) (+874 T/A) polymorphism which is linked to levels of IFNgamma production. These polymorphisms were distributed similarly in the idiopathic bronchiectasis group and controls, suggesting that these two candidate gene polymorphisms are not associated with disease susceptibility.

Hunt KA, Monsuur AJ, McArdle WL, Kumar PJ, Travis SPL, Walters JRF, Jewell DP, Strachan DP, Playford RJ, Wijmenga C, van Heel DA. 2006. Lack of association of MYO9B genetic variants with coeliac disease in a British cohort. Gut, 55 (7), pp. 969-972. | Show Abstract | Read more

BACKGROUND AND AIMS: Development of coeliac disease involves an interaction between environmental factors (especially dietary wheat, rye, and barley antigens) and genetic factors (there is strong inherited disease susceptibility). The known human leucocyte antigen (HLA)-DQ2 and -DQ8 association explains only a minority of disease heritability. A recent study in the Dutch population suggested that genetic variation in the 3' region of myosin IXB (MYO9B) predisposes to coeliac disease. MYO9B is a Rho family GTPase activating protein involved in epithelial cell cytoskeletal organisation. MYO9B is hypothesised to influence intestinal permeability and hence intestinal antigen presentation. METHODS: Four single nucleotide polymorphisms were chosen to tag all common haplotypes of the MYO9B 3' haplotype block (exons 15-27). We genotyped 375 coeliac disease cases and 1366 controls (371 healthy and 995 population based). All individuals were of White UK Caucasian ethnicity. RESULTS: UK healthy control and population control allele frequencies were similar for all MYO9B variants. Case control analysis showed no significant association of any variant or haplotype with coeliac disease. CONCLUSIONS: Genetic variation in MYO9B does not have a major effect on coeliac disease susceptibility in the UK population. Differences between populations, a weaker effect size than originally described, or possibly a type I error in the Dutch study might explain these findings.

Jewell DP. 2006. New patients, new lessons, new thinking in inflammatory bowel disease: World Congress of Gastroenterology Symposium, Montreal, Canada, September 2005. Colorectal Dis, 8 Suppl 1 (s1), pp. 1-2. | Read more

Fearnhead NS, Chowdhury R, Box B, George BD, Jewell DP, Mortensen NJM. 2006. Long-term follow-up of strictureplasty for Crohn's disease. Br J Surg, 93 (4), pp. 475-482. | Show Abstract | Read more

BACKGROUND: Strictureplasty is an effective means of alleviating obstructive Crohn's disease while conserving bowel length. The aim of this study was to establish long-term outcomes of strictureplasty. METHODS: Between 1978 and 2003, 479 strictureplasties were performed in 100 patients during 159 operations. Information on Crohn's disease, medical therapy, laboratory indices, surgical details, complication rates and outcomes was recorded. The primary endpoint was abdominal reoperation. RESULTS: Mean follow-up was 85.1 (range 0.2-240.9) months. The overall morbidity rate was 22.6 per cent, with septic complications in 11.3 per cent, obstruction in 4.4 per cent and gastrointestinal haemorrhage in 3.8 per cent. The 30-day mortality rate was 0.6 per cent and the procedure-related series mortality rate 3.0 per cent. Perioperative parenteral nutrition was the only marker for morbidity (P < 0.001). Reoperation rates were 52 per cent at a mean of 40.2 (range 0.2-205.8) months after a first, 56 per cent at 26.1 (range 3.5-63.5) months after a second, 86 per cent at 27.4 (range 1.4-74.5) months after a third, and 62.5 per cent at 25.9 (range 7.3-70.5) months following a fourth strictureplasty procedure. The major risk factor for reoperation was young age (P < 0.001). CONCLUSION: Long-term follow-up has confirmed the safety of strictureplasty in Crohn's disease. Morbidity is appreciable, although the surgical mortality rate is low. Reoperation rates are comparable following first and repeat strictureplasty procedures.

Anderson RP, van Heel DA, Tye-Din JA, Jewell DP, Hill AVS. 2006. Antagonists and non-toxic variants of the dominant wheat gliadin T cell epitope in coeliac disease. Gut, 55 (4), pp. 485-491. | Show Abstract | Read more

BACKGROUND: Coeliac disease (CD) is due to an inappropriate T cell mediated response to specific gluten peptides. Measured by interferon gamma (IFN-gamma) ELISPOT, about half of the gliadin specific T cells induced with in vivo wheat gluten exposure in HLA-DQ2+ CD are specific for an alpha/beta-gliadin peptide (p57-73 QE65; QLQPFPQPELPYPQPQS) that includes two overlapping T cell epitopes (PFPQPELPY and PQPELPYPQ). AIM: To define minimally substituted variants of p57-73 QE65 universally devoid of IFN-gamma stimulatory capacity but capable of antagonising IFN-gamma secretion from polyclonal T cells specific for p57-73 QE65. METHODS: Peripheral blood mononuclear cells collected from 75 HLA-DQ2+ CD patients after in vivo gluten challenge were used in overnight ELISPOT assays to screen 218 single or double substituted variants of p57-73 QE65 for cytokine stimulatory and antagonist activity. RESULTS: The region p60-71 (PFPQPELPYPQP) and especially p64-67 (PELP) was sensitive to substitution. Twelve substitutions in p64-67 stimulated no IFN-gamma ELISPOT response. Among 131 partial agonists identified, 45 produced statistically significant inhibition of IFN-gamma ELISPOT responses when cocultured in fivefold excess with p57-73 QE65 (n = 10). Four substituted variants of p57-73 QE65 were inactive by IFN-gamma ELISPOT but consistently antagonised IFN-gamma ELISPOT responses to p57-73 QE65, and also retained interleukin 10 stimulatory capacity similar to p57-73 QE65. CONCLUSIONS: Altered peptide ligands of p57-73 QE65, identified using polyclonal T cells from multiple HLA-DQ2+ CD donors, have properties in vitro that suggest that a single substitution to certain alpha/beta-gliadins could abolish their capacity to stimulate IFN-gamma from CD4 T cells and also have anti-inflammatory or protective effects in HLA-DQ2+ CD.

Campbell S, Cripps S, Jewell DP. 2005. Therapy Insight: pyoderma gangrenosum-old disease, new management. Nat Clin Pract Gastroenterol Hepatol, 2 (12), pp. 587-594. | Show Abstract | Read more

Well-designed studies that help guide physicians to apply the optimal therapeutic strategy for the management of pyoderma gangrenosum are lacking in the literature. A multidisciplinary approach is paramount for the effective management of this condition, with close involvement of a wound-care specialist and a microbiologist. Treatment should be stepwise in nature. Local wound care, avoidance of trauma and the application of local steroid or tacrolimus ointment are the first-line treatments. Steroid therapy is the most widely published effective therapy for achieving resolution of pyoderma gangrenosum, although there is growing evidence for the efficacy of infliximab in refractory cases. Other therapies such as dapsone and clofazamine should be left as third-line agents for refractory pyoderma gangrenosum, while novel treatments such as granulocyte apheresis should only be used under trial conditions, to gain an objective evaluation of their efficacy. This article reviews the published treatment strategies in current use, and aims to guide the effective management of pyoderma gangrenosum.

van Heel DA, Ghosh S, Hunt KA, Mathew CG, Forbes A, Jewell DP, Playford RJ. 2005. Synergy between TLR9 and NOD2 innate immune responses is lost in genetic Crohn's disease. Gut, 54 (11), pp. 1553-1557. | Show Abstract | Read more

BACKGROUND: Nucleotide binding oligomerisation domain 2 (NOD2; also known as CARD15) mutations are associated with Crohn's disease but how mutations cause disease is poorly understood. Innate immune responses are reportedly enhanced by combined NOD2 ligand (muramyl dipeptide, MDP) and Toll-like receptor 4 ligand (TLR4, lipopolysaccharide) stimulation. Intestinal TLR signalling has a dual role-maintaining intestinal homeostasis and protection from injury as well as initiating inflammatory responses. TLR9 is functional in the intestinal epithelium where it is most strongly expressed in Paneth cells. AIMS: To study possible interactions between CpG DNA (TLR9 ligand) and MDP using primary human cells of differing NOD2 genotypes. SUBJECTS: NOD2 wild-type healthy controls (n = 7) and NOD2 homozygous Crohn's disease patients (n = 19), age and sex matched. METHODS: Peripheral blood mononuclear cells were stimulated with CpG DNA and MDP. Cytokines were measured by enzyme linked immunosorbent assay. RESULTS: Tumour necrosis factor alpha (TNF-alpha) and interleukin 8 (IL-8) responses to CpG DNA were similar in NOD2 wild-type and homozygous mutant cells. Concomitant NOD2 stimulation had a marked synergistic effect on CpG DNA induced TNF-alpha responses at 10-100 ng/ml MDP. A mean 2.1-fold increase in CpG DNA induced TNF-alpha responses and a mean 3.7-fold increase in IL-8 responses were observed in NOD2 wild-type cells with 10 ng/ml MDP. This effect was abolished in NOD2 homozygous cells. CONCLUSIONS: NOD2 stimulation normally enhances innate immune responses to CpG DNA. This marked synergistic effect is lost in Crohn's disease patients homozygous for NOD2 mutations, with implications for TLR mediated intestinal homeostasis and inflammation.

Herrlinger KR, Cummings JRF, Barnardo MCNM, Schwab M, Ahmad T, Jewell DP. 2005. The pharmacogenetics of methotrexate in inflammatory bowel disease. Pharmacogenet Genomics, 15 (10), pp. 705-711. | Show Abstract | Read more

OBJECTIVES: Methotrexate (MTX) is an effective immunosuppressive treatment in inflammatory bowel disease (IBD) but its use is limited by unpredictable toxicity and efficacy. MTX metabolism is complex involving a number of enzymes. An individual's response to MTX may in part be genetically determined by functional genetic variation in genes encoding these enzymes. We report a pharmacogenetic evaluation of MTX therapy in IBD. METHODS: We studied 102 IBD patients treated with MTX, and 202 patients with Crohn's disease (CD), 205 patients with ulcerative colitis (UC) and 189 healthy volunteers served as controls to assess allele frequencies in the disease and healthy populations. All subjects were genotyped for four polymorphisms: G80A in the reduced folate carrier (RFC1) gene, G452T in the gamma-glutamyl hydrolase (GGH) gene and C677T and A1298C in the methylenetetrahydrofolate reductase (MTHFR) gene. Three non-conservative SNPs in the RFC1 and the MTHFR gene could not be detected in our patient cohort. Genotype-phenotype associations were evaluated with respect to efficacy and toxicity of MTX therapy. RESULTS: No significant differences in the allele frequencies between CD, UC and healthy controls were detected. Overall 21% of patients experienced MTX side effects. Patients homozygous for the MTHFR 1298C allele were more likely to experience one or more side effects compared to patients with the wild-type 1298AA genotype (21.0 vs. 6.3%, P < 0.05). None of the genotyped SNPs or haplotypes, either alone or in combination, was associated with short-term efficacy or sustained response. CONCLUSIONS: Side effects of MTX in IBD are associated with a SNP in the MTHFR gene but response cannot be predicted by any of the investigated SNPs.

Jewell DP, Satsangi J, Lobo A, Probert C, Forbes A, Ghosh S, Shaffer J, Frenz M, Drummond H, Troy G et al. 2005. Infliximab use in Crohn's disease: impact on health care resources in the UK. Eur J Gastroenterol Hepatol, 17 (10), pp. 1047-1052. | Show Abstract | Read more

OBJECTIVE: To quantify the impact of infliximab therapy on health care resource utilization in the UK. METHODS: A retrospective audit was undertaken at seven centres in the UK, which reviewed patient notes for a period of 6 months before and 6 months after an initial infliximab infusion. Details of hospital admissions, outpatient visits, operations, diagnostic procedures, drug usage, and overall efficacy were collected. Results were compared for the two 6 month study periods. RESULTS: A total of 205 patients (62% female, median age 33 years) with moderate/severe Crohn's disease were audited. The majority of patients had chronic active disease (62%) and most received one infusion initially (72%). Clinicians rated 74% of responses as good to excellent and patients 72%. Most patients had concomitant immunosuppression (pre: 75%, post: 75%). Approximately half of the patients (45%) stopped taking steroids, with a further 34% having a dosage reduction. A fall of 1093 inpatient days was seen (1435 vs. 342) in the 6 months following infliximab administration. There were seven fewer operations, 33 fewer examinations under anaesthetic, and 99 fewer diagnostic procedures. Outpatient visits were similar pre- versus post- (555 vs. 534). The total reduction in direct costs amounted to an estimated pounds 591,006. Three hundred and fifty-three infliximab infusions were administered at an estimated cost of pounds 562,719. Thus, there was a net reduction of pounds 28,287 or pounds 137.98 per patient. CONCLUSIONS: Infliximab appears to be a potentially cost effective treatment for selected patients based on the reduced number of inpatient stays, examinations under anaesthetic, and diagnostic procedures over a 6 month period.

Silverberg MS, Satsangi J, Ahmad T, Arnott IDR, Bernstein CN, Brant SR, Caprilli R, Colombel J-F, Gasche C, Geboes K et al. 2005. 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. Can J Gastroenterol, 19 Suppl A (suppl a), pp. 5A-36A. | Show Abstract | Read more

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 Crohn's 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.

van Heel DA, Dart J, Nichols S, Jewell DP, Playford RJ. 2005. Novel presentation of coeliac disease after following the Atkins' low carbohydrate diet. Gut, 54 (9), pp. 1342. | Read more

Anderson RP, van Heel DA, Tye-Din JA, Barnardo M, Salio M, Jewell DP, Hill AVS. 2005. T cells in peripheral blood after gluten challenge in coeliac disease. Gut, 54 (9), pp. 1217-1223. | Show Abstract | Read more

BACKGROUND: Current understanding of T cell epitopes in coeliac disease (CD) largely derives from intestinal T cell clones in vitro. T cell clones allow identification of gluten peptides that stimulate T cells but do not quantify their contribution to the overall gluten specific T cell response in individuals with CD when exposed to gluten in vivo. AIMS: To determine the contribution of a putative dominant T cell epitope to the overall gliadin T cell response in HLA-DQ2 CD in vivo. PATIENTS: HLA-DQ2+ individuals with CD and healthy controls. METHODS: Subjects consumed 20 g of gluten daily for three days. Interferon gamma (IFN-gamma) ELISPOT was performed using peripheral blood mononuclear cells (PBMC) to enumerate and characterise peptide and gliadin specific T cells before and after gluten challenge. RESULTS: In 50/59 CD subjects, irrespective of homo- or heterozygosity for HLA-DQ2, IFN-gamma ELISPOT responses for an optimal concentration of A-gliadin 57-73 Q-E65 were between 10 and 1500 per million PBMC, equivalent to a median 51% of the response for a "near optimal" concentration of deamidated gliadin. Whole deamidated gliadin and gliadin epitope specific T cells induced in peripheral blood expressed an intestinal homing integrin (alpha4beta7) and were HLA-DQ2 restricted. Peripheral blood T cells specific for A-gliadin 57-73 Q-E65 are rare in untreated CD but can be predictably induced two weeks after gluten exclusion. CONCLUSION: In vivo gluten challenge is a simple safe method that allows relevant T cells to be analysed and quantified in peripheral blood by ELISPOT, and should permit comprehensive high throughput mapping of gluten T cell epitopes in large numbers of individuals with CD.

McGovern DPB, Jewell DP. 2005. Risks and benefits of azathioprine therapy. Gut, 54 (8), pp. 1055-1059. | Show Abstract | Read more

The risk of lymphoma may be increased by about fourfold in patients with inflammatory bowel disease treated with thiopurines. The increased risk could be a result of the medications, the severity of the underlying disease, or a combination of the two.

Chambers WM, Warren BF, Jewell DP, Mortensen NJM. 2005. Cancer surveillance in ulcerative colitis. Br J Surg, 92 (8), pp. 928-936. | Show Abstract | Read more

BACKGROUND: Patients with ulcerative colitis are at a higher risk of developing colorectal cancer than those without the disease. Surveillance programmes are used routinely to detect dysplasia and cancer in patients with ulcerative colitis. However, such programmes are poorly effective. This article discusses possible improvements suggested by recent research. METHODS: Papers relating to cancer associated with ulcerative colitis and surveillance programmes to detect such cancer were identified using Medline searches. Further papers were identified from the reference lists of identified papers. RESULTS: The probability of cancer for all patients with ulcerative colitis regardless of disease extent was 2 per cent at 10 years, 8 per cent at 20 years and 18 per cent at 30 years; the overall prevalence of colorectal cancer in any patient was 3.7 per cent. Indications for colonoscopic surveillance are extensive disease for 8-10 years, especially in those with active inflammation, a family history of colorectal cancer and primary sclerosing cholangitis. Problems affecting surveillance include the diagnosis of dysplasia, difficulty in differentiating 'sporadic' adenomas from a dysplasia-associated lesion or mass, and decision making based on surveillance findings. Molecular genetic and endoscopic advances to alleviate these problems are discussed. CONCLUSION: Rates of detection of dysplasia can be improved by chromoendoscopy. Molecular genetics has the potential to identify patients most at risk of cancer and can differentiate between different types of lesion.

Yang X, Ahmad T, Gogus F, Verity D, Wallace GR, Madanat W, Kanawati CA, Stanford MR, Fortune F, Jewell DP, Marshall SE. 2005. Analysis of the CC chemokine receptor 5 (CCR5)Delta 32 polymorphism in Behcet's disease (vol 31, pg 11, 2004) INTERNATIONAL JOURNAL OF IMMUNOGENETICS, 32 (3), pp. 219-219.

van Heel DA, Ghosh S, Butler M, Hunt KA, Lundberg AMC, Ahmad T, McGovern DPB, Onnie C, Negoro K, Goldthorpe S et al. 2005. Muramyl dipeptide and toll-like receptor sensitivity in NOD2-associated Crohn's disease. Lancet, 365 (9473), pp. 1794-1796. | Show Abstract | Read more

Both NOD2 (CARD15) alleles are mutated in roughly 15% of patients with Crohn's disease, but functional effects are unclear. We analysed the cytokine response of peripheral blood mononuclear cells to muramyl dipeptide (MDP), the ligand for NOD2. MDP induced little TNFalpha or interleukin 1beta, but strong interleukin-8 secretion. MDP also substantially upregulated secretion of TNFalpha and interleukin 1beta induced by toll-like receptor ligands. These effects were abolished by the most common Crohn's NOD2 double mutant genotypes at low nanomolar MDP concentrations, and provide the basis to develop a test of NOD2 functional deficiency. In Crohn's disease, there are defects in neutrophil recruitment driven by NOD2 and interleukin 8 and in cross talk between the NOD2 and toll-like receptor pathways, which suggests that the immune system fails to receive an early priming signal.

Meinzer U, Hugot J-P. 2005. Nod2 and Crohn's disease: many connected highways. Lancet, 365 (9473), pp. 1752-1754. | Read more

McGovern DPB, Hysi P, Ahmad T, van Heel DA, Moffatt MF, Carey A, Cookson WOC, Jewell DP. 2005. Association between a complex insertion/deletion polymorphism in NOD1 (CARD4) and susceptibility to inflammatory bowel disease. Hum Mol Genet, 14 (10), pp. 1245-1250. | Show Abstract | Read more

The identification of the role of genetic variants within NOD2 (CARD15) in Crohn's disease and ulcerative colitis susceptibility highlight the role of the innate immune system in inflammatory bowel disease (IBD) pathogenesis. NOD1 (CARD4) is located on chromosome 7p14.3, in a region of known linkage to IBD and encodes an intracellular bacterial pathogen-associated molecular pattern receptor that is closely related to NOD2. We have identified strong association between haplotypes in the terminal exons of NOD1 and IBD (multi-allelic P = 0.0000003) in a panel of 556 IBD trios. The deletion allele of a complex functional NOD1 indel polymorphism (ND(1) + 32656*1) was significantly associated with early-onset IBD (P = 0.0003) in unrelated cases and controls. ND1 + 32656*1 was also associated with extra-intestinal manifestations of IBD (P = 0.04). These findings in two independent populations provide strong evidence for a role for NOD1 variants in IBD susceptibility and reinforce the role of the innate immune system in IBD pathogenesis.

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European Pubmed Central

Wheeler JMD, Banerjee A, Ahuja N, Jewell DP, Mortensen NJM. 2005. Long-term function after restorative proctocolectomy. Dis Colon Rectum, 48 (5), pp. 946-951. | Show Abstract | Read more

PURPOSE: Early functional outcome after restorative proctocolectomy and formation of an ileoanal pouch is known to be good, but there are minimal data on the long-term function of the pouch. The aim of this study was to look at the long-term functional outcome in patients who had undergone restorative proctocolectomy and formation of an ileoanal pouch. METHODS: A total of 151 consecutive patients (96 males, 55 females) who underwent ileoanal pouch surgery between April 1983 and May 1993 were identified. Functional outcomes from the previous 12 months were appraised by a standardized questionnaire. RESULTS: The median age at surgery was 31 years (range, 6-63 years), with a median follow-up of 142 months (range, 100-221 months). Eighteen patients have had their pouches excised, with another patient being defunctioned. Therefore 19 patients (13 percent) had suffered pouch failure. Altogether, 115 patients were available for follow-up, and 98 patients (85 percent) returned questionnaires. The median pouch-emptying frequency was five times (range, 1-17) during the day and one time (range, 0-6) at night. A total of 74 percent of patients had perfect continence during the day. Most of the patients had no life-style restrictions related to the pouch, and 98 percent of patients would recommend a pouch to others. CONCLUSIONS: Long-term functional outcome after ileoanal pouch surgery is good in most patients. For patients requiring proctocolectomy, ileoanal pouch surgery can now be recommended as an excellent long-term option.

Frenz MB, Dunckley P, Camporota L, Jewell DP, Travis SPL. 2005. Comparison between prospective and retrospective evaluation of Crohn's disease activity index. Am J Gastroenterol, 100 (5), pp. 1117-1120. | Show Abstract | Read more

The Crohn's disease activity index (CDAI) is the most widely used measure of clinical disease activity in patients entered into clinical trials. The prospective nature of the CDAI calculation precludes its use as a clinical assessment tool. We compared the retrospective evaluation of the CDAI with the prospective evaluation in a heterogeneous patient population of 100 patients with Crohn's disease. The correlation between the two assessment methods was good with an r-value of 0.84 (p < 0,0001). There was a tendency of patients with a high retrospective CDAI to have a lower prospective CDAI which is explained by intention to treat. This study shows that a retrospective assisted evaluation of the CDAI is as accurate as the traditional prospective evaluation.

Robertson MD, Bickerton AST, Dennis AL, Vidal H, Jewell DP, Frayn KN. 2005. Enhanced metabolic cycling in subjects after colonic resection for ulcerative colitis. J Clin Endocrinol Metab, 90 (5), pp. 2747-2754. | Show Abstract | Read more

Colonic resection leads to insulin resistance, but the mechanisms are unknown. We used an integrated approach to examine adipose tissue and skeletal muscle metabolism in patients lacking a colon. Ten healthy colectomized patients having undergone surgery for ulcerative colitis and 10 matched control subjects were studied with a hyperinsulinemic-euglycemic clamp to measure insulin sensitivity, an arteriovenous sampling meal tolerance study to measure postprandial substrate flux across adipose tissue and skeletal muscle, and adipose tissue and skeletal muscle biopsies to quantify the expression of genes involved in glucose and lipid metabolism. Colectomized subjects exhibited lower insulin sensitivity (homeostatic model assessment model, 33% reduction, P = 0.03; minimal model, 29% reduction, P = 0.05), elevated aldosterone (9-fold, P = 0.003), leptin (2.2-fold, P = 0.03), and an increased rate of nonesterified fatty acid and glycerol release from adipose tissue (P = 0.02) especially in the late postprandial period. The uptake of fatty acids into muscle was also significantly increased (P = 0.007), as were muscle CD36 and LPL mRNA expression compared with controls. In adipose tissue, hormone-sensitive lipase mRNA expression was increased (P = 0.015), whereas peroxisome proliferator-activated receptor-gamma expression was decreased (P = 0.02), as was that of CD36 (P = 0.001). In this study, alterations in fatty acid metabolism after colonic resection altered may have contributed to the impairment of insulin sensitivity.

Ahmad T, Zhang L, Gogus F, Verity D, Wallace G, Madanat W, Fayyad F, James T, Neville M, Kanawati C et al. 2005. CARD15 polymorphisms in Behçet's disease. Scand J Rheumatol, 34 (3), pp. 233-237. | Show Abstract | Read more

BACKGROUND: Behçet's disease (BD) is a chronic multi-system inflammatory disorder of unknown aetiology, which shares many features of the inflammatory bowel diseases (IBDs). CARD15 has recently been identified as the first susceptibility gene in Crohn's disease (CD). OBJECTIVE: Given certain clinical and pathological similarities between CD and BD, and recent evidence of linkage of BD to the CARD15 genomic region, the aim of this study was to investigate the role of CARD15 variants in determining susceptibility to BD. METHODS: We studied 374 BD patients from three ethnically homogeneous cohorts (white English, Turkish, and Middle Eastern Arabs of Palestinian and Jordanian descent). Mutation detection of CARD15 was performed by direct sequencing in a subset of patients from each group and the identified variants were genotyped in the complete cohorts. Case-control analyses were carried out with additional stratification by the BD-associated allele, HLA-B*51. RESULTS: Mutation detection identified six previously described CARD15 polymorphisms at a frequency of > 3%. Additionally, two of the three CD-associated polymorphisms were present, but at low frequency. The frequency of haplotypes, constructed from nine genotyped polymorphisms, demonstrated significant variation between different ethnic groups. However, case-control analyses demonstrated no association between the CARD15 polymorphisms and susceptibility to BD, irrespective of HLA-B*51 status. CONCLUSION: CARD15 variant alleles are not associated with susceptibility to BD. Other shared loci, currently under investigation, may determine susceptibility to both CD and BD.

Hunt KA, McGovern DPB, Kumar PJ, Ghosh S, Travis SPL, Walters JRF, Jewell DP, Playford RJ, van Heel DA. 2005. A common CTLA4 haplotype associated with coeliac disease. Eur J Hum Genet, 13 (4), pp. 440-444. | Show Abstract | Read more

Coeliac disease is a common enteropathy with a strong inherited risk characterised by dietary wheat, rye and barley induced T-cell activation. Although there is replicated linkage to 2q33, results are inconsistent from association studies of the most promising candidate genes: the CD28/CTLA4/ICOS cluster. CTLA4 plays a key role in regulating T lymphocyte mediated inflammatory responses, and variants in the 3' region influence development of diabetes and thyroid disease. We genotyped CTLA4 variants (-1722 C/T, -658 T/C, -318 C/T, +49 A/G, +1822 C/T, CT60 A/G) to tag all common haplotypes (>5% frequency) and an ICOS variant (IVS+173 C/T) in 340 white UK Caucasian coeliac disease cases. Strict ascertainment criteria for coeliac cases required both villous atrophy at diagnosis and positive serology. In total, 973 healthy controls were available for SNP, and 705 for CTLA4 haplotype, based association analyses. Coeliac disease showed weak association with the CTLA4 +1822T (P=0.019) and CT60 G (P=0.047) alleles. Strong association was seen with a common CTLA4 haplotype (P=0.00067, odds ratio 1.41) of frequency 32.7% in coeliac disease and 25.5% in healthy controls. A common CTLA4 haplotype shows strong association with coeliac disease, and contains multiple alleles reported to affect immunological function. Loss of tolerance to dietary antigens in coeliac disease may be mediated in part by heritable variants in co-signalling genes regulating T-cell responses.

Cummings JRF, Herrlinger KR, Travis SPL, Gorard DA, McIntyre AS, Jewell DP. 2005. Oral methotrexate in ulcerative colitis. Aliment Pharmacol Ther, 21 (4), pp. 385-389. | Show Abstract | Read more

BACKGROUND: We performed an audit of methotrexate for ulcerative colitis, because efficacy is unclear. Aim : To investigate the role of methotrexate in the management of ulcerative colitis. METHODS: Patients with ulcerative colitis treated with oral methotrexate at the inflammatory bowel disease clinics of Oxford and Wycombe General Hospital, UK, were evaluated. Efficacy was defined by remission (complete steroid withdrawal for >3 months) and response (good, partial or nil, proportionate reduction of steroids). RESULTS: There were 50 patients (42 ulcerative colitis alone; eight had rheumatoid arthritis associated with ulcerative colitis and were analysed separately). Indications for methotrexate in ulcerative colitis alone were azathioprine intolerance (31 of 42) and lack of benefit from azathioprine (11 of 42). The mean dose of methotrexate in ulcerative colitis alone was 19.9 mg/week for a median of 30 weeks (range: 7-395). Remission occurred in 42%. The response was good in 54% and partial in 18%. Side-effects occurred in 23%; 10% stopped treatment because of side-effects. Of those treated with methotrexate because of treatment failure with azathioprine, three of 11 achieved remission, but four came to colectomy within 90 days of starting methotrexate. The colitis remained in remission in seven of eight of those with RA treated with methotrexate and ulcerative colitis (mean dose 15.0 mg/week). CONCLUSION: Oral methotrexate (approximately 20 mg/week) is well-tolerated and moderately effective in steroid-dependent or steroid-refractory patients with ulcerative colitis.

Cummings JRF, Jewell DP. 2005. Clinical implications of inflammatory bowel disease genetics on phenotype. Inflamm Bowel Dis, 11 (1), pp. 56-61. | Show Abstract | Read more

The genetic revolution has been with us for over a decade now. We have yet to see this impacting the care of patients except in a few rare examples. However, progress has been made in the field of inflammatory bowel disease (IBD) that could soon be translated to the bedside, both in terms of predicting the disease course as well as in the response to therapy. IBD traditionally has been classified as ulcerative colitis and Crohn's disease, with 10% of patients classified as having indeterminate colitis on the basis of clinical, radiologic, endoscopic, and histologic findings. However, this traditional view is now being challenged. Developments in genetics and serological markers, as well as an appreciation of the disease course, have led to an understanding that IBD is a heterogeneous group of diseases with some common genetic and environmental factors but different clinical manifestations in terms of disease behavior, location, and response to treatment. Data are now emerging that may allow us to more objectively select the correct therapy for the correct patient, rather than the current approach, which is based on clinical experience backed up by a less-than-perfect evidence base. In this article, we will review the evidence for this.

Jewell DPA, Thompson IW, Sullivan BA, Bondeson J. 2004. Reversible focal myositis in a patient taking venlafaxine. Rheumatology (Oxford), 43 (12), pp. 1590-1593. | Read more

Singh B, McC Mortensen NJ, Jewell DP, George B. 2004. Perianal Crohn's disease. Br J Surg, 91 (7), pp. 801-814. | Show Abstract | Read more

BACKGROUND: The management of perianal Crohn's disease is difficult. A wide variety of treatment options exist although few are evidence based. METHODS: A search was conducted using the National Library of Medicine for articles on perianal Crohn's disease and its incidence, classification, assessment and management. RESULTS AND CONCLUSION: Perianal Crohn's disease can manifest as skin tags, ulcers, fissures, abscesses, fistulas or stenoses. Improved radiological imaging with endoanal anal ultrasonography and magnetic resonance imaging has improved its assessment and may be used to predict outcome after surgery. Many treatment options exist. During acute complications they are generally aimed at resolving the immediate problem and limiting damage to anal and perianal tissues; this may be a 'bridge' to definitive treatment. The likelihood of success of definitive treatment must be weighed against the risk of complications, especially faecal incontinence.

Yap LM, Ahmad T, Jewell DP. 2004. The contribution of HLA genes to IBD susceptibility and phenotype. Best Pract Res Clin Gastroenterol, 18 (3), pp. 577-596. | Show Abstract | Read more

The human leukocyte antigen (HLA) region located on chromosome 6p encodes the highly polymorphic, classical class I and II genes essential for normal lymphocyte function; it also encodes a further 224 genes. Many early studies investigating this region were limited by small sample size, poor statistical methodology, population stratification and variable disease definition. Although more recent studies have improved study design, investigators are still challenged by the complex patterns of linkage disequilibrium across this gene-dense region, and by the disease heterogeneity characteristic of all genetically complex disorders. However, a number of important observations have emerged from recent studies: (1) the HLA harbours gene(s) that determine susceptibility to colonic inflammation in both ulcerative colitis (UC) and Crohn's disease (CD); (2) most of the specific associations with UC and CD appear to differ; (3) associations between different ethnic groups differ; (4) markers in the HLA might predict the course of disease and the development of complications, notably the extraintestinal manifestations of disease.

Low JH, Williams FA, Yang X, Cullen S, Colley J, Ling KL, Armuzzi A, Ahmad T, Neville MJ, Dechairo BM et al. 2004. Inflammatory bowel disease is linked to 19p13 and associated with ICAM-1. Inflamm Bowel Dis, 10 (3), pp. 173-181. | Show Abstract | Read more

Genome-wide scans have implicated several susceptibility loci, but linkage of 19p13 (IBD6) to Crohn's disease (CD) has not been fully replicated. We report a replication study of IBD6 in a UK Caucasian population. Two hundred eighty-four affected sibling pairs from 234 families were used for the linkage study. Linkage between IBD6 linkage and CD was replicated (LOD score = 1.59). Two candidate genes (DDXL and ICAM-1) within the IBD6 locus were examined in a case/control study with a total of 228 CD and 243 ulcerative colitis (UC) patients and 407 healthy controls. No association to either UC or CD was found in three novel intronic single nucleotide polymorphisms (SNPs) in DDXL. For ICAM-1, a significant association was found between K469 homozygosity and CD overall (39.9% vs 29.4%; Pc = 0.0096) and between E469 and fistulating disease (21.8% vs 10.0%, Pc = 0.030). In the UC group, limited disease extent was associated with homozygosity of the G241 allele (82.7% vs 64.7%, Pc = 0.0040). These data support linkage for CD at 19p13 and suggest that the amino acid polymorphisms in ICAM-1 may be associated with IBD.

Owens DW, Wilson NJ, Hill AJM, Rugg EL, Porter RM, Hutcheson AM, Quinlan RA, van Heel D, Parkes M, Jewell DP et al. 2004. Human keratin 8 mutations that disturb filament assembly observed in inflammatory bowel disease patients. J Cell Sci, 117 (Pt 10), pp. 1989-1999. | Show Abstract | Read more

We have identified miss-sense mutations in keratin 8 in a subset of patients with inflammatory bowel disease (Crohn disease and ulcerative colitis). Inflammatory bowel diseases are a group of disorders that are polygenic in origin and involve intestinal epithelial breakdown. We investigated the possibility that these keratin mutations might contribute to the course of the disease by adversely affecting the keratin filament network that provides mechanical support to cells in epithelia. The mutations (Gly62 to Cys, Ile63 to Val and Lys464 to Asn) all lie outside the major mutation hotspots associated with severe disease in epidermal keratins, but using a combination of in vitro and cell culture assays we show that they all have detrimental effects on K8/K18 filament assembly in vitro and in cultured cells. The G62C mutation also gives rise to homodimer formation on oxidative stress to cultured intestinal epithelial cells, and homodimers are known to be polymerization incompetent. Impaired keratin assembly resulting from the K8 mutations found in some inflammatory bowel disease patients would be predicted to affect the maintenance and re-establishment of mechanical resilience in vivo, as required during keratin cytoskeleton remodeling in cell division and differentiation, which may lead to epithelial fragility in the gut. Simple epithelial keratins may thus be considered as candidates for genes contributing to a risk of inflammatory bowel disease.

Langmead L, Feakins RM, Goldthorpe S, Holt H, Tsironi E, De Silva A, Jewell DP, Rampton DS. 2004. Randomized, double-blind, placebo-controlled trial of oral aloe vera gel for active ulcerative colitis. Aliment Pharmacol Ther, 19 (7), pp. 739-747. | Show Abstract | Read more

BACKGROUND: The herbal preparation, aloe vera, has been claimed to have anti-inflammatory effects and, despite a lack of evidence of its therapeutic efficacy, is widely used by patients with inflammatory bowel disease. AIM: To perform a double-blind, randomized, placebo-controlled trial of the efficacy and safety of aloe vera gel for the treatment of mildly to moderately active ulcerative colitis. METHODS: Forty-four evaluable hospital out-patients were randomly given oral aloe vera gel or placebo, 100 mL twice daily for 4 weeks, in a 2 : 1 ratio. The primary outcome measures were clinical remission (Simple Clinical Colitis Activity Index </= 2), sigmoidoscopic remission (Baron score </= 1) and histological remission (Saverymuttu score </= 1). Secondary outcome measures included changes in the Simple Clinical Colitis Activity Index (improvement was defined as a decrease of >/= 3 points; response was defined as remission or improvement), Baron score, histology score, haemoglobin, platelet count, erythrocyte sedimentation rate, C-reactive protein and albumin. RESULTS: Clinical remission, improvement and response occurred in nine (30%), 11 (37%) and 14 (47%), respectively, of 30 patients given aloe vera, compared with one (7%) [P = 0.09; odds ratio, 5.6 (0.6-49)], one (7%) [P = 0.06; odds ratio, 7.5 (0.9-66)] and two (14%) [P < 0.05; odds ratio, 5.3 (1.0-27)], respectively, of 14 patients taking placebo. The Simple Clinical Colitis Activity Index and histological scores decreased significantly during treatment with aloe vera (P = 0.01 and P = 0.03, respectively), but not with placebo. Sigmoidoscopic scores and laboratory variables showed no significant differences between aloe vera and placebo. Adverse events were minor and similar in both groups of patients. CONCLUSION: Oral aloe vera taken for 4 weeks produced a clinical response more often than placebo; it also reduced the histological disease activity and appeared to be safe. Further evaluation of the therapeutic potential of aloe vera gel in inflammatory bowel disease is needed.

Yang X, Cullen SN, Li JH, Chapman RW, Jewell DP. 2004. Susceptibility to primary sclerosing cholangitis is associated with polymorphisms of intercellular adhesion molecule-1. J Hepatol, 40 (3), pp. 375-379. | Show Abstract | Read more

BACKGROUND/AIMS: Intercellular adhesion molecule-1 (ICAM-1, CD54) gene polymorphisms have been implicated in the susceptibility to a range of inflammatory diseases, including inflammatory bowel disease (IBD). Primary sclerosing cholangitis (PSC) is an immune-mediated chronic cholestatic liver disease associated with IBD. ICAM-1 is expressed on proliferating bile ducts and interlobular bile ducts in late stage PSC and serum levels of soluble intercellular adhesion molecules are increased in PSC. The aim of this study was to analyse ICAM-1 gene polymorphisms in PSC patients. METHODS: In this study, 104 patients with PSC and 213 healthy controls were recruited from Oxfordshire Caucasians. PCR with sequence-specific primers (PCR-SSP) was used to detect both ICAM-1 biallelic polymorphisms G241R and K469E. The results were controlled for the HLA haplotypes associated with PSC. RESULTS: The E/E frequency of K469E in PSC was 12% (12/104), significantly lower than that in controls (24%, 51/213;P = 0.009; Pc = 0.02; OR, 0.41). The occurrence of the haplotype G241-E469/G241-E469 in PSC was 4% (4/104), significantly lower than the control group (13%, 28/213; P = 0.01; Pc = 0.04; OR, 0.26). There was no difference between PSC and control groups in the frequencies of the genotype R241G or in allele frequencies of K469E. CONCLUSIONS: The E469E homozygote status for ICAM-1 is associated with protection against PSC.

McGovern DPB, Van Heel DA, Negoro K, Ahmad T, Jewell DP. 2003. Further evidence of IBD5/CARD15 (NOD2) epistasis in the susceptibility to ulcerative colitis. Am J Hum Genet, 73 (6), pp. 1465-1466. | Read more

Ahmad T, Armuzzi A, Neville M, Bunce M, Ling K-L, Welsh KI, Marshall SE, Jewell DP. 2003. The contribution of human leucocyte antigen complex genes to disease phenotype in ulcerative colitis. Tissue Antigens, 62 (6), pp. 527-535. | Show Abstract | Read more

Linkage and association studies implicate the human leucocyte antigen (HLA) region in genetic susceptibility to ulcerative colitis (UC). However, associations with specific variants have been inconsistent, even within defined ethnic groups. A genetic basis for the disease heterogeneity of UC may account for these discrepant findings from studies in unselected populations. Here, we examine the contribution of the HLA region to the clinical phenotype of UC. We studied 321 accurately phenotyped patients recruited from a single UK centre, with a median follow-up time of 15 years. Individuals were genotyped for 340 polymorphisms constructed into 25 gene-specific allelic haplotypes between HLA-A and Tapasin. Data were analysed with respect to age of onset, disease extent and severity. Strongest association with overall susceptibility was identified with HLA-DRB1 alleles replicating previous studies (DRB1*0103, DRB1*1502 and DRB1*0401). We report a novel association with homozygosity of a tumour necrosis factor (TNF) promoter haplotype (TNF-1031T, -863C, -857C, -380G, -308G and -238G) and distal disease extent that does not extend with time (distal vs total 40.9 vs 25.7%; RR = 2.0; 95% CI 1.23-3.24). We confirm the association of DRB1*0103 with total disease and/or disease requiring colectomy and further demonstrate that DRB1*0103 is associated with shorter time to surgery. Genes in the HLA play a role in modifying disease phenotype. Further studies are required to dissect how these genes functionally interact with each other and with environmental factors to determine clinical patterns of disease

van Heel DA, Dechairo BM, Dawson G, McGovern DPB, Negoro K, Carey AH, Cardon LR, Mackay I, Jewell DP, Lench NJ. 2003. The IBD6 Crohn's disease locus demonstrates complex interactions with CARD15 and IBD5 disease-associated variants. Hum Mol Genet, 12 (20), pp. 2569-2575. | Show Abstract | Read more

Genetic studies in inflammatory bowel disease have identified multiple susceptibility loci, whose relevance depends critically on verification in independent cohorts. Genetic variants associated with Crohn's disease have now been identified on chromosomes 5 (IBD5/5q31 risk haplotype) and 16 (IBD1 locus, CARD15/NOD2 mutations). Stratification of genome-wide linkage analyses by disease associated variants is now possible, offering both increased power for identification of other loci and improved understanding of genetic mechanisms. We performed a genome-wide scan of 137 Crohn's disease affected relative pairs from 112 families. Multipoint non-parametric linkage analyses were performed, with further stratification of affection status by common CARD15 mutations and the IBD5 haplotype. We verified linkage of Crohn's disease to regions on chromosome 3 (P=0.0009) and X (P=0.001) in our cohort. Linkage to chromosome 16 (IBD1) was observed in Crohn's disease pairs not possessing common CARD15 mutations (P=0.0007), approximately 25 cM q telomeric of CARD15. Evidence for linkage to chromosome 19 (IBD6) was observed in Crohn's disease pairs not possessing CARD15 mutations (P=0.0001), and in pairs possessing one or two copies of the IBD5 risk haplotype (P=0.0005), with significant evidence for genetic heterogeneity and epistasis, respectively. These analyses demonstrate the complex genetic basis to Crohn's disease, and show that the discovery of disease-causing variants may be used to aid identification of further susceptibility loci in complex disease.

Sonwalkar SA, James RM, Ahmad T, Zhang L, Verbeke CS, Barnard DL, Jewell DP, Hull MA. 2003. Fulminant Crohn's colitis after allogeneic stem cell transplantation. Gut, 52 (10), pp. 1518-1521. | Show Abstract | Read more

We report a case of fulminant Crohn's colitis that occurred following non-myeloablative allogeneic stem cell transplantation for Hodgkin's lymphoma. Adoptive transfer of inflammatory bowel disease by haematopoietic cells is recognised in several animal models of inflammatory bowel disease and remission of Crohn's disease has been reported in patients who have received a bone marrow transplant. However, adoptive transfer of Crohn's disease susceptibility leading to phenotypic manifestation of the disease after transplantation has not been previously reported. Having ruled out an infective cause of a colitis in this case, we speculated that adoptive transfer of Crohn's disease may have occurred and performed a genetic analysis of known susceptibility loci for significant donor-recipient mismatches. The donor and recipient had several haplotype mismatches in HLA class III genes at the IBD3 locus. In addition, the donor (but not the recipient) had a polymorphism of the 5' UTR of NOD2/CARD15 that may be associated with Crohn's disease. This case highlights the question of whether adoptive transfer of Crohn's disease can occur between allogeneic stem cell transplant donor and recipient, in a similar fashion to that reported for other autoimmune diseases. This report should also stimulate debate regarding the need for stem cell transplant donor screening for inflammatory bowel disease.

Armuzzi A, Ahmad T, Ling K-L, de Silva A, Cullen S, van Heel D, Orchard TR, Welsh KI, Marshall SE, Jewell DP. 2003. Genotype-phenotype analysis of the Crohn's disease susceptibility haplotype on chromosome 5q31. Gut, 52 (8), pp. 1133-1139. | Show Abstract | Read more

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 (p(c)=0.002; relative risk (RR) 2.0). Genotype-phenotype analyses demonstrated that this association was particularly strong in patients with perianal disease (p(c)=0.0005; RR 1.7), especially in individuals homozygous for this haplotype (p(c)=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.

Leong RWL, Armuzzi A, Ahmad T, Wong ML, Tse P, Jewell DP, Sung JJY. 2003. NOD2/CARD15 gene polymorphisms and Crohn's disease in the Chinese population. Aliment Pharmacol Ther, 17 (12), pp. 1465-1470. | Show Abstract | Read more

BACKGROUND: Crohn's disease affects people world-wide, but the incidence in Asia is lower than in Western countries. This difference may be due to genetic and/or environmental factors. Three single nucleotide polymorphisms (SNPs) of the NOD2/CARD15 gene have been identified to be independently associated with the development of Crohn's disease in Caucasians. Whether these SNPs are involved in the pathogenesis of Crohn's disease in the Chinese population is unknown. AIM: To determine if NOD2/CARD15 gene polymorphisms are found in Chinese patients with Crohn's disease. METHODS: Sixty-five consecutive Chinese Crohn's disease patients had genotyping performed using sequence-specific PCR directed against the wild-type and the Arg702Trp, Gly908Arg and 3020insC variants of the NOD2/CARD15 gene. Controls consisted of 63 patients with ulcerative colitis and 70 patients with dyspepsia. RESULTS: None of the patients with Crohn's disease had heterozygous or homozygous SNP variants. Similarly none of the ulcerative colitis or dyspeptic controls had these SNPs. CONCLUSION: The three previously described SNPs associated with the development of Crohn's disease in Caucasians are not found in Chinese patients with Crohn's disease.

Robertson MD, Parkes M, Warren BF, Ferguson DJP, Jackson KG, Jewell DP, Frayn KN. 2003. Mobilisation of enterocyte fat stores by oral glucose in humans. Gut, 52 (6), pp. 834-839. | Show Abstract | Read more

BACKGROUND AND AIMS: When a high fat oral load is followed several hours later by further ingestion of nutrients, there is an early postprandial peak in plasma triacylglycerol (TG). The aim of this study was to investigate the location and release of lipid from within the gastrointestinal tract. METHODS: Ten healthy patients undergoing oesopho-gastro-duodenoscopy (OGD) were recruited. At t=0, all patients consumed a 50 g fat emulsion and at t=5 hours they consumed either water or a 38 g glucose solution. OGD was performed at t=6 hours and jejunal biopsy samples were evaluated for fat storage. A subgroup of five subjects then underwent a parallel metabolic study in which postprandial lipid and hormone measurements were taken during an identical two meal protocol. RESULTS: Following oral fat at t=0, samples from patients that had subsequently ingested glucose exhibited significantly less staining for lipid within the mucosa and submucosa of the jejunum than was evident in patients that had consumed only water (p=0.028). There was also less lipid storage within the cytoplasm of enterocytes (p=0.005) following oral glucose. During the metabolic study, oral glucose consumed five hours after oral fat resulted in a postprandial peak in plasma TG, chylomicron-TG, and apolipoprotein B48 concentration compared with oral water. CONCLUSION: After a fat load, fat is retained within the jejunal tissue and released into plasma following glucose ingestion, resulting in a peak in chylomicron-TG which has been implicated in the pathogenesis of atherosclerosis.

Robertson MD, Currie JM, Morgan LM, Jewell DP, Frayn KN. 2003. Prior short-term consumption of resistant starch enhances postprandial insulin sensitivity in healthy subjects. Diabetologia, 46 (5), pp. 659-665. | Show Abstract | Read more

AIMS/HYPOTHESIS: Diets rich in insoluble-fibre are linked to a reduced risk of both diabetes and cardiovascular disease; however, the mechanism of action remains unclear. The aim of this study was to assess whether acute changes in the insoluble-fibre (resistant starch) content of the diet would have effects on postprandial carbohydrate and lipid handling. METHODS: Ten healthy subjects consumed two identical, low-residue diets on separate occasions for 24 h (33% fat; <2 g dietary fibre). Of the diets one was supplemented with 60 g resistant starch (Novelose 260). On the following morning a fibre-free meal tolerance test (MTT) was carried out (59 g carbohydrate; 21 g fat; 2.1 kJ) and postprandial insulin sensitivity (SI(ORAL)) assessed using a minimal model approach. RESULTS: Prior resistant starch consumption led to lower postprandial plasma glucose (p=0.037) and insulin (p=0.038) with a higher insulin sensitivity(44+/-7.5 vs 26+/-3.5 x 10(-4) dl kg(-1) min(-1) per micro Uml(-1); p=0.028) and C-peptide-to-insulin molar ratio (18.7+/-6.5 vs 9.7+/-0.69; p=0.017). There was no effect of resistant starch consumption on plasma triacylglycerol although non-esterified fatty acid and 3-hydroxybutyrate levels were suppressed 5 h after the meal tolerance test. CONCLUSION: Prior acute consumption of a high-dose of resistant starch enhanced carbohydrate handling in the postprandial period the following day potentially due to the increased rate of colonic fermentation.

Negoro K, McGovern DPB, Kinouchi Y, Takahashi S, Lench NJ, Shimosegawa T, Carey A, Cardon LR, Jewell DP, van Heel DA. 2003. Analysis of the IBD5 locus and potential gene-gene interactions in Crohn's disease. Gut, 52 (4), pp. 541-546. | Show Abstract | Read more

BACKGROUND AND AIMS: Genetic variation in the chromosome 5q31 cytokine cluster (IBD5 risk haplotype) has been associated with Crohn's disease (CD) in a Canadian population. We studied the IBD5 risk haplotype in both British and Japanese cohorts. Disease associations have also been reported for CARD15/NOD2 and TNF variants. Complex interactions between susceptibility loci have been shown in animal models, and we tested for potential gene-gene interactions between the three CD associated loci. METHODS: Family based association analyses were performed in 457 British families (252 ulcerative colitis, 282 CD trios) genotyped for the IBD5 haplotype, common CARD15, and TNF-857 variants. To test for possible epistatic interactions between variants, transmission disequilibrium test analyses were further stratified by genotype at other loci, and novel log linear analyses were performed using the haplotype relative risk model. Case control association analyses were performed in 178 Japanese CD patients and 156 healthy controls genotyped for the IBD5 haplotype. RESULTS: The IBD5 haplotype was associated with CD (p=0.007), but not with UC, in the British Caucasian population. The CARD15 variants and IBD5 haplotype showed additive main effects, and in particular no evidence for epistatic interactions was found. Variants from the IBD5 haplotype were extremely rare in the Japanese. CONCLUSIONS: The IBD5 risk haplotype is associated with British CD. Genetic variants predisposing to CD show heterogeneity and population specific differences.

Ahmad T, Neville M, Marshall SE, Armuzzi A, Mulcahy-Hawes K, Crawshaw J, Sato H, Ling K-L, Barnardo M, Goldthorpe S et al. 2003. Haplotype-specific linkage disequilibrium patterns define the genetic topography of the human MHC. Hum Mol Genet, 12 (6), pp. 647-656. | Show Abstract | Read more

Detailed knowledge of linkage disequilibrium (LD) is regarded as a prerequisite for population-based disease gene mapping. Variable patterns across the human genome are now recognized, both between regions and populations. Here, we demonstrate that LD may also vary within a genomic region in a haplotype-specific manner. In 864 Caucasian unrelated individuals, we describe haplotype-specific LD patterns across the human MHC by the construction of gene-specific allelic haplotypes at 25 loci between HLA-A and Tapasin. Strong and extensive LD is found across both common and rare haplotypes, suggesting that haplotype structure is influenced by factors other than genetic drift, including both selection and differential haplotype recombination. Knowledge of haplotype-specific LD in the HLA may explain the apparent discrepant data from previous studies of global LD, help delineate key areas in mapping HLA-associated diseases and, together with recombination data, provide valuable information about a population's demographic history and the selective pressures operating on it.

Ahmad T, Wallace GR, James T, Neville M, Bunce M, Mulcahy-Hawes K, Armuzzi A, Crawshaw J, Fortune F, Walton R et al. 2003. Mapping the HLA association in Behçet's disease: a role for tumor necrosis factor polymorphisms? Arthritis Rheum, 48 (3), pp. 807-813. | Show Abstract | Read more

OBJECTIVE: Experimental evidence suggests that inappropriate regulation of tumor necrosis factor alpha (TNF alpha) may play a role in the pathogenesis of Behçet's disease (BD). This is supported by recent reports highlighting the efficacy of anti-TNF alpha agents in the treatment of this disease. The TNF gene is encoded in the class III region of the HLA complex adjacent to HLA-B. This genetic proximity to a gene that is already widely implicated in disease susceptibility led us to investigate the association between TNF promoter polymorphisms and susceptibility to BD. METHODS: We studied 133 UK white Caucasoid patients with BD and 354 healthy controls. We attempted to dissect the contribution of individual polymorphisms in this gene-dense region by linkage disequilibrium mapping across 6 adjacent genes. RESULTS: We report a novel association with the TNF promoter allele TNF-1031C. Subsequent analysis identified 2 extended HLA haplotypes associated with BD. One of them contained the previously recognized susceptibility gene HLA-B*51, while the other was defined by HLA-B*5701. Both of these haplotypes contained the TNF promoter polymorphism -1031C, an allele that was associated with disease even in individuals who did not carry either HLA-B*51 or HLA-B*5701. CONCLUSION: The TNF-1031C allele is independently associated with susceptibility to BD in Caucasoid patients. Further studies will be required to determine the functional effects of this polymorphism, its influence in disease pathogenesis, and its role in other ethnic groups.

Roussomoustakaki M, Koutroubakis I, Vardas EM, Dimoulios P, Kouroumalis EA, Baritaki S, Koutsoudakis G, Krambovitis E. 2003. NOD2 insertion mutation in a Cretan Crohn's disease population. Gastroenterology, 124 (1), pp. 272-273. | Read more

Hyde GM, Jewell DP, Warren BF. 2002. Histological changes associated with the use of intravenous cyclosporin in the treatment of severe ulcerative colitis may mimic dysplasia. Colorectal Dis, 4 (6), pp. 455-458. | Show Abstract | Read more

BACKGROUND: During six years experience of intravenous cyclosporin (i.v. Cy) for severe ulcerative colitis we have noted that changes of villous architecture and epithelial regeneration occur even when the disease fails to enter clinical remission and colectomy is required. OBJECTIVE: To describe the histological changes in patients who received i.v. Cy and steroids compared with those treated with i.v. steroids alone. PATIENTS AND METHODS: Two groups of histological sections were reviewed. The first group was of 23 colectomy specimens from patients who had been treated with i.v. Cy and steroids. For 11 patients pre-Cy histological sections were available. The second group was of 10 colectomy specimens from patients who had received i.v. steroids alone. Biopsies were scored for their histological disease activity (HDAI), villous architecture and epithelial regeneration. The HDAI assesses the degree of acute and chronic inflammation. RESULTS: The post-Cy group had higher median scores for villous architecture and epithelial regeneration compared to the pre-Cy and poststeroid groups. For the patients where both pre- and post-Cy histological sections were available 63% increased their villous score post-Cy and 82% increased their epithelial regeneration score post-Cy. CONCLUSION: Although villous transformation and epithelial regeneration may be seen in UC they are more frequent and more severe in those patients who received i.v. Cy and i.v. steroids, compared to controls who received i.v. steroids alone. These histological changes may mimic dysplasia. Increased awareness of this potential mimic of dysplasia is crucial for patient management.

Fraser AG, Warren BF, Chandrapala R, Jewell DP. 2002. Microscopic colitis: a clinical and pathological review. Scand J Gastroenterol, 37 (11), pp. 1241-1245. | Read more

Mitchell SA, Thyssen M, Orchard TR, Jewell DP, Fleming KA, Chapman RW. 2002. Cigarette smoking, appendectomy, and tonsillectomy as risk factors for the development of primary sclerosing cholangitis: a case control study. Gut, 51 (4), pp. 567-573. | Show Abstract | Read more

BACKGROUND AND AIMS: The strong clinical association between primary sclerosing cholangitis (PSC) and ulcerative colitis (UC) suggests common factors in their pathogenesis. Smoking, previous appendectomy, and tonsillectomy have been associated with a decreased risk of developing UC. In this study, our aim was to examine these risk factors in patients with PSC with and without underlying inflammatory bowel disease (IBD). METHODS: The smoking habits and history of previous appendectomy and/or tonsillectomy of 170 patients with PSC, 41 without underlying IBD, 170 patients with UC but normal liver function tests, and 170 age and sex matched community controls were obtained by questionnaire. RESULTS: A total of 112 PSC patients (66%) had never smoked compared with 66 controls (39%). Only 12 PSC patients (7%) were current smokers versus 43 controls (25%). The resultant odds ratio of having PSC was 0.17 (95% confidence interval (CI) 0.08-0.35) among current smokers and 0.33 (95% CI 0.21-0.52) among ever (former+current) smokers. Among former smokers, the odds of having PSC were also significantly decreased (odds ratio 0.45, 95% CI 0.26-0.73; p<0.05). In the subgroup of PSC patients without IBD, only 5% were current smokers versus 26% of matched controls, and never smokers were overrepresented (68% v 37%). The rate of previous appendectomy was similar in all three study groups (14%, 12%, and 13%) but the frequency of tonsillectomy was reduced in the PSC group (21% v 31%; p=0.05). CONCLUSION: PSC, like UC, is a disease of non-smokers as the odds of having PSC was significantly decreased among current and former smokers. The association between non-smoking and PSC was independent of whether the PSC patient had underlying IBD. Previous tonsillectomy but not appendectomy may also be associated with a decreased risk of PSC but this warrants further study.

Jewell DP. 2002. Treatment of Crohn's disease--the new era. Dig Liver Dis, 34 (10), pp. 689-691. | Read more

Simmons J, Jewell DP. 2002. Infliximab for ulcerative colitis. Dig Liver Dis, 34 (9), pp. 616-618. | Read more

Orchard TR, Chua CN, Ahmad T, Cheng H, Welsh KI, Jewell DP. 2002. Uveitis and erythema nodosum in inflammatory bowel disease: clinical features and the role of HLA genes. Gastroenterology, 123 (3), pp. 714-718. | Show Abstract | Read more

BACKGROUND & AIMS: There are few systematic studies on the natural history or immunogenetic associations of erythema nodosum (EN) or ocular inflammation in inflammatory bowel disease (IBD), but they are reportedly more common in patients with other extraintestinal manifestations (EIMs), particularly arthritis. Immunogenetic associations have previously been described in IBD arthritis and in EN associated with sarcoidosis. This study examined the clinical features and HLA-B, DR, and tumor necrosis factor alpha (TNF-alpha) associations of ocular inflammation and EN and their clinical and immunogenetic relationship to arthritis in IBD. METHODS: Details of EN and ocular inflammation were gathered by case-note review and questionnaire in 976 ulcerative colitis patients and 483 Crohn's patients. Sequence-specific PCR typing for polymorphisms in HLA-B, DR, and TNF-alpha was performed in 39 EN and 40 ocular patients. Results were compared with 490 IBD controls without EIMs, 38 patients with type 1 and 31 with type 2 peripheral arthritis, and 16 AS patients. RESULTS: EN and ocular inflammation were more common in women, were associated with IBD relapse, and recurred in approximately 30% of patients. They occurred more commonly with arthritis and AS than expected by chance. Ocular inflammation was strongly associated with HLA-B*27, B*58, and HLA-DRB1*0103. There is a weak association between EN and HLA-B*15 but a strong association with the -1031 TNF-alpha. CONCLUSIONS: EN, uveitis, and arthritis associated with IBD occur together commonly. They are associated with genes in the HLA region, and linkage disequilibrium between these genes may account for the clinical picture of overlapping but independent clinical manifestations.

van Heel DA, McGovern DPB, Cardon LR, Dechairo BM, Lench NJ, Carey AH, Jewell DP. 2002. Fine mapping of the IBD1 locus did not identify Crohn disease-associated NOD2 variants: implications for complex disease genetics. Am J Med Genet, 111 (3), pp. 253-259. | Show Abstract | Read more

Crohn disease (CD) is a chronic relapsing inflammatory condition of the gastrointestinal tract. Recently, polymorphisms in NOD2 (CARD15), a gene mapping to the chromosome 16 IBD1 susceptibility locus, have been associated with susceptibility to CD. One group identified the gene by using classic positional cloning methods. Here, we report linkage and fine mapping analyses using 27 microsatellite markers encompassing the IBD1 susceptibility locus in 131 CD affected sibling pairs, and a simplex family cohort. No evidence for linkage was observed, and microsatellite markers close to NOD2 did not show association. However, significant association was confirmed in 294 CD trios for the NOD2 variants Arg702Trp and Leu1007fsinsC. Our fine mapping study of the IBD1 locus did not enable us to identify NOD2 as a CD gene, despite the presence of association with disease-causing alleles. This study illustrates the difficulties facing microsatellite linkage and linkage disequilibrium mapping methods for identifying disease genes in complex traits.

Ahmad T, Marshall SE, Mulcahy-Hawes K, Orchard T, Crawshaw J, Armuzzi A, Neville M, van Heel D, Barnardo M, Welsh KI et al. 2002. High resolution MIC genotyping: design and application to the investigation of inflammatory bowel disease susceptibility. Tissue Antigens, 60 (2), pp. 164-179. | Show Abstract | Read more

The highly polymorphic nonclassical MHC class I chain-related (MIC) genes MICA and MICB encode stress inducible glycoproteins expressed on a variety of epithelial cells including intestinal cells. Interaction with the receptor NKG2D is likely to provide an important costimulatory signal for activation and proliferation of NK cells, activated macrophages and CD8 alphabeta and gammadelta T cells. Fifty-four MICA and 17 MICB alleles have been described to date. Although the functional significance of this polymorphism is not known, the high degree of nonconservative substitution, concentration to the putative ligand-binding site and recent observation that different MICA alleles bind to NKG2D with varying affinity has generated much interest. The MIC genes are attractive functional and positional candidate genes for inflammatory bowel disease susceptibility as a consequence of their position in the HLA region and expression on the gastrointestinal epithelium. We developed a robust, high-resolution PCR-SSP genotyping method that can be incorporated into the standard 'Phototyping' system and which effectively identifies 46 of 54 MICA alleles, and all 17 MICB alleles. We applied this system in combination with microsatellite genotyping of the exon 5 variable number of tandem repeats (VNTR) to the investigation of genetic susceptibility to the inflammatory bowel diseases, ulcerative colitis and Crohn's disease. We studied 248 patients with Crohn's disease, 329 with ulcerative colitis and 354 ethnically matched controls. Linkage disequilibrium patterns between HLA-B, MICA and MICB are presented. Analysis by individual allele or by multilocus haplotype failed to identify any significant disease associations.

Fraser AG, Orchard TR, Robinson EM, Jewell DP. 2002. Long-term risk of malignancy after treatment of inflammatory bowel disease with azathioprine. Aliment Pharmacol Ther, 16 (7), pp. 1225-1232. | Show Abstract | Read more

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. METHOD: A retrospective review of clinical notes was performed. RESULTS: Azathioprine was given to 626 of 2204 patients (855 with Crohn's disease and 1349 with ulcerative colitis). The mean total duration of azathioprine use was 27 months. The mean follow-up from diagnosis was 13.7 years and the mean follow-up from the start of azathioprine treatment was 6.9 years. Thirty-one cancers were observed in 30 patients treated with azathioprine (4.5%) and 77 cancers were observed in 70 patients not treated with azathioprine (4.5%; P=N.S.). Logistic regression analysis (including in the model the age, sex, diagnosis and extent of disease) showed that treatment with azathioprine did not significantly affect the risk of the development of cancer. Eight patients had lymphoma; three had been given azathioprine (P=N.S.). For patients with ulcerative colitis, the number of colorectal cancers (including high-grade dysplasia) in patients given azathioprine was eight of 355 (2.2%), compared with 28 of 994 (2.8%) for patients not given azathioprine (P=N.S.). The cumulative risk of colorectal cancer or dysplasia/dysplasia-associated lesion or mass (adjusted to exclude post-colectomy patients) after 10, 20, 30 and 40 years of ulcerative colitis was 0.4%, 1.3%, 9%and 15.5%, respectively. CONCLUSION: No increased risk of cancer diagnosis following azathioprine treatment was observed.

van Heel DA, Udalova IA, De Silva AP, McGovern DP, Kinouchi Y, Hull J, Lench NJ, Cardon LR, Carey AH, Jewell DP, Kwiatkowski D. 2002. Inflammatory bowel disease is associated with a TNF polymorphism that affects an interaction between the OCT1 and NF(-kappa)B transcription factors. Hum Mol Genet, 11 (11), pp. 1281-1289. | Show Abstract | Read more

Tumour necrosis factor-alpha (TNF) expression is increased in inflammatory bowel disease (IBD), and TNF maps to the IBD3 susceptibility locus. Transmission disequilibrium and case-control analyses, in two independent Caucasian cohorts, showed a novel association of the TNF(-857C) promoter polymorphism with IBD (overall P=0.001 in 587 IBD families). Further genetic associations of TNF(-857C) with IBD sub-phenotypes were seen for ulcerative colitis and for Crohn's disease, but only in patients not carrying common NOD2 mutations. The genetic data suggest a recessive model of inheritance, and we observed ex vivo lipopolysaccharide-stimulated whole-blood TNF production to be higher in healthy TNF(-857C) homozygotes. We show the transcription factor OCT1 binds TNF(-857T) but not TNF(-857C), and interacts in vitro and in vivo with the pro-inflammatory NF(-kappa)B transcription factor p65 subunit at an adjacent binding site. Detailed functional analyses of these interactions in gut macrophages, in addition to further genetic mapping of this gene-dense region, will be critical to understand the significance of the observed association of TNF(-857C) with IBD.

Ahmad T, Armuzzi A, Bunce M, Mulcahy-Hawes K, Marshall SE, Orchard TR, Crawshaw J, Large O, de Silva A, Cook JT et al. 2002. The molecular classification of the clinical manifestations of Crohn's disease. Gastroenterology, 122 (4), pp. 854-866. | Show Abstract | Read more

BACKGROUND & AIMS: Crohn's disease is a common inflammatory disorder of the gut characterized by variation in both location and behavior. Chromosome 16 and the HLA region on chromosome 6 have been implicated in susceptibility to disease. Mutations in the NOD2/CARD15 gene, recently identified on chromosome 16, have been associated with disease overall but are found in only 25% of patients. No data regarding their contribution to specific disease subtypes exist. Here we report a detailed genotype-phenotype analysis of 244 accurately characterized patients. METHODS: A total of 244 white patients with Crohn's disease recruited from a single center in the United Kingdom were studied. All patients were rigorously phenotyped and followed-up for a median time of 16 years. By using linkage disequilibrium mapping we studied 340 polymorphisms in 24 HLA genes and 3 NOD2/CARD15 polymorphisms. RESULTS: We show that NOD2/CARD15 mutations determine ileal disease only. We confirm that alleles on specific long-range HLA haplotypes determine overall susceptibility and describe novel genetic associations with susceptibility, location, and behavior of Crohn's disease. CONCLUSIONS: The clinical pattern of Crohn's disease may be defined by specific genotypes. This study may provide the basis for a future molecular classification of disease.

Fraser AG, Orchard TR, Jewell DP. 2002. The efficacy of azathioprine for the treatment of inflammatory bowel disease: a 30 year review. Gut, 50 (4), pp. 485-489. | Show Abstract | Read more

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 Crohn's 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 Crohn's 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 Crohn's 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 x 10(9) (p=0.03) and in male patients (p=0.01; Crohn's disease only). There was no difference in relapse rates between Crohn's 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 Crohn's disease. The efficacy of azathioprine is reasonably well sustained over five years.

Fraser AG, Morton D, McGovern D, Travis S, Jewell DP. 2002. The efficacy of methotrexate for maintaining remission in inflammatory bowel disease. Aliment Pharmacol Ther, 16 (4), pp. 693-697. | Show Abstract | Read more

BACKGROUND: The management of patients with inflammatory bowel disease who are resistant to or intolerant of azathioprine remains a challenge. Low-dose methotrexate has been shown to be effective in inducing remission in Crohn's disease. AIM: This review was conducted because there are limited long-term follow-up data during and after stopping treatment. There are also limited data on the use of methotrexate in ulcerative colitis. METHODS: The study was a retrospective review of clinical notes. Remission was defined as minimal bowel symptoms without the need for oral steroids for 3 months. Relapse was defined as bowel symptoms that required steroid treatment or surgery. RESULTS: Seventy patients were reviewed; 48 had Crohn's disease and 22 had ulcerative colitis. The mean duration of treatment was 17.1 months; the mean maintenance dose was 20 mg weekly. Remission was achieved in 34 of 55 patients who completed more than 3 months of treatment (62%). Life-table analysis showed that the chances of remaining in remission at 12, 24 and 36 months (if treatment was continued) were 90%, 73% and 51%, respectively. The chances of remaining in remission after stopping treatment at 6, 12 and 18 months were 42%, 21% and 16%, respectively. The dose of methotrexate (mg/kg) was associated with the induction of remission (P=0.02). Treatment was equally effective for Crohn's disease and ulcerative colitis. CONCLUSIONS: Maintenance methotrexate treatment gives acceptable remission rates for treatment periods up to 3 years. After stopping treatment, relapse is frequent and occurs early (usually within 1 year).

Borley NR, Mortensen NJM, Chaudry MA, Mohammed S, Warren BF, George BD, Clark T, Jewell DP, Kettlewell MGW. 2002. Recurrence after abdominal surgery for Crohn's disease: relationship to disease site and surgical procedure. Dis Colon Rectum, 45 (3), pp. 377-383. | Show Abstract | Read more

PURPOSE: We investigated the hypothesis that there is an "aggressive" subtype of Crohn's disease characterized by early recurrence and that disease location and surgical procedure are associated with differing patterns of recurrence. METHODS: We analyzed 280 patient records totaling 482 major abdominal operations from a prospectively compiled Crohn's disease database. Patterns of recurrence, as defined by reoperation, were analyzed by Kaplan-Meier plots and log-rank tests for the group as a whole, as well as according to disease location and operation performed using log-rank and Cox regression analysis. RESULTS: The overall survival curve followed a simple curve with no apparent early rise in recurrence. There was a significantly higher recurrence rate for ileal disease than for ileocolic or colic disease (median reoperation-free survival, 37.8 vs. 47.8 and 54.7 months, respectively; log-rank test = 13.6; P = 0.001), and there was a significantly shorter reoperation-free survival for those patients treated by strictureplasty alone or stricture-plasty combined with resection than for those treated by resection alone (41.7 and 48.6 vs. 51 months, respectively; log-rank test = 12; P = 0.002), but only disease site was confirmed as an independent risk factor for recurrence by multiple regression analysis. CONCLUSIONS: These data suggest that there is no evidence for the existence of a separate, early recurring, aggressive disease type. Shorter reoperation-free survival after strictureplasty may reflect patterns of recurrence in ileal disease.

Popat S, Hearle N, Hogberg L, Braegger CP, O'Donoghue D, Falth-Magnusson K, Holmes GKT, Howdle PD, Jenkins H, Johnston S et al. 2002. Variation in the CTLA4/CD28 gene region confers an increased risk of coeliac disease. Ann Hum Genet, 66 (Pt 2), pp. 125-137. | Show Abstract | Read more

Susceptibility to coeliac disease involves HLA and non-HLA-linked genes. The CTLA4/CD28 gene region encodes immune regulatory T-cell surface molecules and is a strong candidate as a susceptibility locus. We evaluated CTLA4/CD28 in coeliac disease by genetic linkage and association and combined our findings with published studies through a meta-analysis. 116 multiplex families were genotyped across CTLA4/CD28 using eight markers. The contribution of CTLA4/CD28 to coeliac disease was assessed by non-parametric linkage and association analyses. Seven studies were identified that had evaluated the relationship between CTLA4/CD28 and coeliac disease and a pooled analysis of data undertaken. In our study there was evidence for a relationship between variation in the CTLA4/CD28 region and coeliac disease by linkage and association analyses. However, the findings did not attain formal statistical significance (p = 0.004 and 0.039, respectively). Pooling findings with published results showed significant evidence for linkage (504 families) and association (940 families): p values, 0.0001 and 0.0014 at D2S2214, respectively, and 0.0008 and 0.0006 at D2S116, respectively. These findings suggest that variation in the CD28/CTLA4 gene region is a determinant of coeliac disease susceptibility. Dissecting the sequence variation underlying this relationship will depend on further analyses utilising denser sets of markers.

Borley NR, Mortensen NJM, Chaudry MA, Mohammed S, Clarke T, Jewell DP. 2002. Evidence for separate disease phenotypes in intestinal Crohn's disease. Br J Surg, 89 (2), pp. 201-205. | Show Abstract | Read more

BACKGROUND: This study investigated the hypothesis that separate phenotypes of Crohn's disease exist which display differing patterns of recurrence with a tendency to preservation of phenotype between serial operations. METHODS: Some 483 abdominal operations (278 patients) were identified from a prospectively compiled database. Patterns of recurrence (reoperation) were analysed by Kaplan-Meier plots and log rank tests according to disease phenotype (perforated, stenosed or ulcerated). Serial operations were analysed by agreement of phenotype and microscopic features of disease using kappa statistics and correlation coefficients. RESULTS: There was no significant difference in recurrence according to disease phenotype (median reoperation-free survival time 43.0, 50.2 and 47.9 months for perforated, stenosed and ulcerated types respectively; log rank chi(2) = 3.5, P = 0.18). There was poor agreement in phenotype between serial operations (kappa = 0.22 for first/second operation and kappa= 0.15 for second/third operation) and no significant correlation between pathological features was identified (r between -0.19 and 0.48). CONCLUSION: No evidence was found for the existence of separate disease phenotypes with differing natural histories or underlying pathological characteristics.

van Heel DA, Carey AH, Jewell DP. 2001. Identification of novel polymorphisms in the beta7 integrin gene: family-based association studies in inflammatory bowel disease. Genes Immun, 2 (8), pp. 455-460. | Show Abstract | Read more

Linkage studies from five groups worldwide have confirmed the presence of an inflammatory bowel disease susceptibility locus on chromosome 12q. Beta 7 integrin is a strong candidate gene within this region, and is involved in lymphocyte homing to the gut and retention of intra-epithelial lymphocytes. Monoclonal antibodies to beta7 integrin ameliorate colitis in animal models. We obtained genomic sequence for beta7 integrin, and screened all 16 exons and 1.7 kb of 5' promoter region for polymorphisms in 24 individuals. Fourteen single nucleotide polymorphisms were identified in total and, of these, two common (frequency > or =10%) intronic and two amino acid changing polymorphisms were assessed for potential disease associations. Data were available from 102 multiply affected inflammatory bowel disease families (affected sibling pairs) and 362 simplex (one affected proband) families containing 254 ulcerative colitis, 13 indeterminate colitis and 300 Crohn's disease trios (parents + affected child). No significant associations with any disease phenotype were found with the transmission disequilibrium test. Beta 7 integrin is unlikely to be involved in the genetic susceptibility to inflammatory bowel disease, and therefore future studies on chromosome 12 should focus on other positional candidate genes.

Orchard TR, Dhar A, Simmons JD, Vaughan R, Welsh KI, Jewell DP. 2001. MHC class I chain-like gene A (MICA) and its associations with inflammatory bowel disease and peripheral arthropathy. Clin Exp Immunol, 126 (3), pp. 437-440. | Show Abstract | Read more

MHC class I chain gene A (MICA) is a non-classical Class I gene which is expressed on the surface of epithelia without beta 2-microglobulin. The gene is found in the major histocompatibility complex (MHC) in tight linkage disequilibrium with human leucocyte antigen-B (HLA-B). Its precise function is unknown, but it interacts with gamma delta T cells of the intestinal immune system. This region of the MHC has been implicated in inflammatory bowel disease (IBD) pathogenesis by recent association mapping studies and this study was performed to examine the prevalence of MICA gene polymorphisms in IBD, in particular in type 2 peripheral arthropathy (PeA), which also has a strong HLA-B association. An assessment of the prevalence of MICA polymorphisms in IBD was made. Blood from 50 ulcerative colitis (UC) and 50 Crohn's disease controls was taken and MICA status determined using allele-specific PCR for 16 known alleles of MICA. A further 91 UC patients were recruited to confirm the results of this stage, and then the polymorphisms were studied in 52 type 1 and 45 type 2 PeA patients. The MICA status of these groups was compared with 118 blood and organ donor controls with appropriate correction for multiple comparisons. UC overall was associated with possession of MICA*007 in 32% compared to 11% of controls (P(c) = 0.017). This association was confirmed in a second cohort of 91 patients (23% versus 11%, P = 0.02). These were independent of HLA class I status. Type 2 IBD PeA was associated with MICA*008 in 98% compared to 73% of controls (P = 0.0001). MICA*007 is associated with susceptibility to UC in our population and MICA*008 with type 2 IBD PeA. Further work is now required to assess the distribution and expression of MICA throughout the gut in health and disease.

McGovern DP, van Heel DA, Ahmad T, Jewell DP. 2001. NOD2 (CARD15), the first susceptibility gene for Crohn's disease. Gut, 49 (6), pp. 752-754. | Read more

Hyde GM, Jewell DP, Kettlewell MG, Mortensen NJ. 2001. Cyclosporin for severe ulcerative colitis does not increase the rate of perioperative complications. Dis Colon Rectum, 44 (10), pp. 1436-1440. | Show Abstract | Read more

PURPOSE: Cyclosporin is used in severe ulcerative colitis that is refractory to intravenous steroids. Cyclosporin is a potent immunosuppressant and can cause side effects such as opportunistic infections. This study aimed to investigate the incidence of perioperative complications in patients treated with intravenous cyclosporin and steroids compared with patients treated with intravenous steroids alone. METHODS: We retrospectively reviewed the case notes of 44 patients with severe ulcerative colitis who underwent total abdominal colectomy and ileostomy. Twenty-five patients were treated with intravenous steroids and 19 patients were treated with intravenous cyclosporin and steroids. Details were recorded with respect to age, length of illness, extent of disease, Truelove and Witt's criteria, hemoglobin and albumin at surgery, surgical procedure, and perioperative morbidity. RESULTS: Twenty-four percent of patients treated with intravenous steroids alone and 15.8 percent of patients treated with intravenous cyclosporin and steroids had major surgical complications. Sixteen percent of patients treated with intravenous steroids alone and 5.2 percent of patients treated with intravenous cyclosporin and steroids had minor surgical complications. Eight percent of patients treated with intravenous steroids alone and 10.5 percent of patients treated with intravenous cyclosporin and steroids had major medical complications. There was no mortality in either group. CONCLUSIONS: There is no increased incidence of perioperative complications associated with the use of intravenous cyclosporin in addition to steroids in acute severe ulcerative colitis provided cyclosporin treatment is for a defined period and surgery is not delayed.

Mahmud N, Kamm MA, Dupas JL, Jewell DP, O'Morain CA, Weir DG, Kelleher D. 2001. Olsalazine is not superior to placebo in maintaining remission of inactive Crohn's colitis and ileocolitis: a double blind, parallel, randomised, multicentre study. Gut, 49 (4), pp. 552-556. | Show Abstract | Read more

BACKGROUND AND AIMS: The benefit of 5-aminosalicylic acid therapy for maintenance of remission in Crohn's disease is controversial. The primary aim of this study was to evaluate the prophylactic properties of olsalazine in comparison with placebo for maintenance of remission in quiescent Crohn's colitis and/or ileocolitis. METHODS: In this randomised, double blind, parallel group study of olsalazine versus placebo, 328 patients with quiescent Crohn's colitis and/or ileocolitis were recruited. Treatment consisted of olsalazine 2.0 g daily or placebo for 52 weeks. The primary end point of efficacy was relapse, as defined by the Crohn's disease activity index (CDAI) and by clinical relapse. Laboratory and clinical disease activity indicators were also measured. Safety analysis consisted of documentation of adverse events and laboratory values. RESULTS: No differences in the frequency of termination due to relapse or time to termination due to relapse were noted between the two treatment groups (olsalazine 48.5% v placebo 45%) for either colitis or ileocolitis. The failure rate, defined as not completing the study, was significantly higher in olsalazine treated patients compared with placebo treated patients for the overall population (colitis and/or ileocolitis: olsalazine 65.4% v 53.9%; p=0.038). Similar failure rates were seen for patients with colitis. A significantly higher percentage of olsalazine treated patients experienced adverse gastrointestinal events. Drug attributed adverse events were reported more frequently in the olsalazine treated group with gastrointestinal symptoms being causally related to olsalazine treatment (olsalazine 40.7% v placebo 26.9%; p=0.010). Back pain was reported significantly more often by the placebo treated group. However, serious medical events did not differ between the two groups. Adverse events led to more early withdrawals in the olsalazine treated group than in the placebo treated group; thus average time in the study for patients in the olsalazine treatment group was significantly shorter than that of patients in the placebo group. CONCLUSIONS: Patients treated with olsalazine were more likely to terminate their participation in the trial than those taking placebo. This difference was not related to relapse of disease, as measured by CDAI and clinical measures, but rather was due to the development of intolerable adverse medical events of a non-serious nature related to the gastrointestinal tract. The gastrointestinal related events in the olsalazine treated group may be due to the difference in gastrointestinal status at baseline which favoured the placebo treatment group.

Parkes M, Satsangi J, Jewell DP, Weeks DE, Barmada MM, Duerr RH. 2001. Ulcerative colitis is more strongly linked to chromosome 12 than Crohn's disease. Gut, 49 (2), pp. 311. | Read more

Satsangi J, Chapman RW, Haldar N, Donaldson P, Mitchell S, Simmons J, Norris S, Marshall SE, Bell JI, Jewell DP, Welsh KI. 2001. A functional polymorphism of the stromelysin gene (MMP-3) influences susceptibility to primary sclerosing cholangitis. Gastroenterology, 121 (1), pp. 124-130. | Show Abstract | Read more

BACKGROUND AND AIMS: We have investigated the influence of a biallelic polymorphism of the promoter region of stromelysin (matrix metalloproteinase 3) on susceptibility to primary sclerosing cholangitis (PSC). The 5A allele is associated with increased transcription, compared with wild-type (6A). METHODS: An allelic association study was performed: in stage 1, 52 PSC patients (43 with inflammatory bowel disease [IBD]) and 99 healthy subjects (HS) were genotyped. In stage 2, 59 PSC patients (49 IBD), 84 patients with uncomplicated ulcerative colitis, and 72 HS were genotyped. RESULTS: In stage 1, 5A carriage rate (90.4% vs. 72.7%; P = 0.012) and 5A allelic frequency (65.4% vs. 48.5%; P = 0.005) were increased, and 6A homozygosity was reduced in PSC (9.6% vs. 27.3%; P = 0.012). In stage 2, 5A allelic carriage was increased in PSC (93.2% vs. 76.4% in HS; P = 0.0092) and 6A homozygosity was reduced (6.8% vs. 23.8% in HS; P = 0.0092). Portal hypertension was associated with 5A homozygosity in PSC (P = 0.035; odds ratio [OR], 3.88). In the combined data set, 5A allelic frequencies (63.5% vs. 49.4%; P = 0.001; OR, 1.78) and 5A carriage rates (91.9% vs. 74.2%; P = 0.0002; OR, 3.92) were increased, and 6A homozygosity was reduced in PSC (8.1% vs. 25.7%; P = 0.0002; OR, 0.25). Overall, portal hypertension was associated with 5A homozygosity (P = 0.0192; OR, 3.12). CONCLUSIONS: Stromelysin polymorphism may influence susceptibility and disease progression in PSC.

Van Heel DA, McGovern DP, Jewell DP. 2001. Crohn's disease: genetic susceptibility, bacteria, and innate immunity. Lancet, 357 (9272), pp. 1902-1904. | Read more

Parkes M, Jewell DP. 2001. Review article: the management of severe Crohn's disease. Aliment Pharmacol Ther, 15 (5), pp. 563-573. | Show Abstract | Read more

The treatment of severe and active Crohn's disease is currently based on immunosuppression, but also involves the management of nutrition, appropriate selection of patients for surgery, and maintenance of remission in the long term. Corticosteroids remain the drug of the first choice, particularly in the acute setting. However, there is evolving understanding of the role of other immunosuppressants and immune modifiers, as major concerns regarding side-effects and efficacy of steroids in the medium to long-term drive the search for alternatives.

Jewell DP. 2001. Refractory pouchitis. Acta Gastroenterol Belg, 64 (2), pp. 220-222.

van Heel DA, Jewell DP. 2001. Genetics of inflammatory bowel disease--an update. Acta Gastroenterol Belg, 64 (2), pp. 160-164.

Borley NR, Mortensen NJ, Kettlewell MG, George BD, Jewell DP, Warren BF. 2001. Connective tissue changes in ileal Crohn's disease: relationship to disease phenotype and ulcer-associated cell lineage. Dis Colon Rectum, 44 (3), pp. 388-396. | Show Abstract | Read more

PURPOSE: Abnormalities of enteric collagen and smooth-muscle cell content have been documented in Crohn's disease. We studied the relationships among connective tissue changes, disease "type," and other disease features using immunohistochemistry and image analysis. METHODS: Twenty consecutive ileal resections for Crohn's disease and ten normal terminal ileal specimens were evaluated using conventional histopathologic examination. Monoclonal antibodies to smooth-muscle actin and Type III collagen fibers were used to determine the percentage area of the submucosa occupied by these constituents using image analysis. RESULTS: There were no significant differences in smooth-muscle content among stenosed, perforated, and ulcerated specimens. There was a significantly increased submucosal Type III collagen content in stenosed vs. other types. The only factor that correlated with smooth-muscle cell content was the amount of ulcer-associated cell lineage present. CONCLUSIONS: Increased deposition of Type III collagen fibers rather than smooth-muscle proliferation is associated with a stenotic phenotype. Loss of Type III collagen fibers may play a role in the development of perforating complications. We have found no evidence that smooth-muscle cells are the source of Type III collagen fiber production although there is evidence that ulcer-associated cell lineage may be related to the stimulus leading to submucosal neomuscularization.

Vermeire S, Satsangi J, Peeters M, Parkes M, Jewell DP, Vlietinck R, Rutgeerts P. 2001. Evidence for inflammatory bowel disease of a susceptibility locus on the X chromosome. Gastroenterology, 120 (4), pp. 834-840. | Show Abstract | Read more

BACKGROUND & AIMS: The technique of genomewide scanning has been applied successfully in inflammatory bowel disease (IBD). A number of putative susceptibility loci have been identified through genomewide searches including replicated regions of linkage on chromosomes 12, 16, 6 (the HLA region), and 14. We have investigated the contribution of the X chromosome in 145 Belgian affected relative pairs. METHODS: In the first stage of the study, 79 (68 CD, 11 mixed) sibling pairs were genotyped at 12 microsatellite markers covering the X chromosome. In the second stage, 10 additional markers in the X-pericentromeric region were studied in the families involved in stage 1 together with 62 additional families (52 sibling pairs, 14 second-degree relative pairs). RESULTS: In the first stage, evidence for linkage was found over a 30-cM pericentromeric region spanning dXs991, dXs990, and dXs8096 (multipoint maximum LOD score in the CD subgroup, 2.5; P = 0.0003). The remainder of the X chromosome was excluded (exclusion under LOD-2) for a locus with lambda(s) = 2. Fine mapping in the second stage confirmed linkage, and narrowed and shifted the linked region to Xq21.3 around dXs1203 (nonparametric linkage [NPL], 2.90; P = 0.0017). The NPL-1 interval around the linkage peak comprises 19.7 cM. CONCLUSIONS: These data provide suggestive evidence for the presence and chromosomal location of an X-linked susceptibility gene in IBD.

Lucas AD, Chadwick N, Warren BF, Jewell DP, Gordon S, Powrie F, Greaves DR. 2001. The transmembrane form of the CX3CL1 chemokine fractalkine is expressed predominantly by epithelial cells in vivo. Am J Pathol, 158 (3), pp. 855-866. | Show Abstract | Read more

Fractalkine (CX3CL1) is synthesized as a type I transmembrane protein. Its unique CX(3)C chemokine domain is attached to a 241-amino acid mucin stalk, a 19-amino acid transmembrane domain, and a 37-amino acid intracellular domain of unknown function. A soluble form of fractalkine can be generated by proteolytic cleavage at the base of the mucin stalk. Novel monoclonal and polyclonal antibodies that specifically recognize only the amino- or carboxyl-terminal ends of the human fractalkine molecule have revealed that epithelial cells are the predominant cell type expressing transmembrane forms of fractalkine in human skin, the tonsil, and the large intestine. Using these specific anti-fractalkine reagents we do not detect high-level expression of fractalkine on endothelial cells in normal or inflamed colon samples obtained from patients with Crohn's disease or ulcerative colitis. In contrast to previous reports we do not detect fractalkine expression by Langerhans cells or immature dendritic cells in mucosal-associated lymphoid tissues in vivo. We show that the reagent used in previous studies, an anti-fractalkine N-terminal peptide antisera, cross-reacts with human CD84. Finally we discuss potential roles for fractalkine in constitutive leukocyte trafficking based on its observed pattern of expression in epithelia.

Parkes M, Barmada MM, Satsangi J, Weeks DE, Jewell DP, Duerr RH. 2000. The IBD2 locus shows linkage heterogeneity between ulcerative colitis and Crohn disease. Am J Hum Genet, 67 (6), pp. 1605-1610. | Show Abstract | Read more

The IBD2 locus on chromosome 12 has been linked to both Crohn disease (CD) and ulcerative colitis (UC) but has not been detected in some CD-dominated data sets. In the present study, we genotyped 581 relative pairs with inflammatory bowel disease (252 from CD-only families, 138 from UC-only families, and 191 from mixed families containing cases of both CD and UC), using 12 markers spanning the IBD2 locus. A GENEHUNTER-PLUS multipoint LOD score of 3.91 was detected for pairs from UC-only families, compared with 1.66 for CD-only and 1.29 for mixed families. The difference between the LOD scores for UC and CD was significant in two different tests for heterogeneity (P=.0057 for one test and P=.0375 for the other). IBD2 thus appears to make a major contribution to UC susceptibility but to have only a relatively minor effect with regard to CD, for which there may be substantially more locus heterogeneity.

Jewell DP. 2000. Celiac disease. Can J Gastroenterol, 14 (8), pp. 665-666. | Read more

van Heel DA, Allen M, Jewell DP, Carey AH. 2000. A revised sequence of the human beta7 integrin gene (ITGB7) promoter region obtained by inverse PCR. Immunogenetics, 51 (10), pp. 863-865. | Read more

Edwards CM, George BD, Jewell DP, Warren BF, Mortensen NJ, Kettlewell MG. 2000. Role of a defunctioning stoma in the management of large bowel Crohn's disease. Br J Surg, 87 (8), pp. 1063-1066. | Show Abstract | Read more

BACKGROUND: The faecal stream plays a significant role in the pathogenesis of Crohn's disease. This retrospective study aimed to assess the effect of faecal diversion on the natural history of refractory Crohn's colitis (RCC) and severe perianal disease (PAD). METHODS: All patients undergoing a defunctioning stoma without resection for RCC or PAD between 1970 and 1997 were studied. Indications for surgery, acute clinical response, subsequent outcome and stoma rates were recorded. RESULTS: Some 73 patients underwent a defunctioning stoma (55 RCC and 18 PAD). Acute remission was achieved in 63 patients (48 RCC, 15 PAD). Twenty-nine patients had subsequent closure of the defunctioning stoma (25 of 48 acute responders with RCC and four of 15 acute responders with PAD). Eleven patients with RCC and two with PAD achieved good long-term function without disease relapse (median follow-up 36 months). Overall 52 patients have undergone proctocolectomy or remain with a defunctioning stoma (37 with RCC and 15 with PAD). CONCLUSION: Faecal diversion is associated with acute clinical remission in the majority of patients with RCC and PAD, but sustained benefit occurs less often. For selected patients, diversionary surgery alone offers a realistic alternative to major bowel resection.

Simmons JD, Mullighan C, Welsh KI, Jewell DP. 2000. Vitamin D receptor gene polymorphism: association with Crohn's disease susceptibility. Gut, 47 (2), pp. 211-214. | Show Abstract | Read more

BACKGROUND: The vitamin D receptor (VDR) gene represents a strong positional candidate susceptibility gene for inflammatory bowel disease (IBD). The VDR gene maps to a region on chromosome 12 that has been shown to be linked to IBD by genome screening techniques. It is the cellular receptor for 1,25(OH)(2) vitamin D(3) (calcitriol) which has a wide range of different regulatory effects on the immune system. IBD is characterised by activation of the mucosal immune system. AIM: To determine if polymorphisms in the VDR gene are associated with susceptibility to IBD SUBJECTS: European Caucasoids: 158 patients with ulcerative colitis, 245 with Crohn's disease, and 164 cadaveric renal allograft donor controls. METHOD: Single nucleotide polymorphisms (TaqI, ApaI, and FokI) in VDR were typed in patients with Crohn's disease, ulcerative colitis, and controls by polymerase chain reaction with sequence specific primers. RESULTS: There were significantly more homozygotes for the TaqI polymorphism at codon 352 of exon 8 (genotype "tt") among patients with Crohn's disease (frequency 0.22) than patients with ulcerative colitis (0.12) or controls (0.12) (odds ratio 1.99; 95% confidence interval 1.14-3.47; p=0.017). CONCLUSION: This study provides preliminary evidence for a genetic association between Crohn's disease susceptibility and a gene that lies within one of the candidate regions determined by linkage analysis.

Koss K, Fanning GC, Welsh KI, Jewell DP. 2000. Interleukin-10 gene promoter polymorphism in English and Polish healthy controls. Polymerase chain reaction haplotyping using 3' mismatches in forward and reverse primers. Genes Immun, 1 (5), pp. 321-324. | Show Abstract | Read more

A polymerase chain reaction with sequence-specific primers (PCR-SSP) system using primers with mismatches at the 3' ends was developed to determine polymorphisms in IL-10 promoter region. Three previously described biallelic polymorphisms in IL-10 were linked in a 12 reaction PCR-SSP system and the method used to provide genotype data on 233 UK and 166 Polish controls. There are eight possible polymorphic combinations in IL-10 promoter gene but only three were observed in both control groups. Population frequencies of IL-10 genotypes show, in contrast to HLA, that UK and Polish frequencies are remarkably similar.

van Heel DA, Satsangi J, Carey AH, Jewell DP. 2000. Inflammatory bowel disease: progress toward a gene. Can J Gastroenterol, 14 (3), pp. 207-218. | Show Abstract | Read more

The pathogenesis of ulcerative colitis (UC) and Crohn's disease (CD) is still unknown, but the importance of genetic susceptibility has been clearly shown by epidemiological data from family and twin studies. Linkage studies have identified two susceptibility loci for inflammatory bowel disease (IBD) on chromosomes 12 and 16. Importantly, these linkages have been replicated by independent investigators, and studies of positional candidates within these regions continue, together with fine mapping strategies. Regions of 'suggestive' linkage on chromosomes 1, 3, 4, 6, 7, 10, 22 and X have also been reported in individual studies. Other important candidate genes investigated include the interleukin-1 receptor antagonist, MUC3 and genes of the human leukocyte antigen (HLA) system. The apparently conflicting data in different studies from around the world may be explained by ethnic differences, case mix and genetic heterogeneity. Replicated class II HLA associations include HLA DRB1*0103 and DR2 (DRB1*1502), involved in UC susceptibility, and HLA DRB1*03 and DR4 as resistance alleles for CD and UC respectively. Animal studies have provided insights from targeted mutations and quantitative trait locus analysis. The goals of continuing research include narrowing the regions of linkages and analysis of candidate genes, and possibly the application of newly developed methods using single nucleotide polymorphisms. Advances in IBD genetics hold the potential to provide knowledge about the disease pathogenesis at the molecular level, with ensuing benefits for clinical practice.

Anderson RP, Degano P, Godkin AJ, Jewell DP, Hill AV. 2000. In vivo antigen challenge in celiac disease identifies a single transglutaminase-modified peptide as the dominant A-gliadin T-cell epitope. Nat Med, 6 (3), pp. 337-342. | Show Abstract | Read more

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 (alpha1*0501, beta1*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.

Borley NR, Mortensen NJ, Jewell DP, Warren BF. 2000. The relationship between inflammatory and serosal connective tissue changes in ileal Crohn's disease: evidence for a possible causative link. J Pathol, 190 (2), pp. 196-202. | Show Abstract | Read more

The relationship between the gross connective tissue and inflammatory changes in ileal Crohn's disease remains unclear. This study investigated 20 patients undergoing ileal resection for Crohn's disease and 20 normal controls. The specimens were blocked in 1 cm serial sections and fully examined, including fresh morphometry and documentation of a range of pathological features. Pathological features of disease showed uniform distributions within affected segments, although specimens showed different patterns and severity of affliction. Serosal fat wrapping (FW) was present in all cases and was significantly greater than normals [mean 63.5% (SD 27. 8) vs. 21.0% (6.4), p<0.001], as was mesenteric thickening (MTh) [mean 18.0 mm (SD 11.1) vs. 5.9 mm (2.2), p<0.001]. The extent of FW correlated significantly with the degree of acute and chronic inflammation (r()=0.32 and 0.23 respectively, p<0.01), particularly the extent of transmural inflammation in the form of lymphoid aggregates (r()=0.35, p<0.01). MTh did not correlate with any features studied. These findings support the hypothesis that serosal connective tissue changes in Crohn's disease are related to the local effects of underlying chronic inflammatory infiltrates. Full thickness, radial samples from a grossly affected area are representative of the histopathological features present in a diseased segment as a whole.

Koss K, Satsangi J, Fanning GC, Welsh KI, Jewell DP. 2000. Cytokine (TNF alpha, LT alpha and IL-10) polymorphisms in inflammatory bowel diseases and normal controls: differential effects on production and allele frequencies. Genes Immun, 1 (3), pp. 185-190. | Show Abstract | Read more

The influence of biallelic polymorphisms in the tumour necrosis factor-alpha (TNF alpha), lymphotoxin-alpha (LT alpha) and interleukin-10 (IL-10) genes on stimulated TNF alpha and IL-10 production was studied in ulcerative colitis (UC) patients, Crohn's disease (CD) patients and in healthy controls. A polymerase chain reaction sequence-specific primer (PCR-SSP) system was developed to type nine biallelic polymorphisms, three in each of the TNF alpha, LT alpha and IL-10 genes. Production of the TNF alpha and IL-10 was measured by ELISA in lipopolysaccharide (LPS) stimulated whole blood. Four haplotypes of the TNF alpha gene, three haplotypes of LT alpha and three haplotypes of IL-10 were identified. No significant differences in haplotype frequencies were found between patients and controls overall. On subgroup analysis however, haplotype TNF-2 was more frequent in women with extensive colitis compared to distal colitis (31% vs 12%; P = 0.028). This difference was even greater for the combined TNF-2-LT alpha-2 haplotype (56% vs 21%; P = 0.0007). The TNF-2 and LT alpha-2 haplotypes were associated with higher TNF alpha production in CD patients, and the TNF-4 haplotype was associated with lower TNF alpha production in UC patients. The A allele in the IL-10 promoter region at position -1082 was associated with decreased IL-10 production in CD patients and controls (P = 0.005, P = 0.015 respectively). These data provide evidence that the effect of TNF alpha, LT alpha and IL-10 gene polymorphisms on cytokine production differ in CD, UC patients and controls.

Koss K, Satsangi J, Welsh KI, Jewell DP. 2000. Is interleukin-6 important in inflammatory bowel disease? Genes Immun, 1 (3), pp. 207-212. | Show Abstract | Read more

The IL-6 gene maps to an area of chromosome 7 known to be significant for susceptibility to inflammatory bowel disease. The functional effects of interleukin-6 (IL-6) polymorphisms in the 4th intron and in the 3' flanking region of IL-6 gene were studied in 192 inflammatory bowel disease patients and healthy subjects. A polymerase chain reaction with sequence-specific primers (PCR-SSP) was used to determine a G to A polymorphism (* at position 4470 in intron 4 of IL-6 gene). Four alleles in the 3' flanking region were studied using a variable number of tandem repeats PCR (VNTR-PCR) amplification. Production of IL-6 was measured in lipopolysaccharide (LPS) stimulated whole blood samples by an enzyme-linked immunosorbent assay (ELISA). A modest increase in the frequency of the IL-6*G allele was noted in Crohn's disease (CD) patients (50%) and ulcerative colitis (UC) patients (46.1%) as compared to controls (39.8%, P = 0.025). We were unable to find any significant functional effect of the IL-6 polymorphisms tested on IL-6 protein production. We postulate that the IL-6 polymorphisms investigated here may be in linkage disequilibrium with a susceptibility gene and that they may be utilised as genetic markers.

Gasche C, Scholmerich J, Brynskov J, D'Haens G, Hanauer SB, Irvine EJ, Jewell DP, Rachmilewitz D, Sachar DB, Sandborn WJ, Sutherland LR. 2000. A simple classification of Crohn's disease: report of the Working Party for the World Congresses of Gastroenterology, Vienna 1998. Inflamm Bowel Dis, 6 (1), pp. 8-15. | Show Abstract | Read more

Crohn's 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 Crohn's disease based on objective variables. Eight outcome-related variables relevant to Crohn's 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 Crohn's 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 Crohn's disease provides distinct definitions to categorize Crohn's 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.

Orchard TR, Thiyagaraja S, Welsh KI, Wordsworth BP, Hill Gaston JS, Jewell DP. 2000. Clinical phenotype is related to HLA genotype in the peripheral arthropathies of inflammatory bowel disease. Gastroenterology, 118 (2), pp. 274-278. | Show Abstract | Read more

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.

Orchard TR, Satsangi J, Van Heel D, Jewell DP. 2000. Genetics of inflammatory bowel disease: a reappraisal. Scand J Immunol, 51 (1), pp. 10-17. | Show Abstract | Read more

The advent of advanced molecular biological techniques in the last two decades has allowed the study of genetic factors in inflammatory bowel disease (IBD). A variety of techniques have been employed to elucidate the effects of genes, starting with the clinical observations that IBD is more common in the relatives of patients than the general population, and the consistency of clinical features within families. The situation is likely to be much more complicated than single gene disorders, and it is estimated that between 10 and 20 genes may be involved. Genome scanning techniques using microsatellite markers have been employed to highlight areas of chromosomes linked to disease such as those on chromosomes 12 and 16. In addition association studies of specific genes such as HLA and cytokine genes have been carried out on functional or positional grounds. It is likely that a combination of these techniques will be required to elucidate the role of individual genes. Recently much work has been focused on genes that may determine clinical phenotype such as disease extent or severity or the response to treatment. Identification of these genes may lead to better targeting of therapy and prognostication, and they are likely to be easier to identify than disease susceptibility genes.

Premaratna R, Saparamadu A, Samarasekera DN, Warren BF, Jewell DP, de Silva HJ. 1999. Eosinophilic granulomatous vasculitis mimicking a gastric neoplasmn. Histopathology, 35 (5), pp. 479-481. | Read more

Borley NR, Mortensen NJ, Jewell DP. 1999. MRI scanning in perianal Crohn's disease: an important diagnostic adjunct. Inflamm Bowel Dis, 5 (3), pp. 231-233. | Read more

Orchard TR, Jewell DP. 1999. The importance of ileocaecal integrity in the arthritic complications of Crohn's disease. Inflamm Bowel Dis, 5 (2), pp. 92-97. | Show Abstract | Read more

Experiments in animal models have suggested a role for bacterial overgrowth in the caecum in the pathogenesis of extracolonic inflammation in IBD. The aim of this study was to identify patients with Crohn's disease who have undergone ileocaecal resection and to compare the incidence of new arthritic complications in these patients with those who have never undergone surgery. Patients who had undergone surgery were identified by case note review. The date and nature of surgery were noted. The occurrence of new joint complications (Type 1 and 2 peripheral arthropathy and AS) was noted in patients who had undergone ileocaecal resection and in patients who had never undergone surgery. In the surgery group the timing in relation to surgery was determined. The groups were compared using Kaplan-Meier survival curves and the Logrank test. One hundred sixty-four patients who had undergone ileocaecal resection and 221 patients who had never undergone surgery for Crohn's disease were studied. The rate of development of arthritic complications in patients presurgery and in the nonsurgical group was identical. However few arthritic complications occurred postoperatively. There were highly significant differences between the nonsurgical group and the postsurgical group (p = 0.0001) and between patients presurgery and postsurgery (p = 0.0006). New arthritic complications are less common in Crohn's disease after resection of the ileocaecal area. This would be consistent with the hypothesis that luminal bacteria in this region are important in the pathogenesis of these complications.

Orchard TR, Jewell DP. 1999. Peripheral arthropathies in inflammatory bowel disease - Reply GUT, 44 (3), pp. 439-439. | Read more

Sandborn WJ, McLeod R, Jewell DP. 1999. Medical therapy for induction and maintenance of remission in pouchitis: a systematic review. Inflamm Bowel Dis, 5 (1), pp. 33-39. | Show Abstract | Read more

OBJECTIVE: To determine the effectiveness of medical therapy (including metronidazole, bismuth carbomer enemas, oral probiotic bacteria, butyrate suppositories, and glutamine suppositories) for inducing a response or for maintaining remission in pouchitis. SEARCH STRATEGY: Studies were selected using the MEDLINE data base (1966-December 1997), abstracts from major gastrointestinal meetings, and references from published articles and reviews. SELECTION CRITERIA: Four randomized controlled trials of medical therapy in adult patients with pouchitis were identified: two placebo controlled trials in active chronic pouchitis; one maintenance of remission trial comparing two active agents in chronic pouchitis; and one placebo-controlled maintenance of remission trial for chronic pouchitis. A single patient "n-of-1" trial for active chronic pouchitis was excluded. DATA COLLECTION AND ANALYSIS: Data were extracted by three independent observers based on the intention to treat principle. Extracted data were converted to 2 x 2 tables (response versus no response and medical therapy versus placebo or medical therapy versus medical therapy) and an odds ratio with 95% confidence intervals (CI) were determined as described by Cochrane and Mantel and Haenszel. In addition, the absolute risk reduction, relative risk reduction, and number needed to treat were determined. MAIN RESULTS: The odds ratios of inducing a response using oral metronidazole or bismuth carbomer foam enemas compared with placebo in active chronic pouchitis were 12.34 (95% CI 2.34-64.95) and 1.00 (95% CI 0.29-3.42), respectively. The odds ratio of maintaining remission in chronic pouchitis for oral probiotic bacteria (VSL-3) compared with placebo was 15.33 (95% CI 4.51-52.14). There was no difference in the odds ratio of inducing symptomatic remission and then maintaining symptomatic remission after discontinuing suppressive medical therapy for chronic pouchitis with glutamine suppositories compared with butyrate suppositories, 2.75 (95% CI 0.48-15.94). CONCLUSIONS: Metronidazole is an effective therapy for active chronic pouchitis. Bismuth carbomer foam enemas are not effective therapy for active chronic pouchitis. Oral probiotic therapy with VSL-3 is an effective therapy for maintaining remission in patients with chronic pouchitis in remission. There is no difference in maintenance of symptomatic remission in patients with chronic pouchitis treated with glutamine versus butyrate suppositories, and it is unknown whether glutamine and butyrate are equally effective or ineffective. Additional randomized, double-blind, placebo-controlled, dose-ranging clinical trials are needed to determine the efficacy of empiric medical therapies currently being used in patients with pouchitis.

Satsangi J, Parkes M, Jewell DP. 1998. Molecular genetics of Crohn's disease: recent advances. Eur J Surg, 164 (12), pp. 887-891. | Read more

Godkin AJ, Davenport MP, Willis A, Jewell DP, Hill AV. 1998. Use of complete eluted peptide sequence data from HLA-DR and -DQ molecules to predict T cell epitopes, and the influence of the nonbinding terminal regions of ligands in epitope selection. J Immunol, 161 (2), pp. 850-858. | Show Abstract

In diseases with a strong association with an HLA haplotype, identification of relevant T cell epitopes may allow alteration of the pathologic process. In this report we use a reverse immunogenetic approach to predict possible HLA class II-restricted T cell epitopes by using complete pool sequencing data. Data from HLA-DR2(B1*1501), -DR3(B1*0301), -DQ2(A1*0501, B1*0201), and -DQ8(A1*0301, B1*0302) alleles were used by a computer program that searches a candidate protein to predict ligands with a relatively high probability of being processed and presented. This approach successfully identified both known T cell epitopes and eluted single peptides from the parent protein. Furthermore, the program identified ligands from proteins in which the binding motif of the HLA molecule was unable to do so. When the information from the nonbinding N- and C-terminal regions in the pool sequence was removed, the ability to predict several ligands was markedly reduced, particularly for the HLA-DQ alleles. This suggests a possible role for these regions in determining ligands for HLA class II molecules. Thus, the use of complete eluted peptide sequence data offers a powerful approach to the prediction of HLA-DQ and -DR peptide ligands and T cell epitopes.

Jewell DP. 1998. Ulcerative colitis and Crohn's disease--susceptibility genes and clinical patterns. J Gastroenterol, 33 (3), pp. 458-462. | Read more

Satsangi J, Parkes M, Jewell DP, Bell JI. 1998. Genetics of inflammatory bowel disease. Clin Sci (Lond), 94 (5), pp. 473-478. | Show Abstract | Read more

1. The aetiology of the chronic inflammatory bowel diseases, Crohn's disease and ulcerative colitis, is uncertain. Studies of specific environmental factors and immune dysfunction have provided little insight into disease pathogenesis. 2. Concordance rates in twin pairs and siblings provide strong evidence that genetic factors are important in disease pathogenesis. In Oxford, information was obtained from 433 adult patients with Crohn's disease. Compared with the prevalence in the general population, the relative risks in siblings of patients with Crohn's disease calculated from these data were respectively 36.5 for Crohn's disease, 16.6 for ulcerative colitis and 24.7 for inflammatory bowel disease. 3. Clinical patterns of disease were compared in members of over 250 multiply affected families with inflammatory bowel disease. A high degree of concordance for many characteristics was noted (disease type, extent, extra-intestinal manifestations). However, in 77 affected parent-child pairs, the median age of onset in the parents was significantly higher than in offspring (P < 0.0001). These data reflect the results from other studies throughout the world, and are consistent with the phenomenon of genetic anticipation. 4. A detailed study investigating the contribution of the major histocompatibility complex was undertaken. Eighty-three affected sibling pairs were involved in a linkage analysis study; 348 patients with inflammatory bowel disease and 472 controls were involved in a detailed allelic association study. These data provide evidence that the major histocompatibility complex is an important determinant in ulcerative colitis, but not in Crohn's disease. 5. Cytokine genes are important candidate genes in inflammatory bowel disease. Allelic association study was performed to investigate the contribution of the gene encoding the interleukin-1 receptor antagonist and tumour necrosis factor-alpha. These data do not suggest that these genes encode important determinants of disease susceptibility in inflammatory bowel disease. 6. A two-stage genome-wide search for susceptibility loci in inflammatory bowel disease was performed involving 186 affected sibling pairs. The data provide strong evidence for the model of Crohn's disease and ulcerative colitis as related polygenic disorders. Loci on chromosomes 3, 7 and 12 were linked to inflammatory bowel disease overall, whereas loci on chromosomes 2 and 6 were linked only in ulcerative colitis. Linkage with chromosome 16 was noted in Crohn's disease only. Fine mapping of these susceptibility loci is in progress, and may lead to gene identification with attendant clinical benefits.

Hyde GM, Thillainayagam AV, Jewell DP. 1998. Intravenous cyclosporin as rescue therapy in severe ulcerative colitis: time for a reappraisal? Eur J Gastroenterol Hepatol, 10 (5), pp. 411-413. | Show Abstract | Read more

BACKGROUND: Intravenous cyclosporin is the only new therapy in recent years to have made a significant impact on the management of acute severe ulcerative colitis (UC). It is increasingly recommended for use in patients who prove refractory to the standard regimen of intravenous (i.v.) and rectal hydrocortisone but do not warrant immediate surgery. This practice is based on uncontrolled and controlled studies which suggest a short-term efficacy of 80% and long-term efficacy of 60% in avoiding colectomy. AIM: The aim of this study was to assess the short- and long-term efficacy of i.v. cyclosporin in patients admitted to our hospital with acute severe ulcerative colitis refractory to i.v. steroids, over a 6-year period. METHOD: A retrospective survey of patients admitted to the John Radcliffe Hospital, Oxford, with acute severe UC over a 6-year period (1991-97) was performed. Truelove and Witts criteria for acute severe UC were satisfied by 216 patients. RESULTS: The standard regimen achieved remission in 132 patients (61%). Of the 84 patients who failed to respond, 34 (40%) proceeded directly to colectomy whilst 50 received cyclosporin (4 mg/kg by continuous slow infusion). Remission was achieved by i.v. cyclosporin in 28/50 (56%) patients who were subsequently transferred to oral cyclosporin (5 mg/kg). However, 8/28 (29%) who initially responded later relapsed after discharge from hospital and underwent colectomy. The short-term efficacy of 56% therefore falls to 40% in the longer term (mean follow-up of 19 months). CONCLUSION: This is the largest survey to date of patients with refractory severe UC treated with i.v. cyclosporin. The findings confirm the potential value of i.v. cyclosporin in severe UC but its effectiveness in clinical practice is less dramatic than previously reported.

Orchard TR, Wordsworth BP, Jewell DP. 1998. Peripheral arthropathies in inflammatory bowel disease: their articular distribution and natural history. Gut, 42 (3), pp. 387-391. | Show Abstract | Read more

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.

Satsangi J, Landers CJ, Welsh KI, Koss K, Targan S, Jewell DP. 1998. The presence of anti-neutrophil antibodies reflects clinical and genetic heterogeneity within inflammatory bowel disease. Inflamm Bowel Dis, 4 (1), pp. 18-26. | Show Abstract | Read more

A detailed investigation of the relationship between anti-neutrophil cytoplasmic antibodies (ANCA) status, HLA genotype, and clinical patterns of inflammatory bowel disease was carried out, involving 236 European patients resident in the United Kingdom [120 had ulcerative colitis (UC), 116 had Crohn's disease (CD)]. ANCA status was determined on coded plasma samples in Los Angeles using a two-stage assay [fixed neutrophil enzyme-linked immunosorbent assay (ELISA) and indirect immunofluorescence], and HLA genotyping was carried out by polymerase chain reaction. The results provide evidence that ANCA reflect clinical and genetic heterogeneity within the inflammatory bowel diseases. In the UC patients, 78.3% were ANCA positive [64.2 perinuclear (pANCA)], but only 46.5% CD patients were ANCA positive (19.3% pANCA). Furthermore, mean ELISA binding was significantly lower in CD (14.5% +/- 18.8% versus 40.5% +/- 41.0% in UC, p = 2.31 x 10(-9)). Only 15 CD samples, all from patients with colonic disease, displayed ELISA > 20%; and the six CD patients with highest ELISA binding had clinical features very similar to ulcerative colitis. Moreover, in UC, significant relationships between ANCA status and genotype were noted. Thus, 92.7% of patients with the DR3 DQ2 TNF2 haplotype were ANCA positive [p = 0.03 versus DR3 DQ2 TNF2-negative patients (73.9%)]. ELISA binding was increased in DR3 DQ2 TNF2-positive patients (56.0 versus 35.7%, p = 0.02). In this population of UC, ANCA was not associated with DR2, DR4, or clinical pattern. These data emphasize the many factors that need to be considered in genetic marker studies in inflammatory bowel disease. Extensive disease heterogeneity, ethnicity, and methodological differences in ANCA detection are all pertinent.

Orchard T, Jewell DP. 1997. Review article: Pathophysiology of the intestinal mucosa in inflammatory bowel disease and arthritis: similarities and dissimilarities in clinical findings. Aliment Pharmacol Ther, 11 Suppl 3 (3), pp. 10-15. | Show Abstract

Although apparently dissimilar in both structure and function, the gut and locomotor system are linked by a number of clinical syndromes in which both are involved. In inflammatory bowel disease, intestinal mucosal inflammation is the primary problem, but may be associated with both axial and peripheral arthropathies. In the seronegative spondyloarthropathies the primary problem is in the locomotor system, but intestinal abnormalities may also be present. In addition, non-steroidal anti-inflammatory drugs used in their treatment, may cause a distinct enteropathy which may be confused with the disease-related intestinal abnormalities. The clinical, histological and genetic features of these conditions are examined in order to assess their relationship and the central role of the intestinal mucosa in their pathogenesis.

Merrett MN, Owen RW, Jewell DP. 1997. Ileal pouch dialysate is cytotoxic to epithelial cell lines, but not to CaCo-2 monolayers. Eur J Gastroenterol Hepatol, 9 (12), pp. 1219-1226. | Show Abstract

OBJECTIVE: All patients with ileal pouch-anal anastomosis (IPAA) have some degree of villous atrophy, mucin changes and chronic inflammation. The mechanism underlying these changes is unknown. This study investigates the hypothesis that luminal factor(s) may affect epithelial cells in in-vitro studies. DESIGN: IPAA dialysate from eight patients with prior ulcerative colitis was assessed. METHODS: The effect of the dialysate on epithelial cell (i-407, HT-29 and CaCo-2) proliferation (3H-thymidine incorporation) and cytotoxicity (51-chromium release) was determined. Bile acid(s) at concentrations measured in IPAA dialysate were assessed in isolation and in combination for cytotoxicity against CaCo-2 cells. The effect of dialysate and bile acids on immature and mature CaCo-2 monolayer cytotoxicity, transepithelial electrical resistance (TEER) and histology was investigated. RESULTS: IPAA dialysate is antiproliferative and cytotoxic to the cell lines. At concentrations present in dialysate chenodeoxycholic acid and deoxycholic acid were cytotoxic to CaCo-2 cells. IPAA dialysate was not cytotoxic to mature CaCo-2 cell monolayers. TEER was maintained across monolayers with dialysate but not with control Rheomacrodex (P = 0.02). Bile acids at concentrations present in dialysate were cytotoxic to monolayers. CONCLUSION: Ileal pouch dialysate is cytotoxic to epithelial cells due (in part) to bile acids. Bile acids in isolation are cytotoxic to both CaCo-2 cells and monolayers. Despite the presence of bile acid the dialysate is not cytotoxic to CaCo-2 monolayers and preserves epithelial resistance and histological structure.

Borley NR, Mortensen NJ, Jewell DP. 1997. Preventing postoperative recurrence of Crohn's disease. Br J Surg, 84 (11), pp. 1493-1502. | Show Abstract | Read more

BACKGROUND AND METHODS: Risk factors for recurrence of Crohn's disease and the evidence for progress in reducing recurrence following resection were reviewed. A Medline based literature review was carried out. RESULTS AND CONCLUSION: Only smoking has been confirmed as a significant adverse risk factor for recurrence. Evidence for differing recurrence rates in fibrostenosing disease and perforating disease is inconclusive, but such a classification along with the endoscopic findings of recurrence may have a place in the analysis of therapeutic trials. Minimal resectional surgery with clearing of only macroscopic disease seems to be justified, with no clear benefits from different anastomotic techniques. Recent trials offer encouraging evidence of the usefulness of 5-aminosalicylic acid, particularly higher-dose regimens started early after resection, although the long-term benefits are uncertain. The oral steroid, budesonide, offers a potent treatment with minimal side-effects, but evidence of its prevention of recurrence is presently weak.

Thompson-Fawcett MW, Jewell DP, Mortensen NJ. 1997. Ileoanal reservoir dysfunction: a problem-solving approach. Br J Surg, 84 (10), pp. 1351-1359. | Show Abstract | Read more

BACKGROUND: Many technical difficulties of the ileoanal reservoir operation have been overcome, allowing acceptable morbidity in the hands of both the frequent and less frequent operator. However, a minority of patients have persistently unsatisfactory pouch function, which can be a difficult problem to manage. METHODS: A Medline search was carried out to identify relevant papers published from November 1996 to January 1978. For clinical information more emphasis was given to recent publications with larger numbers. Where appropriate, information from other sources and some local data were included. RESULTS: Most patients empty the pouch four to eight times a day with perfect continence and no urgency, and are considered to have acceptable function with which they are satisfied. Patients who have poor function beyond an easily treated episode of pouchitis require the expertise of a multidisciplinary team offering some understanding of the anatomy, physiology and pathology of the gastrointestinal tract in general and of the ileal reservoir in particular. A thorough and persistent approach to difficult cases is often rewarded with a good outcome, with the exception of problems arising from postoperative sepsis. The temptation to use pouchitis as a waste-basket diagnosis for poorly understood dysfunction should be avoided. Problems causing poor function may originate in the pouch (including pelvic sepsis), the pouch outlet, or the small bowel above the pouch, and these areas need to be considered in each case. CONCLUSION: To optimize the benefits of restorative pouch surgery, both patients and physicians need to understand aspects of fine tuning of pouch function, including diet, medication and lifestyle. In managing ileoanal reservoir dysfunction the temptation to procrastinate should be resisted; an approach that is systematic and sympathetic should be adopted.

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Houlston RS, Tomlinson IPM, Ford D, Seal S, Marossy AM, Ferguson A, Holmes GKT, Hosie KB, Howdle PD, Jewell DP et al. 1997. Linkage analysis of candidate regions for coeliac disease genes HUMAN MOLECULAR GENETICS, 6 (8), pp. 1335-1339. | Read more

Hyde GM, Jewell DP. 1997. Review article: the management of severe ulcerative colitis. Aliment Pharmacol Ther, 11 (3), pp. 419-424. | Show Abstract | Read more

Severe ulcerative colitis is a potentially life-threatening condition but the mortality has fallen dramatically over the past 30-40 years. It is now less than 2%, including surgical mortality, and should only be seen in patients with significant co-existing disease. Early recognition of the severity of the colitis, intensive medical therapy, close liaison between physician and surgeon, and prompt surgery when necessary have all contributed to this improved outcome. Despite the use of high-dose intravenous corticosteroids, 20-30% of patients will make a poor response and will require urgent surgery. The use of intravenous cyclosporin has proved effective at reducing the immediate surgical rate in this group of unresponsive patients and appears safe. Whether cyclosporin reduces the need for surgery in the longer term is much less certain. Clinical, radiological, endoscopic and laboratory parameters can now be used to predict the course of a severe attack. These help in the timing of urgent surgery and are potentially helpful in determining when to begin other therapies such as cyclosporin.

Roussomoustakaki M, Satsangi J, Welsh K, Louis E, Fanning G, Targan S, Landers C, Jewell DP. 1997. Genetic markers may predict disease behavior in patients with ulcerative colitis. Gastroenterology, 112 (6), pp. 1845-1853. | Show Abstract | Read more

BACKGROUND & AIMS: Recent studies have suggested that HLA DRB1*0103 and allele 2 of the interleukin 1 receptor antagonist (IL-1RA) gene predict severe and extensive ulcerative colitis, respectively. The aim of this study was to test these hypotheses in patients undergoing surgery for their colitis. METHODS: HLA DRB1 and DQB1 genotyping was performed in 99 patients and 472 controls. Genotyping for polymorphisms of genes encoding tumor necrosis factor alpha and IL-1RA was performed in 107 patients and 89 controls. Measurement of antineutrophil cytoplasmic antibody (ANCA) was performed in 72 patients and 58 healthy subjects by fixed neutrophil enzyme-linked immunosorbent assay and indirect immunofluorescence. RESULTS: The DRB1*0103 allele was increased in patients (14.1% vs. 3.2% in controls; P < 1 x 10[-5]). This association was greatest in patients with extensive disease (15.8%; P < 0.0001) or extraintestinal manifestations (22.8%; P < 0.0001): mouth ulcers (25.8%; P < 0.0001), arthritis (27.2%; P < 0.0001), and uveitis (35.7%; P < 0.0001). The DRB1*04 alleles were reduced in patients (P = 0.005). Differences were noted between extensive and distal disease in the frequency of allele 2 of IL-1RA (10.9% in distal vs. 28.6% in extensive; P = 0.01) and allele 2 homozygosity. ANCA was detected in 76.4% of patients. Carriage of IL-1RA allele 2 and tumor necrosis factor 2 allele was increased in ANCA-positive patients. CONCLUSIONS: Genetic markers may predict disease behavior in ulcerative colitis.

Romanos J, Samarasekera DN, Stebbing JF, Jewell DP, Kettlewell MG, Mortensen NJ. 1997. Outcome of 200 restorative proctocolectomy operations: the John Radcliffe Hospital experience. Br J Surg, 84 (6), pp. 814-818. | Show Abstract | Read more

BACKGROUND: Restorative proctocolectomy is now the operation of choice for the definitive management of ulcerative colitis and familial adenomatous polyposis (FAP). METHODS: A total of 200 patients (117 male, 83 female) underwent restorative proctocolectomy over a 12-year period. Information in a dedicated prospective database was supplemented by chart review. Some 177 had ulcerative colitis, 13 had indeterminate colitis and seven had FAP. Pouch designs were two-loop J (n = 142), four-loop W (n = 45) and three-loop S (n = 13). The majority (73.5 per cent) had a stapled ileoanal anastomosis and 139 patients had a defunctioning ileostomy. RESULTS: There were no deaths. Early morbidity (less than 30 days after operation) included 76 complications in 71 patients (35.5 per cent), of which 35 were related to the pouch itself. Long-term follow-up data were available for 196 patients at a median of 27 months. Sixteen pouches (8.0 per cent) have been excised. Mean daytime frequency was 4.5 (range 1-15). Of 175 patients with colitis, 42 (24.0 per cent) had one or more episodes of pouchitis. CONCLUSION: Continuous improvements in operative technique have simplified the procedure, and functional results, although variable, have generally been acceptable.

Satsangi J, Jewell DP, Bell JI. 1997. The genetics of inflammatory bowel disease. Gut, 40 (5), pp. 572-574. | Read more

Snook JA, Dwyer L, Lee-Elliott C, Knan S, Wheeler DW, Nicholas DS, Merrett MN, Mortensen N, Kettlewell, Jewell DP. 1997. Smoking benefits celiac sprue and pouchitis: implications for nicotine therapy? Gastroenterology, 112 (3), pp. 1048-1050. | Read more

Smithson JE, Campbell A, Andrews JM, Milton JD, Pigott R, Jewell DP. 1997. Altered expression of mucins throughout the colon in ulcerative colitis. Gut, 40 (2), pp. 234-240. | Show Abstract | Read more

BACKGROUND/AIMS: Regional differences in the biology of the colonic epithelium may determine the extent of involvement by ulcerative colitis. Novel monoclonal antibodies (MAbs) were used in this study to investigate regional heterogeneity in the colonic mucosa. METHODS: MAbs generated using a method of tolerisation against common antigens in the proximal colon and distal colon were used for immunoperoxidase staining, comparative histochemistry, immunoblotting, and slot-blot analysis. RESULTS: The colon specific MAbs 5F1 (IgG3) and 6G4 (IgM) stained goblet cell contents throughout the normal distal colon but staining was markedly reduced in the proximal colon (p < 0.0001). In the distal colon of patients with ulcerative colitis, whether quiescent or actively inflamed, reactivity was reduced compared with controls (p < 0.05, p < 0.001 respectively). By contrast, an overall increase in staining was seen in the uninflamed proximal colon in ulcerative colitis compared with controls (p < 0.02). Comparative staining with high iron diamine and biochemical analyses indicated that MAb 6G4 was reactive with mucin bearing sulphate or O-acetylated sialic acid groups, or both. CONCLUSIONS: Regional differences in the staining characteristics of normal colonic mucin have been shown using novel monoclonal antibodies. The pattern of mucin expression throughout the colon in ulcerative colitis is altered even in the absence of histological changes.

Parkes M, Satsangi J, Lathrop GM, Bell JI, Jewell DP. 1996. Susceptibility loci in inflammatory bowel disease. Lancet, 348 (9041), pp. 1588. | Read more

Campbell AP, Smithson J, Lewis C, Kettlewell MG, Mortensen N, Jewell DP, McGee JO. 1996. Altered expression of TGF alpha and TGF beta 1 in the mucosa of the functioning pelvic ileal pouch. J Pathol, 180 (4), pp. 407-414. | Show Abstract | Read more

The mucosa of the functioning pelvic ileal pouch undergoes loss of villous height and an increase in crypt cell proliferation as an adaptive response to its new luminal environment. These changes can occur in the absence of inflammation and could be mediated by growth factors such as transforming growth factors alpha and beta 1 (TGF alpha and TGF beta 1). Expression of TGF alpha and TGF beta 1 messenger RNA (mRNA) and protein was determined by in situ hybridization and immunohistochemistry in sections of terminal ileum taken at the time of pouch formation and of subsequent pouch biopsies from 14 patients (total of 90 specimens). Crypt cell proliferation was assessed using the monoclonal antibody MIB-1. As ileal pouch mucosa underwent loss of villous height and crypt hyperplasia, epithelial expression of TGF alpha mRNA and protein decreased. In contrast, TGF beta 1 mRNA and protein were abundant in both normal and flat mucosa. Epithelial expression of TGF beta 1 protein was maximal in flat, inflamed biopsies. These results suggest that although altered expression of TGF alpha and TGF beta 1 mRNA and protein may play some part in the regulation of the adaptive response in ileal pouch mucosa, TGF alpha does not have a direct, positive role in the regulation of crypt cell proliferation.

Smithson JE, Warren BF, Young S, Pigott R, Jewell DP. 1996. Heterogeneous expression of carcinoembryonic antigen in the normal colon and upregulation in active ulcerative colitis. J Pathol, 180 (2), pp. 146-151. | Show Abstract | Read more

Using a technique of tolerization, a murine monoclonal antibody (MAb 2E8) has been raised which displays regional differences in reactivity in the epithelium of the normal human colon and increased reactivity in active ulcerative colitis. MAb 2E8 (IgG1) was highly colon-specific and gave higher immunoperoxidase staining scores in the proximal colonic mucosa compared with paired rectal sections (P < 0.02). Expression of the antigen reactive with MAb 2E8 was enhanced in active ulcerative colitis compared with quiescent ulcerative colitis (P < 0.05) and normal controls (P < 0.001). Western blotting and indirect immunofluorescent screening on transfected cell lines established that MAb 2E8 was reactive with carcinoembryonic antigen (CEA). This is the first demonstration of regional differences in the expression of CEA in the normal colon and indicates upregulation of this molecule in active ulcerative colitis.

Satsangi J, Parkes M, Louis E, Hashimoto L, Kato N, Welsh K, Terwilliger JD, Lathrop GM, Bell JI, Jewell DP. 1996. Two stage genome-wide search in inflammatory bowel disease provides evidence for susceptibility loci on chromosomes 3, 7 and 12. Nat Genet, 14 (2), pp. 199-202. | Show Abstract | Read more

Crohn's disease (CD) and ulcerative colitis (UC), the chronic inflammatory bowel diseases (CIBD), are common causes of gastro-intestinal disease in the Western world, with a combined prevalence of 100-200/100,000 (ref. 1). Epidemiological studies, particularly concordance rates in twin pairs and siblings, strongly implicate genetic susceptibility in the pathogenesis of CIBD. In fact, the relative contribution of genetic factors to the pathogenesis of CD may be greater than in schizophrenia, asthma or hypertension, and at least equivalent to that in insulin-dependent diabetes. Systematic screening of the entire human genome now provides a strategy for the identification of susceptibility genes in complex polygenic disorders. We undertook a two-stage genome search for susceptibility genes in inflammatory bowel disease involving 186 affected sibling pairs from 160 nuclear families. We provide strong evidence for the presence of susceptibility loci for both CD and UC on chromosome 3, 7 and 12. We obtained the highest lod score (5.47; P = 2.66 x 10(-7) with the marker D12S83 and lod scores of 3.08 and 2.69 for D7S669 and D3S1573, respectively. Our data suggest that CD and UC are closely related, but distinct, polygenic disorders that share some, but not all, susceptibility genes.

Hayward PA, Satsangi J, Jewell DP. 1996. Inflammatory bowel disease and the X chromosome. QJM, 89 (9), pp. 713-718. | Show Abstract | Read more

A review of documented cases demonstrates a significant association of Turner's syndrome with Crohn's disease and ulcerative colitis; this association relates particularly to genetic constitutions comprising an abnormal rather than an absent X chromosome. The karyotype 46XiXq, in pure or mosaic form, appears to be a significant susceptibility factor for inflammatory bowel disease. This karyotype often gives rise to relatively weak phenotypic characteristics of Turner's syndrome, which may be overlooked in short females with inflammatory bowel disease. The association of inflammatory bowel disease with Turner's syndrome may reflect the presence on the X chromosome of genes involved in disease pathogenesis. Linkage analysis studies, involving microsatellite markers on the X chromosome, are being performed.

Satsangi J, Parkes M, Jewell DP. 1996. Genetics of ulcerative colitis. Lancet, 348 (9027), pp. 624-625. | Read more

Merrett MN, Soper N, Mortensen N, Jewell DP. 1996. Intestinal permeability in the ileal pouch. Gut, 39 (2), pp. 226-230. | Show Abstract | Read more

BACKGROUND: Villous atrophy, mucin changes ('colonic metaplasia'), and chronic inflammation occur to varying degrees in all patients with ileal pouchanal anastomosis whereas acute inflammation (pouchitis) affects a subgroup of patients with prior ulcerative colitis. AIM: To measure epithelial barrier function looking for possible functional adaptation in ileal 'pouch' mucosa. PATIENTS: Patients with an ileal pouch prior to ileostomy closure (n = 12), functioning pouch (n = 14), pouchitis (n = 8), and ulcerative colitis (n = 12) were assessed. METHODS: 51Cr-EDTA was administered into the 'pouch' or rectum and urinary recovery over 24 hours was taken as an indication of permeability (barrier function). Histological analysis of 'pouch' biopsy specimens was undertaken. RESULTS: Mucosal permeability is decreased from median 9.4% (range 5.4% to 39.1%) to 1.4% (range 0.38% to 2.2%) after ileostomy closure (p < 0.002) with levels being negatively correlated with two histological parameters of colonic metaplasia-mucin changes (p = 0.03) and villous atrophy (p = 0.05). Pouchitis was associated with increased permeability 5.9% (1.9% to 19.5%) compared with healthy 'pouch' 1.4% (0.35 to 2.2%) (p < 0.006). CONCLUSION: Despite the presence of chronic inflammation in the mature 'pouch' functional adaptation with reduced permeability occurs in conjunction with colonic metaplasia.

Farrant JM, Traill Z, Conlon C, Warren B, Mortensen N, Gleeson FV, Jewell DP. 1996. Pigbel-like syndrome in a vegetarian in Oxford. Gut, 39 (2), pp. 336-337. | Show Abstract | Read more

Enterocolitis necroticans or pigbel is a rare condition characteristically affecting chronically malnourished people who abruptly increase their intake of protein. The classic presentation of the disease as seen in the highlands of Papua New Guinea is that of a necrotising enterocolitis after the ritual ingestion of contaminated pork. In this context, the presentation of the same disease in a well nourished white vegetarian in Oxford was all the more intriguing.

Chen D, Radford-Smith G, Dipaolo MC, McGowan I, Jewell DP. 1996. Cytokine gene transcription of human colonic intraepithelial lymphocytes costimulated with epithelial cells bearing HLA-DR and its inhibition by 5-aminosalicylic acid. J Clin Immunol, 16 (4), pp. 237-241. | Show Abstract | Read more

The objectives of this study were to activate human colonic intraepithelial lymphocytes at the transcriptional level with HLA-DR+ human colonic epithelial cell line (HT29) in synergy with CD3 monoclonal antibody and to investigate the molecular mechanism for the therapeutic effects of 5-aminosalicylic acid. Lymphocytes were isolated by a mechanical method from resected colon of 22 cases and then cocultured on 10 ng/ml CD3mAb immobilized plates with HT29 which had been induced to express MHC class II molecules by interferon gamma. Flow cytometry analysis suggested that the lymphocyte population had a CD4/CD8 ratio similar to that observed in intact tissue sections and that there was no HT29 contamination of the lymphocytes isolated again from cocultured cells. The activation of intraepithelial lymphocytes showed the gene transcription of interferon gamma and tumor necrosis factor alpha, as measured by means of the reverse-transcriptase polymerase chain reaction, and this activation was antagonized by 5-aminosalicylic acid. Thus, epithelial cells bearing HLA-DR are capable of enhancing CD3-induced activation of human colonic intraepithelial lymphocytes and subject to inhibition by 5-aminosalicylic acid, the active moiety of salicylates used in inflammatory bowel disease.

Travis SP, Farrant JM, Ricketts C, Nolan DJ, Mortensen NM, Kettlewell MG, Jewell DP. 1996. Predicting outcome in severe ulcerative colitis. Gut, 38 (6), pp. 905-910. | Show Abstract | Read more

BACKGROUND: Simple criteria are needed to predict which patients with severe ulcerative colitis will respond poorly to intensive medical treatment and require colectomy. AIMS: To find out if the early pattern of change in inflammatory markers or other variables could predict the need for surgery and to evaluate the outcome of medical treatment during one year follow up. PATIENTS: 51 consecutive episodes of severe colitis (Truelove and Witts criteria) affecting 49 patients admitted to John Radcliffe Hospital, Oxford. METHODS: Prospective study monitoring 36 clinical, laboratory, and radiographic variables. All episodes treated with intravenous and rectal hydrocortisone and 14 of 51 with cyclosporine. RESULTS: Complete response in 21 episodes (< or = 3 stools on day 7, without visible blood), incomplete response in 15 (> 3 stools or visible blood on day 7, but no colectomy), and colectomy on that admission in 15. During the first five days, stool frequency and C reactive protein (CRP) distinguished between outcomes (p < 0.00625, corrected for multiple comparisons) irrespective of whether patients or the number of episodes were analysed. It could be predicted on day 3, that 85% of patients with more than eight stools on that day, or a stool frequency between three and eight together with a CRP > 45 mg/l, would require colectomy. For patients given cyclosporine, four of 14 avoided colectomy but two continued to have symptoms. After admission, complete responders remained in remission for a median nine months and had a 5% chance of colectomy. Incomplete responders had a 60% chance of continuous symptoms and 40% chance of colectomy. CONCLUSIONS: After three days intensive treatment, patients with frequent stools (> 8/day), or raised CRP (> 45 mg/l) need to be identified, as most will require colectomy on that admission. The role of cyclosporine for treating severe colitis has yet to be defined. After seven days' treatment, patients with > 3 stools/day of visible blood have a 60% chance of continuous symptoms and 40% chance of colectomy in the following months.

Satsangi J, Welsh KI, Bunce M, Julier C, Farrant JM, Bell JI, Jewell DP. 1996. Contribution of genes of the major histocompatibility complex to susceptibility and disease phenotype in inflammatory bowel disease. Lancet, 347 (9010), pp. 1212-1217. | Show Abstract | Read more

BACKGROUND: Despite strong evidence implicating immune dysfunction and genetic predisposition in the pathogenesis of the chronic inflammatory bowel diseases Crohn's disease and ulcerative colitis, the importance of the genes of the major histocompatibility complex remains uncertain. We have investigated the contribution of HLA DRB1 and DQB genes by the strategies of non-parametric linkage analysis (affected sibling pair method) as well as association study. The relation between genotype and phenotype was examined in detail. METHODS: For linkage analysis 74 families in whom two or more siblings had inflammatory bowel disease were studied. A total of 83 affected sibling pairs were involved: in 42 pairs both siblings had Crohn's disease; in 29 both had ulcerative colitis; in 12 one sibling had Crohn's disease, the other ulcerative colitis. For the association study there were 175 patients with ulcerative colitis, 173 with Crohn's disease, and 472 controls. Details of sex, age of onset, disease extent, and family history were analysed. 24 patients with ulcerative colitis and 92 with Crohn's disease required surgery for refractory disease. HLA DRB1 and DQB1 gene-typing was performed by polymerase chain reaction with sequence-specific primers. FINDINGS: In ulcerative colitis, the sharing of alleles among affected sibling pairs provided evidence for linkage with DRB1 locus (p = 0.017, chi2 = 5.32). Of 29 affected sibling pairs studied, only one pair shared no DRB1 DQB haplotypes. 15 shared two DRB DQB haplotypes. In contrast, no linkage was noted for Crohn's disease (42 sibling pairs; p = 0.30, chi2 = 0.16) or for inflammatory bowel disease overall (83 sibling pairs, p = 0.16, chi2 = 2.28). In the association study the rare DRB1*103 (8.3% vs 3.2% in controls) and DRB1*12 (8.6% vs 2.1% in controls) alleles were associated with ulcerative colitis (p = 0.0074, chi2 = 7.22, odds ratio OR = 2.9 [95% CI 1.3-6.4] and p = 0.0056, chi2 = 12.63, OR = 4.33 [1.8-11.0] respectively). No association with alleles representing DR2 (p = 0.55, chi2 = 0.34) was noted. No overall association was seen in Crohn's disease. In ulcerative colitis, the frequency of DRB1*0301 DQB*0201 (DR3 DQ2) was reduced in females (9.8% vs 26.3% in controls, p = 0.037, chi2 = 8.39 OR = 0.34 [0.15-0.71]), particularly in those with distal disease (2.3%, p = 0.001 vs controls, chi2 = 11.35, OR = 0.07 [0.00-0.39]). In both males and females, the DR3 DQ2 haplotype was predictive of extensive ulcerative colitis (32.9% vs 10.7% in distal disease, p < 0.01, chi2 = 10.94, OR 4.09 [1.70-10.6]) but not of need for surgery (p = 0.93, chi2 = 0.01). INTERPRETATION: These data provide strong evidence for genetic heterogeneity in inflammatory bowel disease. Genes of the major histocompatibility complex are implicated as important inherited determinants of susceptibility to ulcerative colitis and may also influence the pattern of disease. In Crohn's disease, important susceptibility genes are likely to exist outside the HLA region.

Satsangi J, Grootscholten C, Holt H, Jewell DP. 1996. Clinical patterns of familial inflammatory bowel disease. Gut, 38 (5), pp. 738-741. | Show Abstract | Read more

BACKGROUND: Although many recent studies have shown the increased risk of inflammatory bowel disease in relatives of patients with Crohn's disease and ulcerative colitis, clinical patterns of disease within families remain relatively poorly documented. AIMS: In this study, clinical characteristics (disease type, extent, age on onset, need for surgery, and presence of extraintestinal manifestations) have been compared in affected subjects in multiply-affected families, with inflammatory bowel disease. METHODS: 54 families in whom one parent and at least one child were affected (a total of 77 parent-child pairs) and 155 families in whom at least two siblings were affected (a total of 190 affected sibling pairs) were involved. RESULTS: In affected parent-child pairs, parent and child were concordant for disease type in 58 of 77 pairs (75.3%), for extent in 63.6%, extraintestinal manifestations in 70.1%, and smoking history in 85%. The median age of onset in parents was significantly higher than offspring (p < 0.0001). In 40 pairs, 60.6%, the parent was at least 10 years older than child. Siblings were concordant for disease type in 81.6% of the affected sibling pairs, extent in 76.0%, extraintestinal manifestations in 83.8%, and smoking history in 81.3%. In contrast with the parent-child pairs, 68.1% (111 sibling pairs) siblings were diagnosed within 10 years of each other. The median age of onset was 24.0 years. CONCLUSIONS: This study has shown consistent clinical patterns in many families with inflammatory bowel disease. The differences in age of onset between parents and children are not readily explained by a simple cohort effect or ascertainment bias, and may reflect effects of genetic factors, producing anticipation between generations.

McGowan I, Tenant-Flowers M, Jewell DP. 1996. Identification of HIV-1 viral RNA in intestinal tissue from patients with early and late HIV infection. AIDS, 10 (5), pp. 548-549. | Read more

Samarasekera DN, Stebbing JF, Kettlewell MG, Jewell DP, Mortensen NJ. 1996. Outcome of restorative proctocolectomy with ileal reservoir for ulcerative colitis: comparison of distal colitis with more proximal disease. Gut, 38 (4), pp. 574-577. | Show Abstract | Read more

BACKGROUND: An increasing number of patients with severe or refractory ulcerative colitis involving only the rectum and sigmoid colon are being offered restorative proctocolectomy with ileal reservoir but very few data are available concerning the outcome for these patients. AIM: This study was designed to compare the outcome of ileal pouch procedures for distal ulcerative colitis with procedures performed for more extensive disease. PATIENTS: A consecutive series of 177 patients undergoing restorative proctocolectomy for ulcerative colitis between January 1984 and December 1994. METHODS: Data were collected prospectively in a dedicated ileal pouch database and included demographic details, indication for surgery, surgical procedures performed, early (< 30 days) and late morbidity, functional outcome, and histopathology. RESULTS: There was no mortality in the series. The incidence and range of early morbidity (< 30 days) and the functional outcome (daytime stool frequency, nocturnal frequency, and the incidence of incontinence) were similar for all groups. Log rank analysis of Kaplan-Meier estimates showed no significant difference between groups in the likelihood of developing pouchitis (p > 0.2). CONCLUSIONS: Patients undergoing restorative proctocolectomy for distal colitis experience a similar outcome to patients with more extensive disease. These data refute the hypothesis that pouchitis is more common in patients with total colitis.

Radford-Smith G, Jewell DP. 1996. Cytokines and inflammatory bowel disease. Baillieres Clin Gastroenterol, 10 (1), pp. 151-164. | Show Abstract | Read more

Cytokines play an important role in the pathology of inflammatory bowel disease by determining the nature of the mucosal immune response. One way of establishing whether CD and UC are causally related to a defect in the host immune response is to look for polymorphisms that are over-represented in these populations. This is being carried out at great pace both for the cytokine genes and for some other immune response genes. A number of gene expression studies have established that those cytokines produced by activated macrophages such as IL-1, IL-6 and TNF are significantly elevated in both diseases. Differences between the two diseases are less clear, and, where they have been found, they probably reflect the accuracy and sensitivity of quantification. The picture is less clear for the T-cell-derived cytokines, which are generally expressed at a lower copy number in intestinal tissue compared to the monokines. For Crohn's disease, the TH1 cytokines IL-2 and IFN may be abnormally elevated or decreased. In contrast, the TH1/TH2 profile in UC is not significantly different from normal controls. Further work is required to confirm these findings.

Satsangi J, Jewell DP. 1996. Are cytokine gene polymorphisms important in the pathogenesis of inflammatory bowel disease? Eur J Gastroenterol Hepatol, 8 (2), pp. 97-99. | Read more

Lee FI, Jewell DP, Mani V, Keighley MR, Kingston RD, Record CO, Grace RH, Daniels S, Patterson J, Smith K. 1996. A randomised trial comparing mesalazine and prednisolone foam enemas in patients with acute distal ulcerative colitis. Gut, 38 (2), pp. 229-233. | Show Abstract | Read more

Distal ulcerative colitis can be treated with oral or rectal mesalazine, or both. A foam enema preparation has been developed and its efficacy investigated. The aim of this study was to evaluate the efficacy and safety of mesalazine foam enemas compared with prednisolone foam enemas in the treatment of patients with acute distal ulcerative colitis. Patients aged over 18 years presenting with a relapse of distal ulcerative colitis were randomly allocated treatment with mesalazine foam enema (n = 149 evaluable patients) and prednisolone foam enema (n = 146 evaluable patients) for four weeks. A randomised multicentre investigator blind parallel group trial was conducted. It was found that after four weeks of treatment, clinical remission was achieved by 52% of mesalazine treated patients and 31% of patients treated with prednisolone (p < 0.001). There was a trend in favour of more patients in the mesalazine group achieving sigmoidoscopic remission (40% v 31%, p = 0.10). Histological remission was achieved by 27% and 21% of patients receiving mesalazine and prednisolone respectively. Symptoms improved in both treatment groups. Significantly more mesalazine patients had no blood in their stools after four weeks of treatment (67% v 40%, p < 0.001). Prednisolone treated patients had significantly fewer days with liquid stools than mesalazine patients, with a median of 0 and 1 days respectively by week 4 (p = 0.001). In this study mesalazine foam enema was superior to prednisolone foam enema with regards to clinical remission, this was supported by favourable trends in sigmoidoscopic and histological remission rates. Both treatments were well tolerated.

Di Paolo MC, Merrett MN, Crotty B, Jewell DP. 1996. 5-Aminosalicylic acid inhibits the impaired epithelial barrier function induced by gamma interferon. Gut, 38 (1), pp. 115-119. | Show Abstract | Read more

Gamma interferon (IFN gamma) impairs epithelial barrier function and induces HLA-DR expression on colonic cancer cell lines. Salicylates have been shown to reduce IFN gamma induced HLA-DR expression. The effect of 5-aminosalicylic acid (5-ASA) on IFN gamma induced changes in transepithelial resistance and permeability was investigated in HT29 clone 19A and Caco 2 monolayers. Monolayers were incubated with different concentrations of IFN gamma (100, 500, 1000, and 3000 U/ml) and 5-ASA. IFN gamma induced class II expression in a time and dose dependent manner in HT29:19A but not Caco 2 cells. HT29:19A monolayers incubated with both IFN gamma and 5-ASA showed lower HLA-DR expression compared with monolayers incubated with IFN gamma alone. Electrical resistance and 14C-mannitol flux across HT29:19A monolayers were significantly changed by IFN gamma. Addition of both IFN gamma and 5-ASA to the basolateral surface of the monolayers significantly reduced paracellular permeability compared with addition of IFN gamma alone. These data show that IFN gamma is able to induce HLA-DR expression and to impair the barrier function of HT29:19A monolayers, and that 5-ASA reduces IFN gamma induced HLA-DR expression and inhibits the effects of IFN gamma on epithelial barrier function.

Zimmerman MJ, Jewell DP. 1996. Cytokines and mechanisms of action of glucocorticoids and aminosalicylates in the treatment of ulcerative colitis and Crohn's disease. Aliment Pharmacol Ther, 10 Suppl 2 (Sup2), pp. 93-98. | Show Abstract | Read more

Medical therapy of ulcerative colitis and Crohn's disease involves the control of active inflammation to obtain clinical remission and then maintaining that remission. Corticosteroids and 5-aminosalicylic acid are the mainstay of such management. Both have a wide range of properties and are able to inhibit many effector mechanisms which are potentially involved in mucosal inflammation. In in vitro assays, both are able to inhibit the release of a wide variety of pro-inflammatory and immunoregulatory cytokines. In vivo, such effects would limit tissue damage, prevent further amplification of the immune response and restore epithelial function.

Oshitani N, Campbell A, Kitano A, Kobayashi K, Jewell DP. 1996. In situ comparison of phenotypical and functional activity of infiltrating cells in ulcerative colitis mucosa. J Pathol, 178 (1), pp. 95-99. | Show Abstract | Read more

The production of reactive oxygen species may have an important role in the pathogenesis of inflammatory bowel disease, yet the cells responsible in colonic mucosa have not been clearly defined. We studied 28 patients with ulcerative colitis and 13 controls to determine the cells generating reactive oxygen species, using a combined method for determining nitroblue tetrazolium reducing activity and immunohistochemical characterization. In contrast to the proportion of EBM11-positive cells (tissue macrophages), which did not increase in inflamed mucosa, the proportions of PMN-13F6 positive cells, CD11b-positive cells, and eosinophils were significantly increased in inflamed mucosa. PMN-13F6 positive cell and eosinophil counts were significantly correlated with CD11b positivity. Eosinophils, however, showed a stronger correlation with CD11b positivity than PMN-13F6-positive cells. The majority of CD11b-positive cells were eosinophils. Although some nitroblue tetrazolium reducing leukocytes were positively stained with EBM11 or PMN-13F6, eosinophils were the major subset of nitroblue tetrazolium reducing leukocytes. Recruitment and activation of eosinophils may play an important role in the pathogenesis of ulcerative colitis.

Stebbing JF, Jewell DP, Kettlewell MG, Mortensen NJ. 1995. Recurrence and reoperation after strictureplasty for obstructive Crohn's disease: long-term results [corrected]. Br J Surg, 82 (11), pp. 1471-1474. | Show Abstract | Read more

Strictureplasty extends the surgical options for the treatment of obstructive Crohn's disease. Over 15 years, 52 patients had 241 strictureplasties at 76 operations with no operative mortality and with septic complications in only two patients (4 percent). Median (range) follow-up was 49.5 (1-182) months. Nineteen patients (36 percent) required a second operation for Crohn's disease between 1 and 57 months after first strictureplasty. Most symptomatic recurrence was caused by new segments of stricturing or perforating disease, and recurrence of Crohn's disease was noted at only nine strictureplasty sites (3.7 percent) in four patients. Seven patients (13 percent) required a third operation for Crohn's disease. Patients undergoing strictureplasty alone were no more likely to require reoperation than those who had a concomitant resection at the first procedure (X2 = 0.619, P > 0.2). The reoperation rates after first and second operations were similar (X2 = 0.021, P > 0.2). Minimal surgery does not appear to lead to an accelerated or additional need for subsequent operation. Strictureplasty provides a safe, effective and rapid procedure to restore patients to good health while preserving the intestine and may be recommended for carefully selected strictures as an adjunct to conventional excisional surgical treatment.

Jewell DP. 1995. Immunology of inflammatory bowel disease--an update. J Gastroenterol, 30 Suppl 8 (SUPPL. 8), pp. 78-82.

Oshitani N, Campbell A, Bloom S, Kitano A, Kobayashi K, Jewell DP. 1995. Adhesion molecule expression on vascular endothelium and nitroblue tetrazolium reducing activity in human colonic mucosa. Scand J Gastroenterol, 30 (9), pp. 915-920. | Show Abstract | Read more

BACKGROUND: Expression of adhesion molecules is increased in inflamed colonic mucosa, but little is known about their functional activity in vascular endothelium. METHODS: We studied in situ nitroblue tetrazolium reducing activity and expression of E-selectin, ICAM-1, CD31, and VCAM-1 by immunohistochemistry in the same biopsy specimen in controls and patients with ulcerative colitis (UC). RESULTS: VCAM-1 expression was negative in mucosal vessels. E-selectin-positive vessels were significantly increased in endoscopically active colitis compared with normal mucosa. ICAM-1-positive vessels were consistently found in normal, quiescent UC and active UC. CD31-positive vessels were not significantly increased in quiescent UC and active UC compared with control. Only E-selectin significantly correlated with the histologic grade of inflammation. Nitroblue tetrazolium reducing vessels were increased in inflamed mucosa, and these vessels expressed ICAM-1 and CD31. E-selectin positivity in association with nitroblue tetrazolium reduction was mainly seen in the large mucosal vessels, but capillaries showing nitroblue tetrazolium reduction were rarely positive for E-selectin. CONCLUSIONS: Phenotypic and functional activation of vascular endothelium might be involved in the recruitment of leukocytes and tissue destruction of inflamed colonic mucosa.

Bloom S, Simmons D, Jewell DP. 1995. Adhesion molecules intercellular adhesion molecule-1 (ICAM-1), ICAM-3 and B7 are not expressed by epithelium in normal or inflamed colon. Clin Exp Immunol, 101 (1), pp. 157-163. | Show Abstract | Read more

Adhesion molecules are involved in facilitating cell-mediated immune events. Because lymphocyte-epithelial cell interaction has been implicated in the pathogenesis of colonic inflammation, we analysed expression of a range of adhesion molecules on colonic epithelium in vitro and in vivo using flow cytometry, immunohistochemistry and in situ hybridization. Expression of ICAM-1 by cell lines HT29 and int407 was increased by proinflammatory cytokines interferon-gamma (IFN-gamma), tumour necrosis factor-alpha (TNF-alpha) and IL-1 but not by IL-6. Vascular cell adhesion molecule (VCAM) and E-selectin were not expressed. Immunohistochemistry using sections of inflamed colon from 16 patients with ulcerative colitis (UC), five patients with Crohn's disease (CD) and seven patients with normal colonoscopic biopsies, showed no expression of ICAM-1 on colonic epithelium. VCAM was seen in isolated lymphoid aggregates and E-selectin was expressed on endothelium. In situ hybridization showed no ICAM-1 or ICAM-3 mRNA in colonic epithelium. B7, the ligand for CD28, was not found on normal or inflamed colonic epithelium. The adhesion molecules ICAM-1, ICAM-3 and B7 are not involved in lymphocyte-epithelial cell interaction in the normal or inflamed colon. This may have implications for the development of T cell tolerance to intestinal luminal antigens.

Roskell DE, Hyde GM, Campbell AP, Jewell DP, Gray W. 1995. HIV associated cytomegalovirus colitis as a mimic of inflammatory bowel disease. Gut, 37 (1), pp. 148-150. | Show Abstract | Read more

Cytomegalovirus (CMV) colitis may cause symptoms and signs identical to those of idiopathic inflammatory bowel disease. Although difficult to diagnose with certainty, the histological finding of cytomegalovirus inclusions in tissue from a case of suspected inflammatory bowel disease is strongly suggestive. CMV colitis is an entity almost entirely confined to cases of severe immunosuppression. The case of a 79 year old widower who was admitted to hospital with symptoms suggestive of inflammatory bowel disease is presented. Despite medical treatment his condition worsened and he developed toxic dilatation of the colon requiring colectomy. Histological examination showed a mild superficial pancolitis, with focal severe inflammation, deep fissuring ulceration, and pseudopolyposis. Abundant CMV inclusions were seen in cells associated with the ulcerating inflammatory tissue. A diagnosis of indeterminate colitis with CMV was made. The patient's condition worsened after surgery and he died a few days later despite intensive treatment, including antiviral chemotherapy directed against CMV. After death HIV serology was found to be positive. Regardless of the age and perceived lifestyle of the patient, a diagnosis of CMV colitis in someone not known to be immunosuppressed raises the possibility of HIV infection.

Rosenberg WM, Prince C, Kaklamanis L, Fox SB, Jackson DG, Simmons DL, Chapman RW, Trowell JM, Jewell DP, Bell JI. 1995. Increased expression of CD44v6 and CD44v3 in ulcerative colitis but not colonic Crohn's disease. Lancet, 345 (8959), pp. 1205-1209. | Show Abstract | Read more

Immune mechanisms, possibly involving cell-surface molecules such as CD44, have been invoked to explain the pathogenesis of inflammatory bowel disease. We used monoclonal antibodies against epitopes encoded within the variable region of CD44 to investigate CD44 isoform expression in colon, small intestine, and liver in patients with various intestinal disorders and in controls. Biopsy samples from patients with ulcerative colitis showed significantly increased epithelial expression of CD44 isoforms containing the v6 and v3 epitopes, detected with antibodies 2F10 and 3G5, respectively. CD44v6 was detected on colonic crypt epithelial cells in 23 of 25 ulcerative colitis samples compared with 3 of 18 colonic Crohn's disease samples (p = 3.0 x 10(-6); odds ratio 57.5 [95% CI 6.83-702]) and 3 of 52 controls (22 normal colon, 10 infective colitis, 2 radiation colitis, and 18 colonic Crohn's disease; p < 1 x 10(-8); odds ratio 199 [25.5-2294]). No significant expression of CD44v6, CD44v3, or CD44v8/9 was found in samples of normal proximal colon from 4 patients with distal ulcerative colitis, whereas samples from the affected area showed staining for CD44v6 and CD44v3. No expression of CD44 variants was found in 15 samples of normal small intestine, 11 small-bowel pouchitis, 8 coeliac disease, 3 small-bowel Crohn's disease, 6 normal liver, 6 primary biliary cirrhosis, or 9 primary sclerosing cholangitis. The high intensity of CD44v6 and v3 epitope expression on crypt epithelial cells in ulcerative colitis suggests that CD44 isoforms may have an important role in ulcerative colitis. Their detection could have diagnostic potential in differentiating ulcerative colitis from other forms of colonic inflammation including Crohn's disease.

Jewell DP. 1995. Pathogenesis of Crohn's disease: the environment revisited. Eur J Gastroenterol Hepatol, 7 (5), pp. 383-384.

Haggett PJ, Moore NR, Shearman JD, Travis SP, Jewell DP, Mortensen NJ. 1995. Pelvic and perineal complications of Crohn's disease: assessment using magnetic resonance imaging. Gut, 36 (3), pp. 407-410. | Show Abstract | Read more

This study evaluated the role of magnetic resonance imaging (MRI) in the demonstration of the pelvic and perianal complications of Crohn's disease. Twenty five patients with active Crohn's disease were studied (12 male; mean age 41.1 years). MRI examinations were performed using a 1.5 Tesla system, within 14 days after clinical assessment. T1 and T2 weighted fast spin echo sequences in two or three orthogonal planes were performed, with fat suppression in some cases. The MRI results were correlated with surgical and clinical findings. In 16 patients, cutaneous, deep perineal or enterovesical fistulas or abscesses were diagnosed at MRI which showed close correlation with findings at examination under anaesthetic. In eight patients no fistulas or abscesses were seen at MRI nor was there any evidence of complications on clinical examination and flexible sigmoidoscopy. There was one false negative examination in a patient who had a colovesical fistula. In conclusion, MRI can accurately show the pelvic and perineal complications of Crohn's disease and may render examination under anaesthetic unnecessary.

Rees DC, Satsangi J, Cornelissen PL, Travis SP, White J, Jewell DP. 1995. Are serum concentrations of nitric oxide metabolites useful for predicting the clinical outcome of severe ulcerative colitis? Eur J Gastroenterol Hepatol, 7 (3), pp. 227-230. | Show Abstract

OBJECTIVE: To determine serum concentrations of nitric oxide metabolites (NOX) in patients with severe ulcerative colitis and to assess whether these concentrations predict clinical outcome. PATIENTS: Twenty-six patients (16 men and 10 women, mean age 46 years) with severe ulcerative colitis requiring hospitalization for parenteral steroid therapy. Thirteen patients had a complete clinical response and symptoms resolved after 5 days of parenteral steroid administration; 13 made an incomplete recovery and needed further treatment (six cyclosporin, seven colectomy). METHODS: Serum concentrations of NOX and C-reactive protein (CRP) were measured daily for 3 days in all patients and as clinically indicated thereafter. The normal range for NOX was established by measuring the concentration in 25 healthy controls. RESULTS: Mean serum NOX and CRP concentrations were significantly elevated in both the patients with a complete and those with an incomplete response compared with controls (P < 0.001) on day 1 and fell during the first 3 days of therapy. On day 3, mean serum concentrations of NOX and CRP were lower in the patients with a complete response, but only the difference in CRP attained statistical significance (P = 0.02). There was no correlation between NOX and CRP concentrations. CONCLUSIONS: In the majority of patients with severe ulcerative colitis, circulating concentrations of NOX are increased at presentation and fall promptly during parenteral steroid therapy, irrespective of clinical outcome. However, in a small number of patients NOX concentrations do not fall during steroid treatment and such patients will probably require additional medical therapy or surgery.

Travis SP, Crotty B, Jewell DP. 1995. Site of action of platelet-activating factor within the mucosa of rabbit distal colon. Clin Sci (Lond), 88 (1), pp. 51-57. | Show Abstract | Read more

1. To determine how platelet-activating factor stimulates colonic anion secretion and increases epithelial permeability, epithelial sheets of rabbit distal colon excluding the submucosal neural plexus were mounted in Ussing chambers. The influence of specific inhibitors and 50 nmol/l platelet-activating factor on short-circuit current and transepithelial resistance was then investigated. 2. Pretreatment with 1 mumol/l indomethacin or 1 mumol/l doxantrazole abolished the biphasic stimulation of the short-circuit current and decrease in transepithelial resistance induced by platelet-activating factor. Addition of 10 mumol/l mepyramine attenuated the early phase and completely inhibited the late phase. Pretreatment with 1 mumol/l ranitidine, 0.1 mumol/l tetrodotoxin, 0.1 mumol/l ritanserin or a 5-lipoxygenase inhibitor (1 mumol/l MK886) had no effect. 3. To assess the influence of platelet-activating factor on epithelial function isolated from lamina propria elements, monolayers were cultured from a human colonic epithelial cell line (T-84). 4. The short-circuit current across monolayers mounted in Ussing chambers stimulated by 10 mumol/l ionomycin could be inhibited by pretreatment with ouabain or frusemide, consistent with the capacity for chloride secretion. Addition of platelet-activating factor (up to 500 nmol/l) had no effect on short-circuit current or transepithelial resistance. Receptor expression was examined with [3H] platelet-activating factor in isolated T-84 and HT-29 cells and found to be absent. 5. The influence of physiological concentrations of platelet-activating factor on colonic epithelial anion secretion and increased permeability in rabbit distal colon is indirect and consistent with mediation by prostaglandins released from mucosal mast cells.(ABSTRACT TRUNCATED AT 250 WORDS)

McGowan I, Radford-Smith G, Jewell DP. 1994. Cytokine gene expression in HIV-infected intestinal mucosa. AIDS, 8 (11), pp. 1569-1575. | Show Abstract | Read more

OBJECTIVE: Cytokine dysregulation has been implicated in AIDS pathogenesis and the gastrointestinal tract, containing approximately 40% of the body's lymphoid tissue, is likely to act both as a reservoir of viral infection and a site for immune dysregulation. In this study evidence of cytokine dysregulation in intestinal mucosa has been sought using the reverse transcriptase polymerase chain reaction (RT-PCR) to amplify cytokine mRNA. METHODS: RT-PCR was performed on intestinal biopsies obtained from 50 HIV-infected patients and 31 controls. Tissue was obtained at diagnostic endoscopy and total RNA extracted using an RNAzol technique. Following RT, cDNA was amplified using primers specific for beta-actin, interleukin (IL)-1 beta, tumour necrosis factor (TNF)-alpha, interferon (IFN)-gamma, IL-2, IL-4, IL-10 and IL-13. RESULTS: There was a significant increase in the expression of the proinflammatory cytokines IL-1 beta and IFN-gamma in the HIV-infected compared with the control small intestinal samples (P < 0.01). IL-10 was significantly reduced in the respective groups' large intestine (P < 0.02). The expression of IL-2 was also reduced in both the small and large intestinal HIV samples although this was not significant. IL-13 mRNA was only detected in one control patient. CONCLUSIONS: Dysregulation of cytokine gene expression occurs in the intestinal mucosa of patients with HIV infection and is characterized by increased expression of proinflammatory cytokine mRNA. Further studies are needed to localize the cellular origin of such dysregulation and to quantify the degree of abnormality.

Campbell AP, Merrett MN, Kettlewell M, Mortensen NJ, Jewell DP. 1994. Expression of colonic antigens by goblet and columnar epithelial cells in ileal pouch mucosa: their association with inflammatory change and faecal stasis. J Clin Pathol, 47 (9), pp. 834-838. | Show Abstract | Read more

AIMS: To investigate colonic metaplasia of goblet and columnar epithelial cells in ileal pouch mucosa; to correlate this with the degree of morphological and inflammatory change; and to assess whether such changes are related to the presence of faecal stasis. METHODS: Biopsy specimens of ileal pouch mucosa were taken from 31 patients (30 with ulcerative colitis, one with familial adenomatous polyposis) either before (eight patients) or after (23 patients) ileostomy closure. A simple morphological technique was used to assess changes in villous height. Inflammatory change was estimated using an established scoring system for pouchitis, and acquisition of colonic antigens was determined by immunohistochemistry using three monoclonal antibodies which recognise components of the two major epithelial cell types in the colorectum. The degree of staining with the monoclonal antibodies was graded and the grades correlated with an index of villous atrophy and with the inflammatory scores. RESULTS: Five of eight (63%) pre-closure and 15 of 23 (65%) post-closure biopsy specimens showed increased staining with an antibody against components of columnar epithelial cells. One of eight (12%) pre-closure and 15 of 23 (65%) post-closure biopsy specimens stained with an antibody for colonic mucin. Although both types of staining showed a positive correlation with the pouchitis score, they also occurred in the absence of inflammation. CONCLUSIONS: Both goblet and columnar cells acquire colonic characteristics which are incomplete, but may represent a true adaptive response as they can develop in the absence of inflammation. As the change in goblet cells occurs after ileostomy closure, faecal stasis is likely to be a major contributory factor. Changes in columnar cells may occur before ileostomy closure in the absence of faecal stasis.

Travis SP, Tysk C, de Silva HJ, Sandberg-Gertzén H, Jewell DP, Järnerot G. 1994. Optimum dose of olsalazine for maintaining remission in ulcerative colitis. Gut, 35 (9), pp. 1282-1286. | Show Abstract | Read more

To evaluate the optimum dose of olsalazine for maintaining remission in ulcerative colitis, 198 patients in remission for more than three months were randomly assigned to receive 0.5 g, 1.0 g, or 2.0 g/day for 12 months. A dose-ranging effect was detected in the per protocol analysis, with remission rates of 60% (0.5 g), 70% (1.0 g), and 78% (2.0 g) (p = 0.03, trend in proportions). The higher dose was most effective in patients with proctitis (90% remission on 2 g/day, p = 0.03) or those in remission for less than 12 months before the trial (88% remission on 2 g/day, p = 0.0006). There was little dose-ranging effect in patients with extensive colitis or those in remission for more than 12 months. Diarrhoea necessitated treatment withdrawal in 12%. The optimal dose of olsalazine for maintaining remission in ulcerative colitis is 1 g/day. For patients with proctitis or recent relapse, 2 g/day may be preferable, although the dose seems to be less important in patients with more extensive disease or those in long term remission.

Satsangi J, Jewell DP, Welsh K, Bunce M, Bell JI. 1994. Effect of heparin on polymerase chain reaction. Lancet, 343 (8911), pp. 1509-1510. | Read more

Fasoli R, Jewell DP. 1994. Response to treatment of microscopic colitis. Ital J Gastroenterol, 26 (5), pp. 229-232. | Show Abstract

Microscopic colitis is a recently recognized cause of diarrhoea, predominantly affecting older women, but its response to treatment is poorly documented. This report reviews the response to treatment of 16 patients with microscopic colitis and provides evidence for the use of 5-aminosalicylic acid and corticosteroids.

Hoang P, Dalton HR, de Silv HJ, Jewell DP. 1994. Cytokine production by human colonic intraepithelial lymphocytes in controls and ulcerative colitis. Mediators Inflamm, 3 (3), pp. 219-222. | Show Abstract | Read more

Using an ELISA technique, concentrations of gamma-interferon and interleukin-2 were assayed in the supernatants of colonic intraepithelial lymphocytes cultured with or without phytohaemagglutinin (PHA). IntraepitheHal lymphocytes produced low concentrations of gamma-interferon and interleukin-2 when stimulated with PHA, but significantly more than when unstimulated (p < 0.05). There was no difference in production of these cytokines by IEL from control or inflammatory bowel disease.

Travis SP, Jewell DP. 1994. Salicylates for inflammatory bowel disease. Baillieres Clin Gastroenterol, 8 (2), pp. 203-231. | Show Abstract | Read more

Targeted delivery of 5-aminosalicylic acid to the small intestine and colon by controlled-release or azo-bonded compounds potentially offers treatment for ileal Crohn's disease as well as ulcerative colitis. The pharmacokinetics of sulphasalazine and aminosalicylate derivatives have been discussed and potential modes of action reviewed. These include actions on epithelial cell-surface receptors, cellular events and barrier function. Evidence for an influence of salicylates on circulating and tissue inflammatory cells is presented, as well as actions on adhesion molecules, chemotactic peptides, eicosanoids, cytokines and reactive oxygen metabolites. The precise mechanism remains unknown, but a pluripotential mode of action is an advantage when influencing the network of events that constitutes chronic inflammation. Controlled clinical trials of salicylates in ulcerative colitis and Crohn's disease have been reviewed. Their main role remains as maintenance therapy for ulcerative colitis, but relatively high doses of controlled-release preparations benefit patients with ileal Crohn's disease, following resection, or those who have recently relapsed. Finally, issues of clinical relevance have been addressed, including the choice of salicylate and safety, indications for initiating therapy, dose and duration of treatment, role in managing refractory colitis and future developments.

Satsangi J, Jewell DP, Rosenberg WM, Bell JI. 1994. Genetics of inflammatory bowel disease. Gut, 35 (5), pp. 696-700. | Read more

Satsangi J, Jewell DP. 1994. Cytokine production in inflammatory bowel disease. Gut, 35 (5), pp. 714. | Read more

Travis SP, Jewell DP. 1994. The role of platelet-activating factor in the pathogenesis of gastrointestinal disease. Prostaglandins Leukot Essent Fatty Acids, 50 (3), pp. 105-113. | Read more

Radford-Smith G, Jewell DP. 1994. The role of cytokines in inflammatory bowel disease. Mediators Inflamm, 3 (1), pp. 3-9. | Show Abstract | Read more

Cytokines play an important role in the development and persistence of the inflammatory lesions seen in Crohn's disease and ulcerative colitis. This review discusses the current thinking of the role of cytokines in chronic intestinal inflammation including the involvement of immunoregulatory cytokines within the Th1 and Th2 subsets.

Travis SP, Jewell DP. 1994. Salicylates for ulcerative colitis--their mode of action. Pharmacol Ther, 63 (2), pp. 135-161. | Show Abstract | Read more

Delivery of 5-aminosalicylic acid to the colon by sulphasalazine, other azo-bonded compounds and controlled-release preparations is introduced in the context of metabolism by epithelial cells and therapeutic efficacy in ulcerative colitis. Potential modes of action are then reviewed, including actions on luminal bacteria, epithelial cell surface receptors, cellular events (such as nitric oxide release or butyrate oxidation), electrolyte transport and epithelial permeability. Evidence for an influence of salicylates on circulating and lamina propria inflammatory cells is presented, as well as actions on adhesion molecules, chemotactic peptides and inflammatory mediators, such as eicosanoids, platelet-activating factor, cytokines or reactive oxygen metabolites. The precise mechanism will remain uncertain as long as the aetiology of ulcerative colitis is unknown, but a pluripotential mode of action of salicylates is an advantage when influencing the network of events that constitute chronic inflammation.

Winter TA, Dalton HR, Merrett MN, Campbell A, Jewell DP. 1993. Cyclosporin A retention enemas in refractory distal ulcerative colitis and 'pouchitis'. Scand J Gastroenterol, 28 (8), pp. 701-704. | Show Abstract | Read more

The aim of this study was to evaluate the use of cyclosporin enemas in patients with distal ulcerative colitis and 'pouchitis' resistant to all conventional medical therapy. In an trial 12 patients with distal ulcerative colitis unresponsive to treatment with topical and oral corticosteroids, 5-aminosalicylic acid, and oral immunosuppressive therapy together with 1 patient with 'pouchitis' unresponsive to repeated courses of antibiotics, topical corticosteroids, and oral mesalazine received 250 mg cyclosporin administered daily as a retention enema. Changes in symptoms and the sigmoidoscopic/histologic appearances of the rectal mucosa were assessed at monthly intervals. Seven of 12 patients with ulcerative colitis improved. There was a strong correlation between clinical and histologic improvement (p < 0.005). Four of 12 patients showed no response. Three of these required colectomy, two of whom had more extensive disease than had previously been documented. The patient with pouchitis showed improvement in symptoms and 'pouchoscopy' appearance but not in histologic score. Cyclosporin blood concentrations were very low and side effects negligible. Cyclosporin A retention enemas are safe and may be useful in the treatment of severe refractory distal ulcerative colitis. A controlled trial would now seem warranted.

Powis SH, Rosenberg WM, Hall M, Mockridge I, Tonks S, Ivinson A, Ciclitira PJ, Jewell DP, Lanchbury JS, Bell JI. 1993. TAP1 and TAP2 polymorphism in coeliac disease. Immunogenetics, 38 (5), pp. 345-350. | Show Abstract | Read more

Coeliac disease is strongly associated with HLA-DQ2, but it is possible that additional major histocompatibility complex genes also confer disease susceptibility. Encoded close to HLA-DQ are two genes, TAP1 and TAP2, whose products are believed to transport antigenic peptides from the cytoplasm into the endoplasmic reticulum. Comparison of 81 coeliac disease patients with caucasoid controls revealed an increased frequency of the alleles TAP1A and TAP2A in the patient population. However, no significant difference was found when patients were compared with HLA-DR and -DQ matched controls, indicating linkage disequilibrium between TAP1A, TAP2A, and HLA-DQ2. The TAP gene products do not have a major influence on susceptibility or resistance to coeliac disease in a Northern European Caucasoid population.

Dalton HR, Dipaolo MC, Sachdev GK, Crotty B, Hoang P, Jewell DP. 1993. Human colonic intraepithelial lymphocytes from patients with inflammatory bowel disease fail to down-regulate proliferative responses of primed allogeneic peripheral blood mononuclear cells after rechallenge with antigens. Clin Exp Immunol, 93 (1), pp. 97-102. | Show Abstract | Read more

Human colonic intraepithelial lymphocytes from control subjects down-regulate the proliferative responses of primed allogeneic peripheral blood mononuclear cells on rechallenge with antigens or phytohaemagglutinin (PHA). In contrast, human colonic intraepithelial lymphocytes from patients with inflammatory bowel disease fail to down-regulate the proliferative responses of primed allogeneic peripheral blood mononuclear cells on rechallenge with antigens. These findings may be important in the development and maintenance of the mucosal immunological activation of inflammatory bowel disease.

Morita H, Kettlewell MG, Jewell DP, Kent PW. 1993. Glycosylation and sulphation of colonic mucus glycoproteins in patients with ulcerative colitis and in healthy subjects. Gut, 34 (7), pp. 926-932. | Show Abstract | Read more

Studies have been made of mucus glycoprotein biosynthesis in different regions of the lower gastrointestinal tract in normal patients and those with ulcerative colitis (UC), active or inactive, by means of 3H-glucosamine (3H-GlcNH2)--35S-sulphate double labelling of epithelial biopsy specimens under culture conditions. The time based rate of 3H-GlcNH2 labelling of mucus in rectal tissue was similar to that in active or inactive UC whereas the rate of 35SO4(2) labelling was significantly increased in active disease. The 3H specific activities measuring the amount of isotopic incorporation into surface and tissue mucus glycoproteins were increased in patients with active UC compared with normal or inactive subjects. The 35S specific activities did not differ significantly between patients with active UC and those in remission. In the rectum, glycosylation of mucus glycoproteins decreases with the increasing age of the patient. Regional differences in 3H-labelling of mucus components are reported for ascending colon, transverse colon, sigmoid colon, and rectum. Sulphation (35S-labelling) was higher in all parts of the colon in left sided UC. Results point to accelerated glycosylation of core proteins in the active phase of UC.

Campbell AP, Cobb CA, Chapman RW, Kettlewell M, Hoang P, Haot BJ, Jewell DP. 1993. Cap polyposis--an unusual cause of diarrhoea. Gut, 34 (4), pp. 562-564. | Show Abstract | Read more

'Cap polyposis' is a poorly recognised condition with distinct clinical, sigmoidoscopic, and pathological features that may be confused with other inflammatory conditions of the large intestine including pseudomembranous colitis and idiopathic chronic inflammatory bowel disease. The pathogenesis is unknown but on the basis of the characteristic histological appearances, which are similar to those seen in situations where mucosal prolapse is the underlying mechanism, it has been suggested that the latter may be an important aetiological factor. Two cases are described. Histological features in the first (presence of intramucosal elastin) and clinical features in the second (rectal prolapse) support the above hypothesis.

Sachdev GK, Dalton HR, Hoang P, DiPaolo MC, Crotty B, Jewell DP. 1993. Human colonic intraepithelial lymphocytes suppress in vitro immunoglobulin synthesis by autologous peripheral blood lymphocytes and lamina propria lymphocytes. Gut, 34 (2), pp. 257-263. | Show Abstract | Read more

Human colonic intraepithelial lymphocytes have been shown to suppress the proliferation of autologous lamina propria lymphocytes and allogeneic peripheral blood mononuclear cells. This study has shown that, in vitro, intraepithelial lymphocytes suppress IgA and total immunoglobulin synthesis (but not IgG or IgM production) by autologous peripheral blood and lamina propria lymphocytes. This down regulation of IgA production is mediated by a soluble factor secreted by the intraepithelial lymphocytes. There is no difference in immunoglobulin down regulation by intraepithelial lymphocytes of control subjects and patients with inflammatory bowel disease.

Hoang P, Senju M, Lowes JR, Jewell DP. 1992. Phenotypic characterization of isolated intraepithelial lymphocytes in patients with ulcerative colitis and normal controls. Dig Dis Sci, 37 (11), pp. 1725-1728. | Show Abstract | Read more

A method was developed to isolate colonic intraepithelial lymphocytes in patients with ulcerative colitis (N = 8) and normal controls (N = 13) in order to characterize their phenotype using a panel of monoclonal antibodies and flow cytometry. In both groups, the majority of the cells are of the CD3+CD8+ phenotype associated with cytotoxic/suppressor function. The CD4/CD8 ratios were similar. Virtually no B cells or macrophages were found. An increase in cells coexpressing the CD3 and HLA-DR molecules and a decrease in natural killer cells (CD3, CD16+CD56+) were found in ulcerative colitis, but this was not significant. There were no differences in the proportions of CD8+ and CD4+ cells expressing the Leu8 antigen between ulcerative colitis and controls. Thus a population of colonic intraepithelial lymphocytes has been isolated and, although they may be functionally different in ulcerative colitis compared with controls, this cannot be explained in terms of phenotypic characteristics.

Rios-Castellanos E, Sitas F, Shepherd NA, Jewell DP. 1992. Changing pattern of gastric cancer in Oxfordshire. Gut, 33 (10), pp. 1312-1317. | Show Abstract | Read more

This study compares the incidence rates of histologically confirmed gastric carcinoma in Oxfordshire in two five year periods (1960-64, 1984-88). Data were available for 215 patients in the first period, and 200 in the second. The overall incidence fell from 18/100,000 to 15/100,000 but when analysed for site, the incidence of antral tumours fell from 10 to 4.5/100,000. In contrast, there was an increase from 2.8 to 5.2/100,000 of tumours of the cardia. These changes were more pronounced in men. There was a marked association between smoking and tumours of the cardia (relative risk 4.5). Helicobacter pylori was associated with 37.5% of tumours in the 1960s series compared with 25% in the later series. The changing patterns of incidence of gastric carcinoma may, in part, be related to changes in smoking habits and perhaps a change in incidence of H pylori infection.

Ireland A, Priddle JD, Jewell DP. 1992. Comparison of 5-aminosalicylic acid and N-acetylaminosalicylic acid uptake by the isolated human colonic epithelial cell. Gut, 33 (10), pp. 1343-1347. | Show Abstract | Read more

Isolated human colonic epithelial cell suspensions were incubated with either 0.1 mM 5-aminosalicylic acid (5-ASA) or 0.1 mM acetylaminosalicylic acid (Ac-ASA) for up to two hours. Intra- and extracellular 5-ASA and Ac-ASA were measured by high performance liquid chromatography. Mean 5-ASA uptake in one hour was 160.5 nmol/g dry weight, compared with an Ac-ASA uptake of only 5.75 nmol/g dry weight. No unchanged 5-ASA was detected inside the cell. Repeated washing had no effect on the intracellular Ac-ASA concentration. This discrepancy in drug uptake may explain why Ac-ASA seems to be ineffective when given to patients with ulcerative colitis.

Crotty B, Rosenberg WM, Aronson JK, Jewell DP. 1992. Inhibition of binding of interferon-gamma to its receptor by salicylates used in inflammatory bowel disease. Gut, 33 (10), pp. 1353-1357. | Show Abstract | Read more

5-Aminosalicylic acid (5ASA), 4ASA, their N-acetylated metabolites N-acetyl-5ASA and N-acetyl-4ASA, olsalazine, and colchicine impair interferon-gamma (IFN gamma) induced HLA-DR expression on a colonic cell line, HT-29. The mechanism of this effect is now reported. HT-29 cells were cultured with 50 U/ml IFN gamma with or without drug, and northern blot analysis was performed using a probe for the beta chain of the DR molecule. IFN gamma led to a noticeable increase in HLA-DR mRNA which was attenuated by the drugs. Analysis of the specific binding of increasing concentrations of 125I-IFN gamma by non-linear regression showed a Kd of 1.35 x 10(-10) M and 2.3 x 10(5) binding sites per HT-29 cell. Binding of 125I-IFN gamma was reduced by incubation with increasing concentrations of unlabelled IFN gamma but not with IFN alpha. Incubation with therapeutic concentrations of drugs led to the following reductions in binding: 10 mM 5ASA, 20% (p < 0.001); 10 mM N-acetyl-5ASA, 24% (p < 0.01); 10 mM 4ASA, 21% (p < 0.005); 10 mM N-acetyl-4ASA, 29% (p < 0.001); and 1 mM olsalazine, 29% (p < 0.001). Colchicine (10(-7) M) and 10(-5) M prednisolone had no effect. Incubation with higher concentrations of the drugs revealed a dose-response effect on binding with complete inhibition by 100 mM 4ASA and 10 mM olsalazine, and lesser degrees of inhibition by 100 mM 5ASA, N-acetyl-5ASA, and N-acetyl-4ASA. At concentrations found in the rectal lumen, the salicylates used in inflammatory bowel disease impair the binding of IFN gamma to its receptor on colonic epithelial cells.

Crotty B, Jewell DP. 1992. Drug therapy of ulcerative colitis. Br J Clin Pharmacol, 34 (3), pp. 189-198. | Read more

Fasoli R, Talbot I, Reid M, Prince C, Jewell DP. 1992. Microscopic colitis: can it be qualitatively and quantitatively characterized? Ital J Gastroenterol, 24 (7), pp. 393-396. | Show Abstract

This study reports the histological features helpful in diagnosing microscopic colitis. Rectal biopsy specimens from 14 patients with microscopic colitis, 14 with active ulcerative colitis and 14 without colonic inflammation were pooled and then assessed by three observers according to a predetermined protocol. Inter-observer agreement was good except for Paneth cell metaplasia and endocrine cell metaplasia. Compared with healthy tissue, microscopic colitis showed a significant (p less than 0.05) increase in chronic inflammatory cells and a depletion of goblet cells but these changes were less pronounced than those seen in ulcerative colitis (p less than 0.05). In contrast to ulcerative colitis, microscopic colitis was associated with a more marked infiltration with eosinophils and an increase in intra-epithelial lymphocytes. These results show that microscopic colitis can be distinguished both from normal colonic tissue and from ulcerative colitis.

Cappello M, Keshav S, Prince C, Jewell DP, Gordon S. 1992. Detection of mRNAs for macrophage products in inflammatory bowel disease by in situ hybridisation. Gut, 33 (9), pp. 1214-1219. | Show Abstract | Read more

In situ hybridisation has been used to detect mRNAs to the macrophage secretory products, lysozyme, interleukin 1 beta and tumour necrosis factor-alpha. Sections of paraformaldehyde fixed, frozen colonoscopic biopsies from patients with ulcerative colitis, Crohn's disease or normal controls were hybridised with specific radiolabelled probes and the signal detected by autoradiography. Lysozyme mRNA expression was more common in ulcerative colitis (22/27) and Crohn's disease (eight of eight) compared with controls (17/27). Positive cells were found mainly in the subepithelial region in normal colon, while in inflammatory bowel disease they also appeared in the deeper lamina propria. Immunocytochemistry in parallel sections showed that lysozyme mRNA was expressed only in macrophages or in metaplastic Paneth cells in longstanding inflammatory bowel disease. Tissue neutrophils did not express the lysozyme mRNA, though they have large stores of the protein. Tumour necrosis factor mRNA was detected in four of nine controls compared with 11/15 inflammatory bowel disease patients. For interleukin 1 beta, three of eight controls were positive compared with 10/13 with ulcerative colitis. The tumour necrosis factor signal was located mainly in the deeper lamina propria whereas the interleukin 1 beta was seen in subepithelial macrophages. These results confirm increased macrophage activation in inflammatory bowel disease and suggest functional heterogeneity within the intestinal macrophage population.

Hoang P, Crotty B, Dalton HR, Jewell DP. 1992. Epithelial cells bearing class II molecules stimulate allogeneic human colonic intraepithelial lymphocytes. Gut, 33 (8), pp. 1089-1093. | Show Abstract | Read more

HLA-DR+ gut epithelial cells may present antigen to intraepithelial lymphocytes (IEL). This study aimed to isolate an IEL population from the human colon to activate CD3 + IEL by a human colonic epithelial cell line (HT-29), bearing different concentrations of class II antigen (HLA-DR). IEL were isolated by a mechanical method from six patients with ulcerative colitis (UC) and from 14 control patients. IEL were cocultured with HT-29 which had been induced to express class II molecules by gamma-interferon (IFN-gamma) in a dose dependent manner. The phenotype and the subsequent expression of activation markers by the IEL were determined to two colour flow cytometry. The IEL population had a CD4/CD8 ratio similar to that seen in tissue sections. In the mixed cell culture, the degree of IEL activation showed a positive correlation with the degree of HLA-DR expression by the HT29 cells and the IEL secreted a IFN-gamma like factor that in turn stimulated the HT-29. Thus, depending on their expression of HLA molecules, colonic epithelial cells are able to activate CD3+CD8+IEL.

O'Donnell LJ, Arvind AS, Hoang P, Cameron D, Talbot IC, Jewell DP, Lennard-Jones JE, Farthing MJ. 1992. Double blind, controlled trial of 4-aminosalicylic acid and prednisolone enemas in distal ulcerative colitis. Gut, 33 (7), pp. 947-949. | Show Abstract | Read more

Corticosteroid or 5-aminosalicylic acid enemas are the treatment of choice for distal ulcerative colitis but up to one third of patients may be unresponsive. As an alternative therapy might be advantageous, the efficacy of six weeks' treatment with 2 g 4-aminosalicylic acid (4-ASA) (n = 24) and 20 mg prednisolone enemas (n = 21) were compared in a double blind, randomised trial in patients with acute distal (less than 30 cm from the anus) ulcerative colitis. Baseline demography and clinical severity were similar in both groups. Five of 24 patients receiving 4-ASA and 4 of 21 receiving prednisolone did not complete the trial because of deteriorating symptoms, failure to improve, or side effects. At the time of leaving the trial, 24 hour stool frequency, the presence of blood in the stools, and histological and sigmoidoscopic appearances were similar in both groups. Symptomatic improvement occurred in 17 of 24 patients receiving 4-ASA compared with 11 of 21 receiving prednisolone (chi 2 = 1.62, NS). Complete symptomatic improvement occurred in 9 of 24 patients receiving 4-ASA compared with 5 of 21 receiving prednisolone (chi 2 = 0.98, NS). Histological improvement was seen in 9 of 24 patients on 4-ASA compared with 7 of 21 on prednisolone (chi 2 = 0.08, NS). One patient receiving 4-ASA was considered to have an idiosyncratic reaction to the drug but other side effects were not considered to be drug related. Thus, 4-ASA, previously used in the treatment of tuberculosis (para-aminosalicyclic acid), is as good as prednisolone in the treatment of distal ulcerative colitis and should be considered in patients unresponsive to steroids or in whom steroid treatment is undesirable.

Travis SP, Jewell DP. 1992. Regional differences in the response to platelet-activating factor in rabbit colon. Clin Sci (Lond), 82 (6), pp. 673-680. | Show Abstract | Read more

1. Platelet-activating factor is an inflammatory mediator related to eicosanoids which is known to stimulate anion secretion in the distal colon. Since there are regional differences in ion transport within the colon, the influence of platelet-activating factors on ion transport and epithelial permeability has been studied in rabbit caecum and distal colon mounted in Ussing chambers. 2. The effect of platelet-activating factor (1-50 nmol/l) on net electrogenic ion transport was to stimulate a biphasic increase in short-circuit current in the distal colon but not in the caecum. The platelet-activating factor-induced rise in short-circuit current was shown by ion replacement and pharmacological inhibitor studies to be consistent with chloride and bicarbonate secretion in the early phase, but with chloride secretion alone in the later phase. The effect on ion transport was specific and reversible and was enhanced by 0.25% BSA. 3. Colonic permeability, assessed by transmucosal resistance and mannitol flux, was increased by platelet-activating factor in both the distal colon and the caecum. This was consistent with an effect on platelet-activating factor on the paracellular pathway, because resistance decreased even when transcellular chloride transport was inhibited by frusemide or ion replacement. A specific platelet-activating factor antagonist (U66985) inhibited the effects of platelet-activating factor in both the distal colon and the caecum. 4. The results show that platelet-activating factor stimulates anion secretion only in the distal colon, but increases permeability in both the caecum and the distal colon.

Angus P, Snook JA, Reid M, Jewell DP. 1992. Oral fluticasone propionate in active distal ulcerative colitis. Gut, 33 (5), pp. 711-714. | Show Abstract | Read more

Fluticasone propionate is a new corticosteroid with low systemic bioavailability. This study reports the outcome of a double blind clinical trial comparing oral fluticasone propionate (5 mg four times daily) with placebo for the treatment of active distal ulcerative colitis. Sixty patients were treated for four weeks, with assessments at two and four weeks. One patient was withdrawn when she was found to have amoebiasis. Thus, results are presented for 29 patients who received placebo and 30 who received fluticasone propionate. The two groups were well matched for age, sex, length of history, and extent of disease. After four weeks of therapy the clinical, sigmoidoscopic, and histological responses were similar in the two groups. It is concluded that fluticasone propionate (5 mg four times daily) is not effective treatment for active distal ulcerative colitis.

de Silva HJ, Hoang P, Dalton H, de Silva NR, Jewell DP, Peiris JB. 1992. Immune activation during cerebellar dysfunction following Plasmodium falciparum malaria. Trans R Soc Trop Med Hyg, 86 (2), pp. 129-131. | Show Abstract | Read more

Evidence for immune activation was investigated in 12 patients with a rare syndrome of self-limiting, delayed onset cerebellar dysfunction following an attack of falciparum malaria which occurred 18-26 d previously. Concentrations of tumour necrosis factor, interleukin 6 and interleukin 2 were all significantly higher in serum samples of patients during cerebellar ataxia than in recovery sera and in the sera of 8 patients who did not develop delayed cerebellar dysfunction following an attack of falciparum malaria. Cytokine concentrations in the cerebrospinal fluid were also significantly higher in ataxic patients than in controls. These findings suggest that immunological mechanisms may play a role in delayed cerebellar dysfunction following falciparum malaria.

Lowes JR, Radwan P, Priddle JD, Jewell DP. 1992. Characterisation and quantification of mucosal cytokine that induces epithelial histocompatibility locus antigen-DR expression in inflammatory bowel disease. Gut, 33 (3), pp. 315-319. | Show Abstract | Read more

Epithelial histocompatibility locus antigen (HLA) class II expression was studied to evaluate its induction by mucosal mononuclear cells in inflammatory bowel disease and to characterise the responsible cytokine. Unstimulated cells of the HT-29 epithelial cell line did not produce class II molecules. After being stimulated with the mitogenic lectin phytohaemagglutinin mucosal mononuclear cells released a cytokine that induced epithelial HLA-DR expression. The cytokine had the physicochemical and immunological characteristics of interferon-gamma, and no additional cytokines were detected.

Dalton HR, Hoang P, Jewell DP. 1992. Antigen induced suppression in peripheral blood and lamina propria mononuclear cells in inflammatory bowel disease. Gut, 33 (3), pp. 324-330. | Show Abstract | Read more

Using an autologous system, suppressor cell function to a range of mycobacterial antigens and Kunin antigen of peripheral blood mononuclear cells and lamina propria lymphocytes has been investigated in normal subjects and patients with inflammatory bowel disease. In the peripheral blood there was reduced antigen induced suppression in patients with Crohn's disease in remission to Mycobacterium paratuberculosis, purified protein derivative (PPD), M fortuitum, and Kunin antigens (p less than 0.05). In patients with ulcerative colitis in remission there was reduced antigen induced suppression in the peripheral blood to Kunin antigen (p less than 0.001), M avium (p less than 0.01), M nonchromogenecin, and M fortuitum (p less than 0.05). The phenomenon of antigen induced suppression was largely CD8 dependent, as depleting CD8+ cells reduced the effect and the concentration of soluble CD8 in the culture supernatant was directly related to the suppressor index (r = 0.25, p less than 0.05). These results are likely to be a true reflection of the cell mediated response to antigen as patients with a positive Mantoux skin test have a significantly higher suppressor index to PPD than Mantoux negative subjects (p less than 0.05). These findings may have significance in the aetiopathogenesis of inflammatory bowel disease. However, a similar effect could not be shown in the lamina propria lymphocytes of patients having colectomy for active disease.

Crotty B, Hoang P, Dalton HR, Jewell DP. 1992. Salicylates used in inflammatory bowel disease and colchicine impair interferon-gamma induced HLA-DR expression. Gut, 33 (1), pp. 59-64. | Show Abstract | Read more

Colonic epithelial cells express HLA-DR in inflammatory bowel disease. The effect of drugs used in the treatment of inflammatory bowel disease and colchicine on interferon-gamma (IFN-gamma) induced DR expression has been investigated. HT-29 cells were cultured in 25 cm2 flasks. At 48 hours interferon-gamma (0, 50, or 100 U/ml) +/- drug were added. At 120 hours the cells were stained for HLA-DR and analysed by flow cytometry. 10(-2) M 5ASA reduced DR expression induced by 50 U/ml interferon-gamma from 62 (12)% of cells (mean SD) to 29 (20)% (p less than 0.005). Corresponding figures for 10(-2) M N-acetyl 5ASA were 68 (16)% to 39 (17)% (p less than 0.05); for 10(-2) M 4ASA, 61 (4)% to 57 (4)% (p = 0.6); for 10(-2) M N-acetyl 4ASA, 60 (12)% to 35 (13)% (p less than 0.05); for 10(-2) M olsalazine, 72 (9)% to 3 (1)% (p less than 0.001); for 10(-3) M olsalazine, 72 (9)% to 16 (10)% (p less than 0.001); for 10(-6) M colchicine, 62 (13)% to 5 (3)% (p less than 0.001); and for 10(-7) M colchicine, 62 (13)% to 10 (3)%. Similar results were obtained when DR was induced by 100 U/ml of interferon-gamma except with 10(-2) M 4ASA which reduced expression from 77 (4)% to 68 (3)% (p less than 0.05). Sulphapyridine, prednisolone, indomethacin and cyclosporin A had no effect. Concurrent staining with propidium iodide showed that these results were unchanged when viable cells alone were analysed. Prior incubation of cells with drug, followed by washing, had no effect on interferon-gamma induced DR expression. 5ASA, N-acetyl 5ASA, 4ASA, N-acetyl 4ASA, olsalazine and colchicine reduce interferon-gamma induced HLA-DR expression. In inflammatory bowel disease these compounds may impair antigen presentation by the colonic epithelium.

Lowes JR, Priddle JD, Jewell DP. 1992. Production of epithelial cell growth factors by lamina propria mononuclear cells. Gut, 33 (1), pp. 39-43. | Show Abstract | Read more

The effects of lamina propria mononuclear cell culture supernatant on epithelial cell DNA synthesis were studied using cells isolated from patients with inflammatory bowel disease and normal controls. Supernatants from resting and phytohaemagglutinin stimulated cells were studied and supernatants that strongly promoted DNA synthesis were pooled, and growth factor activity partially characterised. The effects of recombinant interleukins-1 beta,2,3,interferon-gamma, and granulocyte macrophage colony stimulating factor were tested in the same system. Resting lamina propria mononuclear cells produce factors that increase DNA synthesis. Production of these factors is increased by phytohaemagglutinin stimulation. No significant differences were found in production of these factors between patients with inflammatory bowel disease and normal controls. The molecular weight of the active factor(s) lies in the region 31-48 kD. Chromatofocusing produced two peaks of activity, one in the region pk 5.5 and one around pk 6.4. The activity was heat and acid pH labile. Activity was not destroyed, however, by 0.05% trypsin. Recombinant granulocyte macrophage colony stimulating factor was a weak stimulus to epithelial DNA synthesis, interleukin-1 beta was weakly inhibitory but other cytokines tested did not have any effect. Granulocyte macrophage colony stimulating factor is probably important in controlling epithelial cell growth.

Chew CN, Nolan DJ, Jewell DP. 1991. Small bowel gas in severe ulcerative colitis. Gut, 32 (12), pp. 1535-1537. | Show Abstract | Read more

The prognostic significance of excess small bowel gas on a plain abdominal radiograph has been assessed in 75 patients with severe attacks of ulcerative colitis requiring intravenous hydrocortisone. The radiographs were reviewed without knowledge of the subsequent outcome. Small bowel distension was defined as the presence of three or more loops of gas filled small bowel. Forty two patients responded to medical treatment and 33 underwent colectomy. The two groups were comparable for age, sex, and length of history. The surgical group had more extensive disease. Of those who did well on medical therapy, 18 (42.9%) had small bowel distension compared with 24 of 33 (72.7%) who failed medical therapy. The difference was significant (p less than 0.05, odds ratio = 3.55, 95% confidence interval of 2.27-5.87). Of the 24 patients with small bowel distension who came to surgery, five had more than four loops of gas filled small bowel. This degree of distension was not seen in any of the patients settling on medical therapy. Thus the presence of small bowel distension on a plain abdominal radiograph in a patient with severe ulcerative colitis may predict a poor response to medical therapy.

Senju M, Makiyama K, Hara K, Hulstaert F, Lowder JN, Jewell DP. 1991. Two-color immunofluorescence and flow cytometric analysis of peripheral blood lymphocyte subsets in Caucasian and Japanese healthy subjects. Jpn J Med, 30 (6), pp. 509-515. | Show Abstract | Read more

Two-color immunofluorescence using multiparameter flow cytometry was employed to examine the antigenic characteristics of peripheral blood lymphocytes in whole blood of healthy Caucasians and Japanese. The CD4/CD8 ratio in Japanese was significantly decreased compared with that in Caucasians, because of the increased number of CD8+ cells. Although the proportions of suppressor-inducer T cells (CD4+, Leu-8+) and helper-inducer T cells (naive T cells) (CD4+, CD45RA-) were low in Japanese subjects, there were no differences in the absolute numbers of suppressor-inducer T cells and helper-inducer T cells (naive T cells) in circulation. The level of activated T cells in Japanese was similar to that in Caucasians. NK cells, CD57+, CD8+ cells and CD57+, CD3+ cells were high in Japanese. Regarding B cell subsets, CD5+ B cells and activated B cells remained unchanged. However, there were slight differences in Leu-8+ B cells and Fc epsilon R+ B cells (CD20+, CD23+) between the two groups. Thus, a differing influence of racial and environmental background between healthy Caucasians and healthy Japanese on human lymphocyte subsets is present in the lymphocyte immunophenotype.

Dalton HR, Jewell DP. 1991. The management of acute severe ulcerative colitis. Ann Med, 23 (4), pp. 389-391. | Read more

Senju M, Wu KC, Mahida YR, Jewell DP. 1991. Two-color immunofluorescence and flow cytometric analysis of lamina propria lymphocyte subsets in ulcerative colitis and Crohn's disease. Dig Dis Sci, 36 (10), pp. 1453-1458. | Show Abstract | Read more

By using two-color immunofluorescence with fluorescein isothiocyanate (FITC) and phycoerythrin (PE)-labelled monoclonal antibodies and multiparameter flow cytometry, we investigated lamina propria lymphocyte subsets of patients with ulcerative colitis (UC) and Crohn's disease (CD). Leu-3/Leu-2 (CD4/CD8) ratio of lamina propria lymphocytes (LPL) of CD (mean +/- SD: 1.9 +/- 0.8, P less than 0.01) was significantly decreased compared with controls (3.3 +/- 1.1), because of an increased number of CD8+ lymphocytes. The majority of lamina propria CD4+ cells were CD4+, Leu-8- and CD4+, CD45R- both in controls and IBD tissue. Many lamina propria T lymphocytes were activated, expressing HLA-DR antigen not only in IBD but also in controls. NK cells defined by CD16 and CD 56 (3.0 +/- 1.4%, P less than 0.01) were significantly decreased in patients with UC compared with controls (6.5 +/- 3.0%). A low proportion of B cells in the intestinal mucosa expressed Leu-8 antigen and CD23 antigen. The proportion of activated B cells of LPL was high in IBD mucosa as well as normal mucosa. These findings suggest that local activation of B cells leads to the loss of the expression of Leu-8 antigen and CD23.

de Silva HJ, Millard PR, Soper N, Kettlewell M, Mortensen N, Jewell DP. 1991. Effects of the faecal stream and stasis on the ileal pouch mucosa. Gut, 32 (10), pp. 1166-1169. | Show Abstract | Read more

This study aimed to investigate the effects of the faecal stream and stasis on the mucosa of ileal pouches. Nine patients were followed up. Two pouch biopsy specimens were obtained from each at the time of pouch formation, ileostomy closure, and three, six, and 12 months after operation. None developed pouchitis. Two pouch biopsy specimens each were also obtained from 20 patients (six with pouchitis), whose pouches had been functioning for at least a year and in whom pouch evacuation was assessed by radioisotope labelled artificial stool. Biopsy specimens were assessed for the degree of acute and chronic inflammation, mucin type (high iron diamine-alcian blue stain), a morphometric index of villous atrophy (villous height:total mucosal thickness), and crypt cell proliferation (using the monoclonal antibody Ki67). Mean values from the two biopsy specimens were obtained for each parameter. After three months of pouch function, the scores for acute and chronic inflammation, the degree of sulphomucin, and crypt cell proliferation were significantly higher, and the index of villous atrophy was significantly lower (indicating a greater degree of villous atrophy), than at pouch formation or at ileostomy closure. The values at pouch formation and ileostomy closure were similar. For all parameters, the changes seen at six and 12 months were not significantly different from those at three months. There was no significant correlation between the efficiency of pouch evacuation and any of the mucosal changes. It is concluded that exposure to the faecal stream is necessary for changes to take place in the pouch mucosa, although the amount of stasis, as measured by radioisotopic evacuation studies, seems to be irrelevant. The mucosal changes occur soon after ileostomy closure and then remain stable for at least one year.

de Silva HJ, Jones M, Prince C, Kettlewell M, Mortensen NJ, Jewell DP. 1991. Lymphocyte and macrophage subpopulations in pelvic ileal pouches. Gut, 32 (10), pp. 1160-1165. | Show Abstract | Read more

This study aimed to characterise the mucosal cellular infiltrate in ileal reservoirs with and without pouchitis (reservoir ileitis). Intraepithelial lymphocyte counts were performed in biopsy specimens obtained from ileal pouches and compared with counts in normal ileum and normal colon. T lymphocyte and macrophage subpopulations were characterised immunohistochemically in pouch biopsy specimens using a panel of monoclonal antibodies. Normal ileum was used as a control. Intraepithelial lymphocyte densities (expressed as intraepithelial lymphocyte/100 epithelial cells) in pouches with and without pouchitis were significantly less than in normal ileum, and approached counts found in normal colon. There was no significant increase in counts even in pouchitis. There were no significant differences in the helper/inducer to suppressor/cytotoxic T cell (CD4:CD8) ratios between normal ileum and pouches with or without pouchitis, either in the epithelium or in the lamina propria. The proportions of RFD9+ (epithelioid cells and tingible body macrophages) and 3G8+ (CD16) macrophages were significantly higher in pouchitis compared with pouches without pouchitis or normal ileum. There were no significant differences between the three groups in the proportions of cells positive for the other macrophage markers (CD68, RFD1-dendritic cells, and RFD7-mature macrophages). The significance of low intraepithelial lymphocyte counts in ileal pouches is unknown, but this may be an adaptive response to the new luminal environment. Since an increase in RFD9+ macrophages occurs in inflammatory bowel disease, but does not occur as a non-specific response to an acute infective process, their presence in pouchitis suggests that effector mechanisms similar to those triggering the original ulcerative colitis may be operating in pouchitis.

de Silva HJ, de Angelis CP, Soper N, Kettlewell MG, Mortensen NJ, Jewell DP. 1991. Clinical and functional outcome after restorative proctocolectomy. Br J Surg, 78 (9), pp. 1039-1044. | Show Abstract | Read more

Restorative proctocolectomy and ileal pouch-anal anastomosis (IPAA) has been carried out on 88 patients since 1982. Three different pouch designs (J, S and W) were used. Ten pouches had to be removed. Detailed analysis was performed on 61 patients (J = 23, S = 15, W = 23) whose pouches had been functioning for at least 6 months. There was no significant difference in surgical complications before or after ileostomy closure between pouch designs but the hospital stay was greater after construction of an S pouch (P less than 0.05). There were no significant differences in stool frequency, degree of continence or urgency between the three types. Twelve patients with J pouches required antidiarrhoeal medication compared with only one with S and five with W pouches. Only seven patients with S pouches could defaecate spontaneously compared with 22 with W pouches and all patients with J pouches (P less than 0.001). Twenty-five of 29 patients who had preservation of the anal transition zone had perfect continence compared with 23 of 32 with a mucosal proctectomy (P = n.s.). Pouchitis occurred in 13 patients, all of whom had ulcerative colitis. In a subgroup of 23 patients, pouch evacuation was assessed scintigraphically. There was no difference in pouch capacity or total volume evacuated, but spontaneous evacuation was better in J and W pouches compared with S pouches.

Hoang P, Dalton HR, Jewell DP. 1991. Human colonic intra-epithelial lymphocytes are suppressor cells. Clin Exp Immunol, 85 (3), pp. 498-503. | Show Abstract | Read more

Human colonic intra-epithelial lymphocytes (IEL) suppress the proliferation of autologous lamina propria lymphocytes, but not autologous peripheral blood mononuclear cells, when stimulated with phytohaemagglutinin. This suppressor function is mediated by a CD8-dependent soluble factor and is not related to the expression of the gamma delta T cell receptor. These findings may be relevant to the induction of mucosal tolerance. However, there is no defect in suppressor activity of colonic IEL in inflammatory bowel disease.

Senju M, Wu KC, Mahida YR, Jewell DP. 1991. Coexpression of CD4 and CD8 on peripheral blood T cells and lamina propria T cells in inflammatory bowel disease by two colour immunofluorescence and flow cytometric analysis. Gut, 32 (8), pp. 918-922. | Show Abstract | Read more

Using two colour immunofluorescence with fluorescein isothiocyanate and phycoerythrin labelled monoclonal antibodies and multiparameter flow cytometry, we investigated the coexpression of CD4 and CD8 antigens on peripheral blood lymphocytes and lamina propria lymphocytes of patients with ulcerative colitis and Crohn's disease and normal control subjects. Both the absolute number and the proportion of peripheral blood CD4+, CD8+ cells in inflammatory bowel disease were small but significantly increased compared with those in normal control subjects. Peripheral blood lymphocytes activated with phytohaemagglutinin showed appreciably increased coexpression of CD4+, CD8+. These CD4, CD8 positive cells were large and granular. Thus the increased number of peripheral blood CD4+, CD8+ cells in inflammatory bowel disease suggests that chronic immune activation occurs not only in the active state of the disease but also in remission. The proportion of CD4+, CD8+ cells in the lamina propria was greater than in peripheral blood in normal subjects, suggesting chronic immune stimulation of the local immune system. This was also seen in patients with Crohn's disease or inactive ulcerative colitis. The proportion of CD4+, CD8+ cells was, however, significantly less in the lamina propria of patients with active ulcerative colitis. Whether this implies a possible defect in mucosal immunoregulation in active ulcerative colitis cannot be determined from these results.

Senju M, Hulstaert F, Lowder J, Jewell DP. 1991. Flow cytometric analysis of peripheral blood lymphocytes in ulcerative colitis and Crohn's disease. Gut, 32 (7), pp. 779-783. | Show Abstract | Read more

Using two colour immunofluorescence with fluorescein isothiocyanate and phycoerythrin labelled monoclonal antibodies, multi-parameter flow cytometry was used to examine the antigenic characteristics of peripheral blood lymphocytes in whole blood of patients with ulcerative colitis and Crohn's disease who were not taking immunosuppressive drugs. The numbers of CD4+ and CD8+ lymphocytes in patients with ulcerative colitis and Crohn's disease remained unchanged so that the CD4/CD8 ratio was the same as that of normal control subjects. In Crohn's disease there were many activated T cells (CD3+, CD25+). Although natural killer cells in active Crohn's disease were lower than in normal control subjects, cytotoxic T lymphocytes, as defined by CD3+, CD16+, did not differ in patients with inflammatory bowel disease compared with normal control subjects. For B cell subsets, there were differences in Leu-1+ B cells, Leu-8+ B cells, Fc epsilon R+B cells (Leu-16+, Leu-20+), and activated B cells (Leu-12+, Leu-21+) between patients with inflammatory bowel disease and normal control subjects. These differences are compatible with local activation of B cells in the inflamed colon.

Mantzaris G, Jewell DP. 1991. In vivo toxicity of a synthetic dodecapeptide from A gliadin in patients with coeliac disease. Scand J Gastroenterol, 26 (4), pp. 392-398. | Show Abstract | Read more

A single dose of a synthetic peptide of A gliadin (residues 206-217) sharing homology with the E1b protein of adenovirus 12 was instilled intraduodenally in two treated coeliac patients. Biopsy specimens were taken before and repeatedly up to 24 h after the instillation by means of a Quinton hydraulic multiple biopsy instrument and processed for histology, morphometry (intraepithelial lymphocyte counts, crypt-to-villus ratio), immunocytochemistry, electron microscopy, and disaccharidase assays. Two subjects with irritable bowel syndrome served as controls. In the coeliac group disaccharidase activities decreased at 24 h, and abnormalities were seen on light and electron microscopy and in morphometric measurements. The lamina propria became infiltrated with mononuclear cells after 2 h, and there was also a rise in IgA-containing cells in one patient. No such abnormalities were seen in the control group. The serum concentrations of C3, C4, and C1 esterase inhibitor remained unchanged. Thus, the dodecapeptide may be one epitope of gliadin mediating the pathogenesis of coeliac disease.

Snook JA, Lowes JR, Wu KC, Priddle JD, Jewell DP. 1991. Serum and tissue autoantibodies to colonic epithelium in ulcerative colitis. Gut, 32 (2), pp. 163-166. | Show Abstract | Read more

Sera and colonic tissue-bound immunoglobulin extracts from patients with ulcerative colitis and disease controls were examined immunohistochemically and by killer cell cytotoxicity assay for the presence of anticolonic epithelial autoantibodies. IgG yields in the tissue extracts from patients with colitis and control subjects were similar, and the extracts were uniformly autoantibody negative. Of 41 sera from patients with inflammatory bowel disease, 'classical' anticolon antibody was present in 41% and was commoner in patients with sclerosing cholangitis. Cytotoxic anticolon antibody was present in 20% overall and was strongly associated with disease activity; it did not correlate with the presence of 'classical' anticolon antibody. The heterogeneous and non-universal antiepithelial autoantibody response and the failure to detect tissue bound autoantibody in vivo argue against the hypothesis that humoral autoimmunity is of major importance in the pathogenesis of ulcerative colitis.

de Silva HJ, Millard PR, Kettlewell M, Mortensen NJ, Prince C, Jewell DP. 1991. Mucosal characteristics of pelvic ileal pouches. Gut, 32 (1), pp. 61-65. | Show Abstract | Read more

This study aimed to investigate the degree of colonic metaplasia in ileo - anal pouches. Biopsy specimens from 25 patients with functioning pouches, eight of whom had pouchitis, were studied using routine histology, mucosal morphometry, mucin histochemistry, and immunoperoxidase staining with monoclonal antibodies directed towards a 40kD colonic protein and a small bowel specific disaccharidase-sucrase isomaltase. Thirteen patients (including all eight with pouchitis) had subtotal or total villous atrophy and crypt hyperplasia. In this group, nine had colorectal type sulphomucin and the 40kD colonic protein was detected in two. These changes were not observed in patients with less severe villous abnormalities. Sucrase-isomaltase activity was, however, present in all 25 pouch specimens. We conclude that although some ileal pouches acquire certain colonic characteristics, complete colonic metaplasia does not occur.

Rhodes JM, Jewell DP. 1990. Lactulose hydrogen breath test in the diagnosis of bacterial overgrowth. Gastroenterology, 99 (5), pp. 1547. | Read more

de Silva HJ, Gatter KC, Millard PR, Kettlewell M, Mortensen NJ, Jewell DP. 1990. Crypt cell proliferation and HLA-DR expression in pelvic ileal pouches. J Clin Pathol, 43 (10), pp. 824-828. | Show Abstract | Read more

To investigate the nature of the morphological changes that occur in ileal pouches, 26 biopsy specimens from patients with functioning ileo-anal pouches (eight with pouchitis) were studied. Normal ileum (n = 10) was used as a control. Mucosal morphometry (using linear measurements), crypt cell proliferation (CCP) (using the monoclonal antibody Ki67), and epithelial HLA-DR expression (monoclonal antibody CR3/43) were assessed. CCP (expressed as the percentage of Ki67 positive nuclei for each crypt) was significantly higher in pouches with pouchitis, compared with those without, and in pouches without pouchitis compared with normal ileum. CCP values in some pouches without pouchitis approached values found in those with pouchitis. CCP was related inversely to villous height and an index of villous atrophy (VH/TMT), and directly to crypt depth. In the presence of pouchitis there was intense epithelial HLA-DR expression that extended into the crypts. In some pouches with high CCP values, but without clinically important inflammation, surface epithelial HLA-DR expression was weak and patchy. It is concluded that villous atrophy and crypt hyperplasia in ileal pouches are associated with high CCP values. These may be increased even in the absence of active inflammation, and this increase may occur as a response to the new luminal environment.

Jewell DP. 1990. The new steroids: clinical experience in ulcerative colitis. Mt Sinai J Med, 57 (5), pp. 293-296.

Mahida YR, Jewell DP. 1990. Macrophage activity in inflammatory bowel disease. Gut, 31 (9), pp. 1086-1087. | Read more

Kelly IM, Frith PA, Hyman NM, Jewell DP. 1990. Retinal periphlebitis in ulcerative colitis. Postgrad Med J, 66 (777), pp. 565-567. | Show Abstract | Read more

A man presented with unilateral visual blurring associated with bilateral retinal periphlebitis which was felt to be a complication of his biopsy-proven active ulcerative colitis. Retinal periphlebitis has been associated rarely with some forms of colitis but we can find no report of its occurrence in association with ulcerative colitis although other ocular inflammatory disorders are well recognized.

Fasoli R, Kettlewell MG, Mortensen N, Jewell DP. 1990. Response to faecal challenge in defunctioned colonic Crohn's disease: prediction of long-term course. Br J Surg, 77 (6), pp. 616-617. | Read more

Mantzaris GJ, Karagiannis JA, Priddle JD, Jewell DP. 1990. Cellular hypersensitivity to a synthetic dodecapeptide derived from human adenovirus 12 which resembles a sequence of A-gliadin in patients with coeliac disease. Gut, 31 (6), pp. 668-673. | Show Abstract | Read more

The human intestinal adenovirus serotype 12 (Ad12) may be implicated in the pathogenesis of coeliac disease by virtue of immunological cross reactivity between epitopes shared by its early region E1b protein and A-gliadin. In the present study a synthetic dodecapeptide from the corresponding viral epitope (Ad12E1b, residues 384-395) was tested for its effect on peripheral blood mononuclear cells from 22 treated and eight untreated patients with coeliac disease, 22 healthy subjects, 11 patients with ulcerative colitis, and 11 patients with Crohn's disease by an indirect leucocyte migration inhibition assay. In addition, the effect of both the viral and the gliadin synthetic peptides was studied by proliferation and migration assays simultaneously performed in an unselected subgroup of 12 treated coeliac patients and 12 healthy subjects of the study. Coeliac patients with untreated disease showed no response to the viral peptide compared with treated patients (p greater than 0.1). Treated coeliac patients showed a significantly different response from healthy control subjects and control patients with disease (p less than 0.001) which was dependent on the concentration of the viral peptide. In the subgroup of the treated coeliac patients (n = 12) there was a significant correlation between the responses in the migration and the proliferation assay using either the viral (p less than 0.02) or the gliadin (p less than 0.005) peptide at the highest concentration (33.3 micrograms/ml). Furthermore, the responses obtained using viral peptide correlated significantly with the responses obtained with gliadin peptide in both the migration (p less than 0.001) and the proliferation (p less than 0.001) assays. These results show that in coeliac patients there is pronounced cross reactivity at the level of T cell recognition between synthetic peptides derived from the Ad12 and A-gliadin. This antigenic cross reactivity may be involved in the pathogenesis of coeliac disease.

Ireland A, Jewell DP. 1990. Mechanism of action of 5-aminosalicylic acid and its derivatives. Clin Sci (Lond), 78 (2), pp. 119-125. | Show Abstract | Read more

The mechanism of action of 5-ASA and its derivatives remains obscure. The most likely mechanisms would appear to be an interrelationship between local production of eicosanoids and reactive oxygen metabolites, in conjunction with activated neutrophils, though the nature of the initial triggering factor/s remains to be determined. The possibility that bacterial-derived chemotactic peptides, such as FMLP, might be a triggering factor is an attractive possibility, made possible by an underlying defect in mucosal permeability.

Rosenberg W, Ireland A, Jewell DP. 1990. High-dose methylprednisolone in the treatment of active ulcerative colitis. J Clin Gastroenterol, 12 (1), pp. 40-41. | Show Abstract | Read more

Twenty patients with severe active ulcerative colitis were entered into a pilot study to test the efficacy of pulsed high-dose methylprednisolone in inducing remission. Of 20 patients, 12 improved, but 8 of 20 patients (40%) who did not went for urgent colectomy. The group proceeding to surgery tended to have more extensive disease. These results contrast unfavorably with historical control data from this unit.

Mantzaris GJ, Priddle JD, Jewell DP. 1990. T lymphocyte responses to a synthetic peptide from the human intestinal adenovirus 12 in coeliac disease. J Clin Lab Immunol, 31 (2), pp. 75-79. | Show Abstract

Peripheral blood mononuclear cells of treated coeliac patients are known to liberate leucocyte migration inhibition factor when challenged with a synthetic dodecapeptide of the E1b protein of adenovirus 12 sharing sequence homology with A gliadin. This study has compared the response of the unfractionated peripheral blood mononuclear cells with a highly purified T cell population. Coeliac mononuclear cells and T lymphocytes showed identical leucocyte migration inhibition activity. The migration indices for the coeliac group were significantly different than for the control group irrespective of the cell population tested. This work justifies the use of the indirect leucocyte migration inhibition assay using mononuclear cell supernatants as a test of in vitro cell-mediated immunity to clearly defined antigens in coeliac disease. It also offers further evidence for the possible implication of adenovirus 12 in the pathogenesis of coeliac disease.

Angus PW, Dixon RM, Rajagopalan B, Ryley NG, Simpson KJ, Peters TJ, Jewell DP, Radda GK. 1990. A study of patients with alcoholic liver disease by 31P nuclear magnetic resonance spectroscopy. Clin Sci (Lond), 78 (1), pp. 33-38. | Show Abstract | Read more

1. Patients with a history of alcohol abuse were studied by 31P n.m.r. spectroscopy of the liver in vivo, and the results were related to the pattern of disease assessed by standard biochemical and histological techniques. 2. The ratios of metabolites measured from the 31P n.m.r. spectra were abnormal in patients with alcoholic hepatitis but not in those with fatty change or cirrhosis in the absence of hepatitis. In particular, the levels of phosphomonoesters were raised, with respect either to Pi, or to adenosine 5'-triphosphate. The level of phosphomonoesters showed a significant positive correlation with the severity of alcoholic hepatitis, assessed by histology. 3. The ratio of Pi to adenosine 5'-triphosphate was used as a measure of the energy status of the hepatocytes, and was unchanged between patients and controls.

Ireland A, Priddle JD, Jewell DP. 1990. Acetylation of 5-aminosalicylic acid by isolated human colonic epithelial cells. Clin Sci (Lond), 78 (1), pp. 105-111. | Show Abstract | Read more

1. This study investigates the acetylation of 5-aminosalicylic acid by isolated human colonic epithelial cells. 2. After incubation of intact cells with 0.1 mmol/l 5-aminosalicylic acid, N-acetyl-5-aminosalicylic acid was detected in a concentration of 141 (+/- 23.8 SEM) nmol/g dry weight in the incubation medium, and 34.8 (+/- 5.5 SEM) nmol/g dry weight intracellularly. No unchanged 5-aminosalicylic acid was detected inside the cell. 3. Acetylation of 5-aminosalicylic acid by a cell homogenate was very poor, but the addition of 1 mmol/l acetyl-CoA resulted in complete conversion of 0.1 mmol/l 5-aminosalicylic acid to N-acetyl-5-aminosalicylic acid. 4. N-Acetyltransferase activity was detected in the cytosol, with a mean of 3.3 nmol min-1 mg-1 of protein. There was no N-acetyltransferase activity in the brush border. There was no difference in enzyme activity between epithelial cells derived from normal, Crohn's disease or ulcerative colitis patients. 5. Preliminary characterization of the N-acetyltransferase enzyme suggests a molecular weight of 150,000.

Mantzaris GJ, Rosenberg WM, Jewell DP. 1990. The immunology of coeliac disease. Springer Semin Immunopathol, 12 (2-3), pp. 219-229. | Show Abstract | Read more

Whether or not the immune system initiates CD, it can be seen to play a role in the natural history of the disease. Genetic susceptibility to CD has been shown to be linked to the HLA, DQw2 and it appears that other genes within the MHC further contribute to disease susceptibility. The search for other immune response genes that may be linked to CD has lead to investigation both within the MHC and elsewhere in the genome. However, environmental factors undoubtedly contribute to the pathogenesis of the disease. The initiating event leading to CD may be exposure to gluten or possibly infection with a virus. Although it has been suggested that the lesions of CD may be a direct consequence of chemical damage caused by gluten, the weight of evidence suggests that damage occurs either as a result, or as a consequence, of the immune response to gluten. Epithelial damage may result from the immune response directed against antigens processed and presented by epithelial cells. Alternatively epithelial damage may be a consequence of the local immune response to absorbed wheat antigens, or possibly other luminal antigens leaking into the mucosa due to increased intestinal permeability. Whether this immune response develops as the result of a cross-reactivity between a viral peptide and a gluten-derived peptide remains to be seen. Histological, immunocytochemical and serological studies clearly demonstrate the involvement of the immune system in established CD. A deeper understanding of the genetic susceptibility to CD, the identity of the immunogenic gluten peptides and the interaction between antigen HLA and lymphocytes will not only help us to understand CD but also provide an insight into many other immune-mediated diseases. © 1990 Springer-Verlag.

Wu KC, Mahida YR, Priddle JD, Jewell DP. 1990. Effect of human intestinal macrophages on immunoglobulin production by human intestinal mononuclear cells isolated from patients with inflammatory bowel disease. Clin Exp Immunol, 79 (1), pp. 35-40. | Show Abstract | Read more

The effect of macrophages on spontaneous immunoglobulin production by isolated human intestinal mononuclear cells (MNC) is unknown. Depletion of macrophages by adherence to fibronectin or by panning with macrophage-specific monoclonal antibody 3C10 lead to a significant reduction in IgA. IgG and IgM production by intestinal MNC from both normal (n = 10) and inflammatory bowel disease (IBD) (n = 13) mucosa. The reduction in immunoglobulin produced by macrophage-depleted intestinal MNC was greater in IBD patients than in normal controls. There was a significant correlation (r = 0.816, P less than 0.001) between the percentage of macrophages depleted by panning with 3C10 and the reduction in IgG produced by macrophage-depleted intestinal MNC. Addition of either fibronectin-adherent cells or the supernatant from these macrophage-enriched cells enhanced immunoglobulin production in a dose-dependent fashion. A greater increase in IgG production by macrophage-depleted cells was seen when cultured with supernatant from inflamed IBD mucosal cells, compared with that from normal mucosal cells. The soluble factor(s) responsible in the supernatant was acid and heat susceptible but was not affected by freezing and thawing. Addition of recombinant human interleukin-1 beta or human interferon-gamma to cell cultures did not influence immunoglobulin production. Thus, human intestinal macrophages enhance spontaneous immunoglobulin production by isolated intestinal MNC by secreting soluble factor(s) which remain to be fully characterized.

Mahida YR, Jewell DP. 1990. Slow-release 5-amino-salicylic acid (Pentasa) for the treatment of active Crohn's disease. Digestion, 45 (2), pp. 88-92. | Show Abstract | Read more

A double-blind, placebo-controlled trial of a slow-release preparation of 5-amino-salicylic acid (Pentasa) has been performed in 40 patients with active Crohn's disease. Over a 6-week period, Pentasa (1.5 g daily) was no different to the dummy tablet in terms of clinical activity (Harvey-Bradshaw Index) or laboratory indicators of inflammation. No serious adverse reactions occurred.

Lowes JR, Jewell DP. 1990. The immunology of inflammatory bowel disease. Springer Semin Immunopathol, 12 (2-3), pp. 251-268. | Read more

Ireland A, Jewell DP. 1989. Sulfasalazine-induced impotence: a beneficial resolution with olsalazine? J Clin Gastroenterol, 11 (6), pp. 711. | Read more

de Silva HJ, Ireland A, Kettlewell M, Mortensen N, Jewell DP. 1989. Short-chain fatty acid irrigation in severe pouchitis. N Engl J Med, 321 (20), pp. 1416-1417. | Show Abstract | Read more

To the Editor: Pouchitis (acute inflammation of the mucosa of the ileal reservoir) is a major long-term complication of restorative proctocolectomy.1Little is known about its pathogenesis or the efficacy of medical treatment. No controlled therapeutic trials have yet been performed.1Concentrations of short-chain fatty acids are lower in pouch effluent than normal stool,2and an inverse correlation has been found between pouch concentrations of butyrate and the degree of villous atrophy.3It has been suggested that this reduction in the level of the short-chain fatty acids in the pouch may enable the growth of enteropathic bacteria that produce toxic. © 1989, Massachusetts Medical Society. All rights reserved.

Jewell DP. 1989. Aetiology and pathogenesis of ulcerative colitis and Crohn's disease. Postgrad Med J, 65 (768), pp. 718-719. | Read more

Mahida YR, Wu KC, Jewell DP. 1989. Respiratory burst activity of intestinal macrophages in normal and inflammatory bowel disease. Gut, 30 (10), pp. 1362-1370. | Show Abstract | Read more

Macrophages isolated from normal mucosa (greater than 5 cm from tumour) and inflamed mucosa (from patients with inflammatory bowel disease) of colon and ileum were studied for their ability to undergo a respiratory burst as assessed by reduction of nitroblue tetrazolium to formazan. Using phorbol myristate acetate (PMA) and opsonised zymosan as triggers, only a minority (median: 8% for zymosan and 9% for PMA) of macrophages isolated from normal colonic mucosa demonstrated release of oxygen radicals. In contrast, a significantly greater (median: 17% for zymosan and 45% for PMA) proportion of macrophages isolated from inflamed colonic mucosa were able to undergo respiratory burst. Studies with normal and inflamed ileum showed similar results. Stimulation of macrophages isolated from normal colon with interferon-gamma produced only a small increase in the proportion of cells showing release of oxygen radicals. We conclude that the respiratory burst capacity of majority of macrophages isolated from normal colon and ileum is downregulated and a greater proportion of macrophages isolated from inflamed colon and ileum are able to undergo a respiratory burst.

Wu KC, Mahida YR, Priddle JD, Jewell DP. 1989. Immunoglobulin production by isolated intestinal mononuclear cells from patients with ulcerative colitis and Crohn's disease. Clin Exp Immunol, 78 (1), pp. 37-41. | Show Abstract

We studied immunoglobulin production by isolated intestinal mononuclear cells from 25 patients with active inflammatory bowel disease (IBD) and 17 controls undergoing surgical resections for intestinal tumour or other disorders. Normal ileal intestinal mononuclear cells spontaneously produced greater amounts of IgA and IgM than did normal colon cells. In cells from patients with IBD there was a significantly reduced IgA production, but production of IgG was enhanced in both colon and ileum. The alteration in IgA and IgG production in IBD was confirmed by comparing the immunoglobulin production by mononuclear cells from inflamed with that from non-inflamed areas of mucosa in six patients with distal ulcerative colitis. The proportion of IgA-containing cells in isolated intestinal mononuclear cells from IBD mucosa was less than normal. However, the proportion of IgG-containing cells from IBD mucosa was not increased in isolated intestinal mononuclear cells although they produced more IgG than normal mucosal cells. Our study showed an altered pattern of immunoglobulin production by intestinal mononuclear cells isolated from patients with inflammatory bowel disease.

Snook JA, de Silva HJ, Jewell DP. 1989. The association of autoimmune disorders with inflammatory bowel disease. Q J Med, 72 (269), pp. 835-840. | Show Abstract

Medical records of patients with ulcerative colitis (n = 858), Crohn's disease (n = 378) and coeliac disease (n = 148) were examined to determine the prevalence of associated autoimmune disorders. Of outpatient controls (n = 300), 2 per cent had at least one autoimmune disorder, compared to 7 per cent with ulcerative colitis, 2 per cent with Crohn's disease and 6 per cent with coeliac disease. Inclusion of primary sclerosing cholangitis with the autoimmune disorders increased the overall prevalence in ulcerative colitis to over 9 per cent. The results provide further indirect evidence of involvement of autoimmune mechanisms in the pathogenesis of ulcerative colitis.

Nanda R, James R, Smith H, Dudley CR, Jewell DP. 1989. Food intolerance and the irritable bowel syndrome. Gut, 30 (8), pp. 1099-1104. | Show Abstract | Read more

Two hundred patients (156 women) with the irritable bowel syndrome were treated with dietary exclusion for three weeks. Of the 189 who completed this study, 91 (48.2%) showed symptomatic improvement. Subsequent challenge with individual foods showed that 73 of these 91 responders were able to identify one or more food intolerances and 72 remained well on a modified diet during the follow up period (mean (SD), 14.7 (7.98) months). Of the 98 patients who showed no symptomatic improvement after three weeks of strict exclusion only three were symptomatically well at follow up (mean (SD), 12.48 (8.09 months). There was no close correlation between response and symptom complex. There was a wide range of food intolerance. The majority (50%) identified two to five foods which upset them (range 1-14). The foods most commonly incriminated were dairy products (40.7%) and grains (39.4%).

Snook JA, Chapman RW, Sachdev GK, Heryet A, Kelly PM, Fleming KA, Jewell DP. 1989. Peripheral blood and portal tract lymphocyte populations in primary sclerosing cholangitis. J Hepatol, 9 (1), pp. 36-41. | Show Abstract | Read more

The relative distribution of lymphocyte subpopulations in the blood and liver of patients with primary sclerosing cholangitis (PSC) and related diseases has been studied using immunoenzyme techniques. The peripheral blood CD4/CD8 T lymphocyte ratio was significantly higher in active ulcerative colitis (UC) and in PSC with inactive UC than in inactive UC alone. In contrast, no relationship with disease activity was seen in Crohn's disease. The portal tract t lymphocyte count per high power field (mean +/- S.D.) was higher in pre-cirrhotic PSC (173 +/- 105) and primary biliary cirrhosis (PBC: 210 +/- 110) than in histologically normal liver (42 +/- 27). However, the overall portal tract CD4/CD8 ratio was similar in PSC (1.49), PBC (1.89) and normal controls (1.63). The results are consistent with immunological involvement in the pathogenesis of PSC, but argue against the hypothesis that changes in the peripheral blood T cell subsets are due to sequestration at the site of tissue inflammation.

Ireland A, Jewell DP. 1989. Mechanisms of carrageenan injury of cell monolayers. Gastroenterology, 97 (1), pp. 242-243. | Read more

Mahida YR, Patel S, Gionchetti P, Vaux D, Jewell DP. 1989. Macrophage subpopulations in lamina propria of normal and inflamed colon and terminal ileum. Gut, 30 (6), pp. 826-834. | Show Abstract | Read more

The aim of this study was to characterise human intestinal macrophages in normal and inflamed ileum and colon. Immunoperoxidase staining with a panel of monoclonal antibodies and histochemical staining for acid phosphatase and non-specific esterase was performed. In the superficial lamina propria, normal colonic macrophages were larger and more strongly positive for acid phosphatase and non-specific esterase than those in normal terminal ileum. There were more macrophages staining with monoclonal antibody RFD1 in the superficial lamina propria of the latter. Studies in inflammatory bowel disease tissue showed the presence of macrophages staining with monoclonal antibodies RFD9 and 3G8 which were rarely present in normal tissue and represented a different pattern from that seen in infectious colitis. Studies on isolated intestinal macrophages confirmed the findings in tissue sections. Subpopulations of intestinal macrophages are likely to have different functional roles. Phenotypic changes during inflammation may be induced by mediators of inflammation or may represent a recently recruited population of cells.

Mahida YR, Wu K, Jewell DP. 1989. Enhanced production of interleukin 1-beta by mononuclear cells isolated from mucosa with active ulcerative colitis of Crohn's disease. Gut, 30 (6), pp. 835-838. | Show Abstract | Read more

IL1-beta production by mononuclear cells isolated from normal and active inflammatory bowel disease mucosa was studied. Significantly more IL1-beta was produced spontaneously by mononuclear cells from the inflamed mucosa compared with those from normal colonic mucosa (median 190 pg/ml (range 45-700) v 20 pg/ml (0-165)). Stimulation with lipopolysaccharide enhanced IL1-beta production by mononuclear cells from active inflammatory bowel disease mucosa but not those from normal mucosa. Depleting the mononuclear cells of macrophages, by panning with monoclonal antibody 3C10, reduced the amount of IL1-beta produced. Enhanced IL1-beta production from the inflamed mucosa may play an important role in the mediation of many inflammatory responses. The enhanced production appears to be the result of a recruited population of cells.

Dehn TC, Kettlewell MG, Mortensen NJ, Lee EC, Jewell DP. 1989. Ten-year experience of strictureplasty for obstructive Crohn's disease. Br J Surg, 76 (4), pp. 339-341. | Show Abstract | Read more

Strictureplasty is controversial in the management of obstructive Crohn's disease. Only a small proportion of patients undergoing surgery for obstructive Crohn's disease are suitable for strictureplasty. Lesions which are most amenable for this procedure are short, fibrous strictures. Over a 10-year period 24 patients have undergone 30 operations at which 86 strictureplasties were performed. The median follow-up has been 40 (range 4-112) months. No leaks or fistulae arose from the strictureplasties. The median weight gain 3 months postoperatively was +4.0 kg. Four patients subsequently required a further 13 strictureplasty procedures, between 12 and 36 (median 18) months after the initial operation; all but one of the previous strictureplasties were patent. Thirteen patients have been symptom free following surgery, four have required further medical therapy for recurrent Crohn's disease and three have sustained episodes of self-limiting intestinal colic. Strictureplasty is a safe and effective procedure in selected patients undergoing surgery for obstructive Crohn's disease.

Baker K, Jewell DP. 1989. Cyclosporin for the treatment of severe inflammatory bowel disease. Aliment Pharmacol Ther, 3 (2), pp. 143-149. | Show Abstract | Read more

A pilot study was performed to assess the role of cyclosporin in the management of severe inflammatory bowel disease. Twelve patients with Crohn's disease and 12 with ulcerative colitis were admitted to hospital with a severe attack. They were treated with an intravenous regimen of corticosteroids for 5 days followed by oral therapy. In addition, they received a 6-week course of oral cyclosporin, initially 15 mg kg-1 day-1 reduced to 7.5 mg kg-1 day-1. In comparison with historical controls, the addition of cyclosporin to standard corticosteroid therapy appeared to have no benefit. Adverse effects were common but minor. The expression of Class II molecules on the inflamed epithelium was rapidly reversed by cyclosporin therapy which may indicate a potential therapeutic benefit over longer periods of time.

Snook JA, Chapman RW, Fleming K, Jewell DP. 1989. Anti-neutrophil nuclear antibody in ulcerative colitis, Crohn's disease and primary sclerosing cholangitis. Clin Exp Immunol, 76 (1), pp. 30-33. | Show Abstract

We have previously described circulating autoantibodies to a portal tract antigen in patients with primary sclerosing cholangitis. In this study the antigen has been shown by double-labelling studies to be specifically located in the nuclei of tissue neutrophils. Using isolated peripheral blood neutrophils and an immunoperoxidase technique, anti-neutrophil nuclear antibody (ANNA) was found in the serum of 84% of patients with primary sclerosing cholangitis (PSC: n = 32) with a median titre of 1/1000 and a peak titre of 1/500,000. ANNA was also detected in 86% of patients with inflammatory bowel disease alone (IBD: n = 76) with a median titre of 1/10 and a peak titre of 1/10,000. In contrast, only 12% of controls had ANNA, and in none was the titre greater than 1/10. In PSC the ANNA titre correlated with the serum aspartate transaminase concentration, suggesting that it is related to disease activity. In IBD the titre of ANNA was significantly higher in patients with recently active disease. There was no significant difference between the titres seen in ulcerative colitis and Crohn's disease. ANNA was not associated with neutropaenia. The results provide further evidence of involvement of autoimmune mechanisms in inflammatory bowel disease and primary sclerosing cholangitis.

Jewell DP. 1989. Corticosteroids for the management of ulcerative colitis and Crohn's disease. Gastroenterol Clin North Am, 18 (1), pp. 21-34. | Show Abstract

Corticosteroids are of proven value for the treatment of active ulcerative colitis and Crohn's disease, but are of little value for the maintenance of remission. The development of new steroid compounds with low systemic bioavailability should allow higher doses to be given for longer periods without risking serious adverse reactions.

Snook JA, Kelly P, Chapman RW, Jewell DP. 1989. Fibrolamellar hepatocellular carcinoma complicating ulcerative colitis with primary sclerosing cholangitis. Gut, 30 (2), pp. 243-245. | Show Abstract | Read more

This case report describes the previously undocumented association between fibrolamellar hepatocellular carcinoma and ulcerative colitis complicated by primary sclerosing cholangitis.

Mahida YR, Patel S, Jewell DP. 1989. Mononuclear phagocyte system of human Peyer's patches: an immunohistochemical study using monoclonal antibodies. Clin Exp Immunol, 75 (1), pp. 82-86. | Show Abstract

Macrophages in sections of human terminal ileal Peyer's patches were studied using a panel of monoclonal antibodies. Germinal centre macrophages were large and strongly positive for acid phosphatase and stained with antibodies RFD1, RFD9, UCHM1 and other macrophage-specific monoclonal antibodies, but not RFD7. In the macrophages of the dome region there was heterogeneity of size and staining for acid phosphatase. The majority of the RFD1 positive cells in this region appeared to be macrophages. However, no RFD9- or RFD7-positive cells were present. By contrast, RFD7-positive but RFD9-negative macrophages were present in the lamina propria. In the interfollicular areas there were cells with a dendritic morphology which were strongly HLA-DR, HLA-DQ and RFD1-positive, but which did not stain with the other macrophage specific monoclonal antibodies or for acid phosphatase. Some macrophages and lymphocytes in the germinal centre and dome regions expressed interleukin 2 and transferrin receptors. These cells were not present in the adjacent lamina propria.

Rosenberg WM, Wordsworth BP, Jewell DP, Bell JI. 1989. A locus telomeric to HLA-DPB encodes susceptibility to coeliac disease. Immunogenetics, 30 (4), pp. 307-310. | Read more

Mahida YR, Patel S, Wu K, Jewell DP. 1988. Interleukin 2 receptor expression by macrophages in inflammatory bowel disease. Clin Exp Immunol, 74 (3), pp. 382-386. | Show Abstract

The expression of interleukin 2 receptor by macrophages from normal and inflamed terminal ileum and colon has been studied by using two monoclonal antibodies. In tissue sections from normal ileum and colon, scattered positive lymphocytes and only occasional weakly positive macrophages were seen. In ileal and colonic Crohn's disease or ulcerative colitis many positive macrophages and lymphocytes were seen in the lamina propria. These findings were confirmed by staining cytospin preparations of isolated intestinal mononuclear cells. The isolated macrophages were able to phagocytose opsonized zymosan and the majority were able to undergo a respiratory burst when triggered with opsonized zymosan or phorbol myristate acetate (PMA), suggesting that they were activated. Stimulation with interferon-gamma or lipopolysaccharide did not increase the number of macrophages staining with the antibodies to the interleukin 2 receptor. Therefore we postulate that a large majority of the macrophages expressing interleukin 2 receptor in inflammatory bowel disease are a recently recruited population of cells.

Mahida YR, Wu KC, Jewell DP. 1988. Characterization of antigen-presenting activity of intestinal mononuclear cells isolated from normal and inflammatory bowel disease colon and ileum. Immunology, 65 (4), pp. 543-549. | Show Abstract

Antigen-presenting activity in mononuclear cells, isolated from normal and inflamed human ileum and colon, has been characterized using allogeneic mixed lymphocyte reaction with resting T cells as responders. Greatest proliferation was induced by fibronectin-adherent (macrophage-enriched) cells, and least by fibronectin non-adherent (macrophage-depleted) cells and by mononuclear cells depleted of macrophages by panning with monoclonal antibody 3C10. When intestinal mononuclear cells and allogeneic T cells were incubated in large numbers, clusters were observed. These clusters contained cells with a dendritic morphology that were strongly HLA-D-positive and which also stained with macrophage-specific monoclonal antibodies 3C10, EMB11 and Y1/82A. These cells were closely associated with proliferating T cells. Studies comparing mononuclear cells isolated from normal and inflamed colonic mucosa suggest that the latter may have enhanced antigen-presenting capacity.

Mahida YR, Chapman RW, Jewell DP. 1988. Association of small intestinal diverticulosis with chronic pancreatitis leading to severe malabsorption. Report of three cases. Postgrad Med J, 64 (757), pp. 893-896. | Show Abstract | Read more

Three cases of chronic pancreatitis occurring in patients with small intestinal diverticulosis and bacterial overgrowth are reported. In two of the cases, pancreatic supplements were therapeutically beneficial (the third being unable to tolerate them). Two of the patients also developed diverticular perforation. The possible nature of the association between small intestinal diverticulosis and chronic pancreatitis is discussed.

Jewell DP. 1988. How I do it. Medical management of severe ulcerative colitis. Int J Colorectal Dis, 3 (3), pp. 186-189. | Show Abstract | Read more

Providing some simple rules are applied, severe attacks of ulcerative colitis can be effectively managed with virtually no mortality. A proportion of patients (1 in 5) will come to surgery but the guidelines for surgical intervention are now clear. Joint management between medical and surgical teams is important and, possibly, the combination of a surgically aggressive physician with a medicallyminded surgeon is the ideal. © 1988 Springer-Verlag.

Ireland A, Mason CH, Jewell DP. 1988. Controlled trial comparing olsalazine and sulphasalazine for the maintenance treatment of ulcerative colitis. Gut, 29 (6), pp. 835-837. | Show Abstract | Read more

One hundred and sixty four patients with ulcerative colitis in remission were entered into a double blind, double dummy trial comparing olsalazine 500 mg bd and sulphasalazine 1 g bd. Clinical examination, sigmoidoscopy and rectal biopsy were performed at 0, three, and six months. Sixteen of 82 (19.5%) patients relapsed on olsalazine and 10/82 (12.2%) relapsed on sulphasalazine. The difference was not statistically significant (p = 0.1632). Adverse events were minor and were similar in both groups. No haematological or biochemical abnormalities were detected. Thus, olsalazine is as effective as sulphasalazine for preventing a relapse of ulcerative colitis.

Gionchetti P, Mahida YR, Patel S, Jewell DP. 1988. Macrophage and lymphocyte subpopulations in magnifying endoscopic lesions of Crohn's disease. Clin Exp Immunol, 72 (3), pp. 373-376. | Show Abstract

Using dye staining and a magnifying colonoscope, small lesions in the rectum of patients with Crohn's disease (which had otherwise appeared normal on sigmoidoscopy) can be detected. Subpopulations of macrophages and lymphocytes in the abnormal and adjacent normal areas of the rectum were studied using a panel of monoclonal antibodies. There was a distinct increase in RFD9+ and 3G8+ macrophages in the abnormal areas compared with the normal. The CD4:CD8 ratio of lymphocytes in the two areas remained unchanged.

Chapman RW, Kelly PM, Heryet A, Jewell DP, Fleming KA. 1988. Expression of HLA-DR antigens on bile duct epithelium in primary sclerosing cholangitis. Gut, 29 (4), pp. 422-427. | Show Abstract | Read more

The expression of HLA class I (HLA-A, B, C) and class II (HLA-DR) antigens on the biliary epithelium of 10 patients (nine men) with primary sclerosing cholangitis (PSC) was investigated using an immunoperoxidase technique on cryostat sections. Five patients were staged as grade II and five grade III on hepatic histology. None were cirrhotic. as grade II and five grade III on hepatic histology. None were cirrhotic. Controls were nine patients with primary biliary cirrhosis (PBC), five with extra hepatic biliary obstruction, 15 with other forms of chronic liver disease and six with normal livers. Bile ducts from the normal subjects and patients with chronic liver disease did not express HLA-DR antigens. In contrast, all 10 of the PSC biopsies showed varying degrees of HLA-DR staining of the biliary epithelium. Expression of DR antigens was also found on the bile ducts of all five patients with extra hepatic biliary obstruction and in six of nine patients with PBC. Expression of HLA class I antigens was seen on the biliary epithelium of all the biopsies examined. Increased numbers of helper and suppressor T-cells were seen in the portal tracts of all the PSC patients. This study has confirmed that aberrant expression of HLA-DR may occur on the biliary epithelium of some, but not all, patients with PBC. In addition, the study has shown that aberrant expression of HLA-DR always occurs in PCS at an early stage of histological liver damage. While this may be important in the pathogenesis of PSC, the aberrant expression in extra hepatic biliary obstruction suggests that it may be a secondary phenomenon.

Gyde SN, Prior P, Allan RN, Stevens A, Jewell DP, Truelove SC, Lofberg R, Brostrom O, Hellers G. 1988. Colorectal cancer in ulcerative colitis: a cohort study of primary referrals from three centres. Gut, 29 (2), pp. 206-217. | Show Abstract | Read more

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.

Ireland A, Priddle JD, Jewell DP. 1988. Studies on the acetylating capacity of human colonic epithelial cells for 5-aminosalicylic acid. Scand J Gastroenterol Suppl, 148 (sup148), pp. 53. | Show Abstract | Read more

Following oral administration of sulphasalazine, 5-aminosalicylic acid (5-ASA) is present in serum at very low concentrations and is mostly in the acetylated form. Analysis of rectal mucosal biopsies from patients on sulphasalazine maintenance therapy has shown that the predominant metabolite present is N-acetyl ASA (Clin Sci 1987: 72; 79P). The authors have now investigated whether this acetylation takes place in the epithelium. Isolated colonic epithelial cell suspensions were prepared in Krebs-Henseleit saline from fresh human resection specimens by EDTA digestion and mechanical disaggregation. Cell suspensions remained viable, as determined by lactate production, over 3 hours. Aliquots of cell suspension were incubated with 5-ASA, 0.1 mM, and glucose, 5 mM, at 37°C for 1 or 2 hours. Following incubation, the supernatant was analysed by high performance liquid chromatography for the presence of acetyl-ASA. Following washing, the cell pellet was disrupted ultrasonically, and intracellular acetyl-ASA was also measured. Production of acetyl-ASA in 1 hour was 112.5 (+27 SD) nmol/g dry weight (extracellular) and 48 (+15.6 SD) nmol/g dry weight (intracellular). No intracellular 5-ASA was detected, suggesting rapid and complete acetylation. A cytosolic fraction of the epithelial cells was prepared by centrifugation of homogenized cells at 13,000 g. In the presence of 5-ASA and acetyl-CoA, this enzyme solution produced acetyl-ASA linearly at a rate of 37 nmol/minutes/ mg protein. No acetyltransferase activity was found in the brush border. The cytosol was further purified by passing it through a Superose 12 gel filtration column. Maximum acetyltransferase activity was found in the fraction corresponding to a molecular weight of approximately 30,000. Thus, the human colonic epithelial cell is probably the primary site of acetylation of 5-ASA, and the N-acetyltransferase activity is found in the cytosol. © 1988 Informa UK Ltd All rights reserved: reproduction in whole or part not permitted.

Jewell DP, Ireland A. 1988. Controlled trial comparing olsalazine and sulphasalazine for maintenance treatment of ulcerative colitis. Scand J Gastroenterol Suppl, 148 (sup148), pp. 45-47. | Show Abstract | Read more

Olsalazine and sulphasalazine were compared in a double-blind, double-dummy trial in the prevention of relapse of ulcerative colitis over 6 months. The majority were taking sulphasalazine. They were randomized to receive either olsalazine, 500 mg b.d., or sulphasalazine, 1 g b.d. Of 82 patients, 16 relapsed on olsalazine compared with 10 of 82 on sulphasalazine. This difference was not statistically significant (p = 0.16). Twenty-one patients reported adverse events in the olsalazine group, of whom 16 were withdrawn, while 20 patients reported adverse events in the sulphasalazine group, with 9 of them being withdrawn. The differences were not statistically significant. No major haematological or biochemical abnormalities occurred. Thus, olsalazine is similar to sulphasalazine for the prevention of relapse of ulcerative colitis.

Ireland A, Jewell DP. 1987. Olsalazine in patients intolerant of sulphasalazine. Scand J Gastroenterol, 22 (9), pp. 1038-1040. | Show Abstract | Read more

Fifty patients with ulcerative colitis, intolerant of sulphasalazine, were treated with 500 mg olsalazine twice daily for a 3-month trial period. Thirty-eight of the patients (76%) tolerated the drug well, and all continued to take it beyond the 3-month period. Twelve (24%) were withdrawn because of side effects, the commonest being diarrhoea. There were no haematologic or biochemical abnormalities. Thus, olsalazine is a useful drug for patients who are intolerant of sulphasalazine.

Sacks SH, Bushell A, Rust NA, Karagiannis JA, Jewell DP, Ledingham JG, Wood KJ, McMichael AJ. 1987. Functional and biochemical subtypes of the haplotype HLA-DR3 in patients with celiac disease or idiopathic membranous nephropathy. Hum Immunol, 20 (2), pp. 175-187. | Show Abstract | Read more

HLA class II beta-chain polymorphism was investigated in the haplotype HLA-DR3 to determine if patients with HLA-DR3-associated diseases express normal or variant class II polymorphisms. Analysis was carried out by two-dimensional gel electrophoresis of immunoprecipitated HLA class II molecules, DNA hybridization with DR beta and DQ beta gene probes on Taq 1, Bam H1, or Rsa 1 digests, and mixed lymphocyte culture. Two subtypes of HLA-DR3 were identified in normal homozygous DR3 individuals on the basis of polymorphism in one of two DR beta chains detected, corresponding to differences in DR beta restriction fragment patterns. These polymorphisms exhibited significant linkage disequilibrium with the A1,B8,DR3 and B18,DR3 haplotypes, respectively. In proliferative experiments, cells with the B18,DR3-associated polymorphism strongly stimulated cells from donors with the B8,DR3-related polymorphism, suggesting that a T-cell epitope recognized by B8,DR3 cells lies on the B18,DR3-associated DR beta chain. In seven HLA-DR3 homozygous patients with celiac disease and three HLA-DR3-homozygous patients with idiopathic membranous nephropathy, only the normal patterns of HLA class II molecules were displayed, the B8,DR3 type occurring in all patients and the B18,DR3 type in one patient. These data suggest that celiac disease and idiopathic membranous nephropathy are not related to disease-specific HLA-DR beta or -DQ beta gene variants within the DR3 population that are revealed by these methods.

Malik AK, Rawcliffe P, Morton JA, Jewell DP, McGee JO. 1987. Immunoperoxidase staining of intermediate filaments in human small bowel. J Clin Pathol, 40 (10), pp. 1262. | Read more

Gebbers JO, Ferguson DJ, Mason C, Crucioli V, Jewell DP. 1987. [Local immune reaction in human intestinal spirochetosis]. Schweiz Med Wochenschr, 117 (29), pp. 1087-1091. | Show Abstract

The pathogenetic and clinical importance of intestinal spirochaetes in man is still unresolved. In 12 patients mainly presenting with mild diarrhoea, light and electron microscopy demonstrated massive spirochaetal infestation of the colonic mucosa (spirochaetosis). There were several hitherto unreported features: spirochaetes adhered not only to the surface epithelium of the intestine but were also present within epithelial cells and subepithelial macrophages; many partially degranulated mast cells were noted within the epithelium; there was a marked increase of IgE plasma cells within the lamina propria. In control biopsies intraepithelial mast cells were absent and IgE cells occurred only sporadically. Penetration of the microorganisms into the intestinal mucosa may be responsible for this unusual immune response. Spirochaetes, symptoms and findings disappeared after antibiotic therapy. The authors therefore suggest that intestinal spirochaetosis can cause clinical symptoms in man, and that spirochaetes should not invariably be considered harmless commensals.

Hodgson HJ, Jewell DP. 1987. Immunology of inflammatory bowel disease. Baillieres Clin Gastroenterol, 1 (3), pp. 531-545. | Read more

Jewell DP. 1987. Aetiopathogenesis of ulcerative colitis. Acta Gastroenterol Belg, 50 (3), pp. 277-282.

Gebbers JO, Ferguson DJ, Mason C, Kelly P, Jewell DP. 1987. Spirochaetosis of the human rectum associated with an intraepithelial mast cell and IgE plasma cell response. Gut, 28 (5), pp. 588-593. | Show Abstract | Read more

In two patients presenting with mild intestinal symptoms, rectal spirochaetosis was the only morphological abnormality diagnosed by light microscopy. A re-evaluation of the morphological changes using electron microscopy and immunohistochemistry showed certain unusual features: the microorganisms were observed within epithelial cells and in subepithelial macrophages; there were numerous partially degranulated intraepithelial mast cells; and there was a marked increase in the proportion of IgE plasma cells within the lamina propria. Mucosal penetration by the organisms may be responsible for the unusual immune response. In one patient, treatment with antibiotics eliminated the spirochaetes and resulted in a clinical improvement. Spirochaetes should not always be considered as harmless commensals in the colon.

Karagiannis JA, Priddle JD, Jewell DP. 1987. Cell-mediated immunity to a synthetic gliadin peptide resembling a sequence from adenovirus 12. Lancet, 1 (8538), pp. 884-886. | Show Abstract | Read more

Cell-mediated immunity to a synthetic peptide, which has a 12-residue sequence from A-gliadin analogous to part of an early-region protein (Elb) from adenovirus 12, was investigated in patients with coeliac disease, healthy subjects, and disease controls by means of an indirect leucocyte-migration-inhibition assay. Patients with coeliac disease being treated with a gluten-free diet showed a significantly greater response than healthy subjects (p less than 0.001) or patients with inflammatory bowel disease. This cellular immune response was dependent on antigen concentration and was not present in untreated coeliac patients.

Guan R, Rawcliffe PM, Priddle JD, Jewell DP. 1987. Cellular hypersensitivity to gluten derived peptides in coeliac disease. Gut, 28 (4), pp. 426-434. | Show Abstract | Read more

Wheat gluten derived antigens have been tested for their ability to inhibit the migration of leucocytes from healthy subjects and patients with coeliac disease. Three preparations of a water soluble fraction (Frazer's fraction III, FIII) of partial peptic tryptic digests of wheat gluten had different effects in a direct (one stage) assay. Subfractions B and B2 caused migration inhibition of leucocytes from patients with treated coeliac disease but not of leucocytes from healthy volunteers or patients with Crohn's disease or ulcerative colitis. This migration inhibition seems to be specific for gluten fractions because maize zein fraction B, beta-lactoglobulin and ovalbumin did not cause it. The sensitivity of coeliac leucocytes to fraction B is not related to factors present in coeliac serum as the migration of leucocytes from healthy individuals preincubated with coeliac sera was not inhibited. Puromycin diminished inhibition by fraction B, which was active at 1.2 micrograms/ml in an indirect (two stage) migration inhibition assay; this is consistent with a process involving elaboration of lymphokine(s). More highly purified fractions of B2, P1-P4 were prepared by reverse phase high performance liquid chromatography (HPLC) and showed differing potency in direct and indirect assays, with P4 being the most active fraction. Inhibition of migration by gluten derived peptides appears to result from the release of lymphokine by leucocytes specifically from coeliac patients.

Hermanowicz A, Gibson PR, Jewell DP. 1987. Tumour related inhibition of macrophage chemotaxis in patients with colon cancer. Gut, 28 (4), pp. 416-422. | Show Abstract | Read more

The chemotactic migration in vitro of peripheral blood, intestinal mucosal, and mesenteric lymph node mononuclear cells has been assessed in patients with colorectal carcinoma. Peripheral blood mononuclear cells of patients exhibited normal chemotaxis. For control patients with non-malignant, non-inflammatory intestinal disease, the chemotaxis of mucosal mononuclear cells was similar to that of autologous peripheral blood mononuclear cells. The chemotactic migration of mucosal mononuclear cells, however, isolated distant from a colon cancer was less than that of autologous peripheral blood mononuclear cells. Chemotactic migration was progressively impaired with increasing closeness to the tumour itself. Chemotaxis of mucosal mononuclear cell was independent of the site of tumour and the Dukes' grading. Mononuclear cells from mesenteric lymph nodes, however, exhibited impaired migration only in patients with Dukes' C tumours. Supernatants of the collagenase digestion of either tumour or adjacent mucosa contained macrophage directed inhibitors of chemotaxis and these inhibitors were not produced by tumour mononuclear cells. The presence of such inhibitors in the digestion supernatants and the demonstration that proximity to the tumour was associated with impaired mononuclear cell motility suggest that the production of macrophage directed chemotactic inhibitors is by colon cancer cells and that this may be occurring in vivo.

Mohsen AQ, Mulvey D, Priddle JD, Parsons DS, Jewell DP. 1987. Effects of olsalazine in the jejunum of the rat. Gut, 28 (3), pp. 346-352. | Show Abstract | Read more

Olsalazine (ADS) is the azo-linked dimer of 5-aminosalicylic acid (5-ASA). It is of value for the management of patients with ulcerative colitis but may be associated with increasing diarrhoea in a few. This study examines the effect of 5-ASA and ADS on small intestinal transport systems of the rat. Krebs-Ringer-bicarbonate solution was circulated through the lumen of a jejunal segment and the appearance of fluid, glucose and lactate on the serosal surface was shown to be linear over a two hour period. Addition of 5-ASA (10 mmol/l) or ADS (5 mmol/l and 10 mmol/l) caused a significant inhibition both of fluid transport (p less than 0.001), and of the appearance of glucose (p less than 0.001) and lactate (p less than 0.001 for 5 mmol/l and 10 mmol/l ADS, p less than 0.01 for 10 mmol/l 5-ASA). The uptake of glucose by rings of rat jejunum was shown to be markedly reduced by ADS. Experiments substituting glucose with either sucrose of 2-aminoisobutyric acid showed that ADS (5 mmol/l, 10 mmol/l) also inhibited the serosal appearance of fructose and the amino acid. These results show that 5-ASA and ADS, at concentrations which could be expected in the jejunum of patients receiving therapeutic doses, are able to inhibit small intestinal transport systems. The resulting increase in load on the diseased colon could be important for the pathogenesis of diarrhoea.

McDonald GB, Jewell DP. 1987. Class II antigen (HLA-DR) expression by intestinal epithelial cells in inflammatory diseases of colon. J Clin Pathol, 40 (3), pp. 312-317. | Show Abstract | Read more

Eighty four colonic biopsy specimens were obtained from patients with ulcerative colitis, Crohn's disease, radiation colitis, infectious colitis, and from normal controls. Paired specimens were examined by histological and immunohistochemical methods using monoclonal antibodies to the beta chain of HLA-DR antigen. The expression of HLA-DR antigen in mucosal epithelial cells was strongly related to whether the specimens were actively inflamed: epithelial cells from 34 of 37 inflamed specimens (nu three of 42 non-inflamed specimens) were HLA-DR positive (p less than 0.0001). Epithelial cells were uniformly HLA-DR negative in specimens from normal control patients despite the presence of HLA-DR positive lymphoid cells and macrophages in the lamina propria. Epithelial cells in specimens from patients with ulcerative colitis, Crohn's disease, and radiation colitis were HLA-DR positive in 30 of 33 inflamed biopsy specimens and in only three of 25 non-inflamed specimens (p less than 0.0001). Epithelial cells were HLA-DR positive in nine of 10 biopsy specimens from patients with acute infectious colitis (p less than 0.01).

Barr GD, Hudson MJ, Priddle JD, Jewell DP. 1987. Colonic bacterial proteases to IgA1 and sIgA in patients with ulcerative colitis. Gut, 28 (2), pp. 186-189. | Show Abstract | Read more

The colonic faecal and mucosal associated bacterial populations of five patients with ulcerative colitis and four control patients were studied in detail to assess their ability to produce IgA1-proteases. A total of 330 bacterial strains were isolated from the patients with ulcerative colitis and IgA1-protease activity was unable to be reliably shown in any. It is therefore unlikely that such enzyme production by colonic bacteria plays a significant role in the pathogenesis of ulcerative colitis.

Chapman RW, Selby WS, Jewell DP. 1986. Controlled trial of intravenous metronidazole as an adjunct to corticosteroids in severe ulcerative colitis. Gut, 27 (10), pp. 1210-1212. | Show Abstract | Read more

A prospective double blind controlled trial was undertaken to examine the role of metronidazole as an adjunct to corticosteroids in the management of severe ulcerative colitis. Thirty nine patients with severe ulcerative colitis were randomised on admission to hospital to receive either intravenous metronidazole 500 mg eight hourly (19 patients) or an identical intravenous placebo (20 patients). The two groups were similar with respect to age, sex, and the extent of colitis. In addition all patients received a standard intravenous regimen consisting of methyl prednisolone 16 mg six hourly and parenteral nutrition together with a twice daily hydrocortisone 100 mg enema. Treatment was continued for five days when the patients were formally assessed. Fourteen of 19 patients (74%) receiving metronidazole and 14/20 (70%) receiving placebo were substantially improved, or in remission at the end of five days. Five patients treated with metronidazole and six with placebo had no improvement and all proceeded to urgent colectomy with no operative mortality. There were three late deaths, one in the metronidazole and two in the placebo group. These results do not support the routine use of intravenous metronidazole in the treatment of severe ulcerative colitis.

Barr GD, Shale DJ, Jewell DP. 1986. Ulcerative colitis and sarcoidosis. Postgrad Med J, 62 (727), pp. 341-345. | Show Abstract | Read more

Ulcerative colitis is not commonly associated with recognizable pulmonary disease and only four sporadic cases of sarcoidosis in association with ulcerative colitis have been previously reported. However, in a series of 680 patients with ulcerative colitis, pulmonary or extra-pulmonary sarcoidosis has at some stage been present in eight. These cases are reported in detail. The onset of either condition bore no relationship to the activity or the presence of recognized peripheral manifestations of the other, suggesting that the two diseases were independent. However, three of the patients had the HLA B8 DR3 phenotype which is a higher prevalence than seen in previous studies of either disease alone. Patients with ulcerative colitis who possess this HLA phenotype may possibly be more susceptible to developing sarcoidosis.

Shepherd HA, Barr GD, Jewell DP. 1986. Use of an intravenous steroid regimen in the treatment of acute Crohn's disease. J Clin Gastroenterol, 8 (2), pp. 154-159. | Show Abstract | Read more

The efficacy of a 5-day intensive intravenous regimen (IVR), used as treatment for severely active Crohn's disease in 49 patients, has been evaluated retrospectively. The value of such systemic therapy has not been reported before. Immediate remission was achieved in 38 (76%) patients with no significant difference between those with established disease and those seen for the first time. Patients with ileocolonic disease had the poorest response. There was no apparent change in the natural history of the Crohn's disease after IVR therapy. Nevertheless, this is a safe and effective method of achieving remission in most sick patients with severely active Crohn's disease.

Chapman RW, Cottone M, Selby WS, Shepherd HA, Sherlock S, Jewell DP. 1986. Serum autoantibodies, ulcerative colitis and primary sclerosing cholangitis. Gut, 27 (1), pp. 86-91. | Show Abstract | Read more

The aetiology of primary sclerosing cholangitis is unknown, but it is closely associated with ulcerative colitis. Serum anticolon antibodies, crossreacting with portal tracts, have been reported in patients with ulcerative colitis but no studies have been carried out in primary sclerosing cholangitis. The frequency of serum anticolon antibodies and portal tract antibodies have been measured in 24 patients with primary sclerosing cholangitis and ulcerative colitis; 15 patients with primary sclerosing cholangitis without ulcerative colitis; 77 patients without primary sclerosing cholangitis: 25 patients with Crohn's colitis; 10 patients with primary biliary cirrhosis; 22 patients with extrahepatic biliary obstruction and 20 normal controls. Serum anticolon and portal tract antibodies were detected using immunoperoxidase techniques on normal colon and obstructed human liver. Tissue typing was undertaken using a standard microcytotoxicity technique. The frequency of anticolon antibodies was markedly increased in primary sclerosing cholangitis patients with ulcerative colitis (62.5%) compared with patients with ulcerative colitis (17%) and Crohn's colitis (16%) (chi 2 = 17.9; p less than 0.001). The antibodies were almost entirely of IgG and IgA classes in all groups. Anticolon antibodies were not found in sera from any other group. Sera from eight of 15 patients with primary sclerosing cholangitis, ulcerative colitis and anticolon antibody reacted with portal tracts of human obstructed liver. This reaction was also seen in four of nine patients with ulcerative colitis and primary sclerosing cholangitis and in three of 15 patients with primary sclerosing cholangitis alone. Portal tract antibody was of IgG class and was not present in sera from any other groups. Unlike anticolon antibody, there was a close relationship between HLA-B8 phenotype and the portal tract antibody (p<0.02; chi 2 = 6.04). Absorption studies confirmed that the anticolon antibody is distinct from portal tract antibody.

Treacher DF, Chapman JR, Nolan DJ, Jewell DP. 1986. Irritable bowel syndrome: is a barium enema necessary? Clin Radiol, 37 (1), pp. 87-88. | Show Abstract | Read more

A retrospective analysis was made of 114 new patients attending a gastroenterology clinic, in whom the initial clinical diagnosis was irritable bowel syndrome. Barium enemas were performed in 84 patients (74%), 15 of whom were found to have significant other disease. In each case this would have been suspected from the routine haematological and biochemical screening tests. It is suggested that, in the investigation of patients under 50 years of age presenting to a gastroenterology clinic with a typical history of irritable bowel syndrome, a barium enema should only be performed if the clinical examination, sigmoidoscopy, rectal biopsy or routine blood tests are abnormal. This policy would reduce substantially the number of normal barium enemas performed.

Gibson PR, Jewell DP. 1986. Local immune mechanisms in inflammatory bowel disease and colorectal carcinoma. Natural killer cells and their activity. Gastroenterology, 90 (1), pp. 12-19. | Show Abstract | Read more

Mononuclear cell (MNC) populations isolated from intestinal mucosa, mesenteric lymph nodes, and peripheral blood have been assessed for their natural killer (NK) (Leu-7+) cell proportions and NK cell activity against K-562 erythroleukemic target cells. In peripheral blood, normal proportions of Leu-7+ cells were found in patients with Crohn's disease or ulcerative colitis, whereas increased proportions in colorectal carcinoma may have been related to the higher mean age of these patients. Low proportions of Leu-7+ cells (less than 3%) were present in intestinal MNCs in Crohn's disease, ulcerative colitis, colon cancer, and miscellaneous intestinal diseases. All groups of patients had diminished NK activity of peripheral blood MNCs compared with a group of healthy controls. Intestinal NK cell activity from histologically normal mucosa correlated with autologous peripheral blood NK cell activity (p less than 0.001) but no such correlation was seen for patients with inflammatory bowel disease. Mucosal or nodal NK cell activity showed a wide range of activity but did not relate to the underlying disease, mucosal histopathology, drug therapy, or, in patients with cancer, Dukes' grading. Intestinal MNCs from all patient groups responded to stimulation with lymphoblastoid interferon, except in a small number of patients whose unstimulated activity was not detectable. In conclusion, the NK cell on intestinal mucosa behaves similarly in various intestinal diseases. However, the disparity between NK activity of autologous peripheral blood and intestinal MNCs in inflammatory bowel disease highlights the difficulty in extrapolating peripheral blood findings to mucosal immune events.

Barbatis C, Grases P, Shepherd HA, Chapman RW, Trowell J, Jewell DP, McGee JO. 1985. Histological features of sclerosing cholangitis in patients with chronic ulcerative colitis. J Clin Pathol, 38 (7), pp. 778-783. | Show Abstract | Read more

Primary sclerosing cholangitis was diagnosed radiologically in 16 of 681 patients (2.2%) with chronic ulcerative colitis in a follow up study at the gastroenterology unit in Oxford. On the basis of established histological criteria, the liver biopsy was considered diagnostic in only half of the cases. The histological findings in these cases were therefore reassessed to determine whether the accuracy of biopsy diagnosis could be improved. The most common specific histological feature was periductal concentric fibrosis of small interlobular bile ducts, even in the absence of inflammation. Other common features were bile ductular proliferation associated with diminution or absence of interlobular bile ducts. Degeneration of bile duct epithelium and diffuse infiltration of portal tracts by mononuclear cells and polymorphonuclear leucocytes were accompanying features. Piecemeal necrosis without rosette formation was found in about half the biopsies. When all these features were considered together a biopsy diagnosis of primary sclerosing cholangitis was established in 14 of 16 cases.

Franklin WA, McDonald GB, Stein HO, Gatter KC, Jewell DP, Clarke LC, Mason DY. 1985. Immunohistologic demonstration of abnormal colonic crypt cell kinetics in ulcerative colitis. Hum Pathol, 16 (11), pp. 1129-1132. | Show Abstract | Read more

A monoclonal antibody, Ki-67, that reacts with cells in the proliferative phases (G1, G2, S, and M) of the cell cycle was used in an immunohistochemical labeling reaction to examine the colonic crypt epithelium in active ulcerative colitis, inactive ulcerative colitis, and normal mucosa. The proportions of labeled cells in the lower two thirds (proliferative zone) and in the upper quarter of the crypt were determined. The proportions of Ki-67-positive crypt epithelial cells in both the proliferative zone and the upper crypt were higher in biopsy specimens from patients with active ulcerative colitis than from patients with normal mucosa or with inactive ulcerative colitis. In inactive ulcerative colitis the proportion of Ki-67-positive epithelial cells in the proliferative zone of the crypt was higher than in normal mucosa. These results are similar to those obtained in studies using tritiated thymidine to determine the proportion of cells in the DNA-synthesizing thymidine to determine the proportion of cells in the DNA-synthesizing phase of the cell cycle and suggest that immuno-histochemical staining with Ki-67 may be a practical method for measuring the proliferative activity of epithelial cells in patients with ulcerative colitis and other disorders of the gastrointestinal tract.

Treacher DF, Jewell DP. 1985. Yersinia colitis associated with Crohn's disease. Postgrad Med J, 61 (712), pp. 173-174. | Show Abstract | Read more

A previously healthy patient developed serologically-proven Yersinia pseudotuberculosis enterocolitis and made a complete recovery. Over a year later, further gastrointestinal symptoms developed and Crohn's disease was diagnosed. The possible relevance to the aetiology of Crohn's disease is discussed.

Jewell DP, Patel C. 1985. Immunology of inflammatory bowel disease. Scand J Gastroenterol Suppl, 114 (sup114), pp. 119-126. | Show Abstract | Read more

Although the aetiology of ulcerative colitis and Crohn's disease remain unknown, immunological effector mechanisms become activated within the inflamed mucosa and may be responsible for the pathogenesis of chronic disease. There is an increased production of immunoglobulin within the mucosa, some of which has specificity for bacterial antigens, and complement activation occurs during exacerbation of the disease. Lymphocytes isolated from peripheral blood, or from the intestinal mucosa, are cytotoxic to colonic epithelial cells in vitro; a reaction which can be modulated by serum factors and bacterial antigens. Within the mucosa, there are increased populations of T lymphocytes although there is no change in the ratio of helper- to suppressor-cells as defined by phenotype. Studies of immunoregulatory control have shown that there may be alterations in the modulation of the local immune response, especially during active disease, although it is not clear whether these changes are primary or merely secondary to inflammation. It is posulated that many of the humoral and cellular responses to gut-associated antigens occur as a result of increased antigen absorption, increased presentation of antigen to the immune system due to the expression of Class II antigens by the inflamed epithelium and altered immuno-regulatory control.

Gibson PR, Jewell DP. 1985. The nature of the natural killer (NK) cell of human intestinal mucosa and mesenteric lymph node. Clin Exp Immunol, 61 (1), pp. 160-168. | Show Abstract

The relationship of the mononuclear cell (MNC) from human intestinal mucosa and mesenteric lymph node mediating anti-K-562 activity with that of peripheral blood has been assessed. Depletion of macrophages did not alter the measured cytotoxicity confirming that the effector cells were lymphocytes. Complement lysis of Leu 7 and Leu 11b coated cells reduced intestinal natural killer (NK) activity by a similar degree to that of peripheral blood but mesenteric lymph node NK activity was affected to a lesser extent. The response in NK activity of mucosal and nodal MNC to short incubation with lymphoblastoid interferon was similar to that for peripheral blood MNC. Twenty-four hours incubation of MNC with low concentrations of purified interleukin-2 (IL-2) consistently augmented intestinal and nodal NK activity but failed to augment that of peripheral blood MNC. No differences between the inhibitory effects of cAMP and prostaglandin E2 on NK activity from the three sites were seen. In addition, inhibition of cyclo-oxygenase activity with indomethacin had no effect on NK activity of intestinal and peripheral blood MNC while the lipoxygenase inhibitor, nordihydroguaiaretic acid, suppressed intestinal and peripheral blood NK activity similarly. In conclusion, anti-K-562 activity by intestinal MNC is mediated by NK cells with similar phenotypic and functional properties to those of peripheral blood. However, the increased sensitivity of mucosal NK cells to IL-2 suggests that higher proportions of NK cell precursors may be present in intestinal MNC populations.

Selby WS, Barr GD, Ireland A, Mason CH, Jewell DP. 1985. Olsalazine in active ulcerative colitis. Br Med J (Clin Res Ed), 291 (6506), pp. 1373-1375. | Show Abstract | Read more

Olsalazine (azodisalicylate) is a new drug in which two molecules of 5-aminosalicylic acid are linked by an azo bond. Its role in the treatment of mildly active, distal ulcerative colitis was investigated. Sixty patients were randomly allocated to receive olsalazine 1 g or a placebo as a retention enema nightly for two weeks. Clinical improvement was seen in 19 (66%) and sigmoidoscopic improvement in 17 (59%) of the 29 patients receiving olsalazine compared with 12 (43%) and 11 (39%), respectively, of the 28 in the control group. These differences were not significant. In a second trial 40 patients were randomised to receive oral olsalazine 2 g daily or a placebo capsule for two weeks. Significant clinical and sigmoidoscopic improvement was seen in the patients receiving oral olsalazine compared with the patients receiving placebo capsules. Oral olsalazine may be valuable in the treatment of mildly active ulcerative colitis. Its role in maintaining remission is yet to be determined.

Rawcliffe PM, Priddle JD, Jewell DP. 1985. Antigenic reactivity of peptides derived from wheat gluten with sera from patients with coeliac disease. Clin Sci (Lond), 69 (1), pp. 97-104. | Show Abstract | Read more

Fraction B from a peptic-tryptic digest of gluten from Scout 66 wheat has already been shown to cause histological damage to the jejunal mucosa of coeliac patients. Peptide fractions, designated P1-P4, have been prepared from it by a combination of gel filtration (producing an intermediate fraction pseudo-B2: psi B2) and reverse-phase high pressure liquid chromatography. An enzyme-linked immunosorbent assay (ELISA) has been used to measure IgG antibodies to fraction B in sera from untreated coeliac patients, patients with inflammatory bowel disease (IBD) and healthy individuals. The coeliac group had significantly higher (P less than 0.05) antibody levels to fraction B than either of the control groups [medians: coeliac disease (n = 21), 0.247; IBD (n = 17) 0.019; healthy controls (n = 13) 0.020]. Five coeliac sera which gave high absorbance values in the ELISA were chosen and preincubated with fraction B in a range of concentrations, before assay by ELISA: a dose-dependent inhibition of binding was found. Two sera which gave high ELISA values were preincubated with fractions B2 and P1-P4. B2, P1, P2 and P4 gave a dose-dependent inhibition, with P1 being the most potent. Absolute values were different for the two sera but the same relative pattern of reactivity was observed for each. With the serum giving the higher ELISA value the concentration of fraction (microgram/ml) giving a 50% inhibition of binding when 0.5 ml was added to 0.5 ml of a 1/500 dilution of the serum (IC50) was 2.6 for fraction B, 61 for P1, 155 for B2 and 285 and 295 for P4 and P2 respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Bennett MK, Sachdev GK, Jewell DP, Anand BS. 1985. Jejunal mucosal morphology in healthy north Indian subjects. J Clin Pathol, 38 (4), pp. 368-371. | Show Abstract | Read more

Morphometric measurements have been performed on small intestinal biopsy specimens obtained from 18 healthy adult Indian volunteers. The measurements were made using a computer aided measuring system, and results were similar to those previously reported for an adult Caucasian population.

Rawcliffe PM, Jewell DP, Faux JA. 1985. Specific IgG subclass antibodies, IgE and IgG S-TS antibodies to wheat gluten fraction B in patients with coeliac disease. Clin Allergy, 15 (2), pp. 155-162. | Show Abstract | Read more

Antibodies were measured in the sera of fifteen patients with untreated coeliac disease and twenty-eight patients with inflammatory bowel disease. Increased levels of specific IgG, IgG1, IgG2, and IgG4 antibody to wheat gluten fraction B, measured by an enzyme-linked immunosorbent assay, were shown in the coeliac disease group, but not in the inflammatory bowel disease group. No specific IgE antibody to fraction B was detected but 33% of the patients with coeliac disease had specific short-term sensitizing (anaphylactic) IgG antibody activity (IgG S-TS) to fraction B. There was no correlation between the IgG2 or IgG4 specific antibody and the presence of IgG S-TS activity.

Gibson PR, Hermanowicz A, Verhaar HJ, Ferguson DJ, Bernal AL, Jewell DP. 1985. Isolation of intestinal mononuclear cells: factors released which affect lymphocyte viability and function. Gut, 26 (1), pp. 60-68. | Show Abstract | Read more

Whether toxic or immunomodulatory factors are released during the collagenase digestion phase of the isolation of mononuclear cells from human intestinal mucosa was investigated by assessing the effect of the collagenase supernatant on the viability and natural killer activity of normal peripheral blood mononuclear cells. Three hours' incubation in collagenase supernatant suppressed natural killer activity by 25 +/- 4% and decreased the viability of peripheral blood mononuclear cells by 11 +/- 2%. The ability of collagenase supernatants to kill 51Cr-labelled peripheral blood mononuclear cells over four hours was assessed in 16 collagenase supernatants, eight of which produced lysis of 20 +/- 4%. There was no ultrastructural evidence of early degenerative changes in the viable intestinal mononuclear cells fresh from the isolation process or in peripheral blood mononuclear cells incubated in collagenase supernatant. Because prostaglandins are known to inhibit natural killer activity, PGE was measured in 20 collagenase supernatants by radioimmunoassay and found to be high at 27.5 +/- 4.0 ng/ml. Addition of indomethacin to the collagenase medium, however, failed to abolish the inhibitory effect of collagenase supernatant on natural killer activity and did not increase the natural killer activity of isolated intestinal mononuclear cells. The release of cytotoxic and immunomodulatory factors during the isolation of intestinal mononuclear cells indicates the necessity for careful assessment of the potential effects of the isolation process on any function being examined and casts doubt upon the relationship between in vitro findings and in vivo functional capabilities.

Chapman RW, Jewell DP. 1985. Primary sclerosing cholangitis--an immunologically mediated disease? West J Med, 143 (2), pp. 193-195. | Show Abstract

Primary sclerosing cholangitis (PSC) is an uncommon, chronic disorder characterized by inflammatory fibrosis usually involving the entire biliary tree. The etiology has been unknown, but PSC is closely associated with ulcerative colitis, which coexists in more than two thirds of patients with PSC. In recent studies 3% to 5% of all patients with ulcerative colitis had PSC. We propose that PSC is, at least in part, an immunologically mediated disease; it is closely associated with human leckocyte antigens B8 and DR3, and circulating autoantibodies to colon and portal tract are frequently present. The anticolon antibody cross-reacts with enteric Escherichia coli. The disease may possibly be triggered in susceptible patients with ulcerative colitis by immunization with antigens shared between enteric microorganisms and the biliary system.

Gibson PR, Jewell DP. 1985. Sulphasalazine and derivatives, natural killer activity and ulcerative colitis. Clin Sci (Lond), 69 (2), pp. 177-184. | Show Abstract | Read more

The effects of sulphasalazine, 5-aminosalicylic acid (5-ASA), sulphapyridine and azodisalicylic acid (ADS) in vitro on the natural killer (NK) activity of peripheral blood mononuclear cells (MNC) have been examined and compared with those of the lipoxygenase inhibitor, nordihydroguaiaretic acid (NDGA) and the cyclooxygenase inhibitor, indomethacin. Sulphasalazine, sulphapyridine and ADS inhibited NK activity with 50% inhibitory concentrations (IC50) of 0.7, 2.5 and 4.0 mmol/l respectively. The effect was rapidly reversible. In contrast, 5-ASA minimally inhibited NK activity at 50 mmol/l only. NDGA potently inhibited NK activity (IC50 27 mumol/l) but this was only partly reversible in short term incubations. Indomethacin had no effect at concentrations less than those inhibiting cyclo-oxygenase activity (1-10 mumol/l) but potently and reversibly inhibited NK activity at or above 25 mumol/l. The inhibitory effects observed were unlikely to be due to direct toxicity of effector cells as 5-ASA, sulphapyridine and ADS had no effect on the viability of peripheral blood MNC, whereas NDGA and indomethacin lysed MNC only at maximal concentrations tested. Though sulphasalazine produced MNC lysis at and above 1 mmol/l, the rapid reversibility of the inhibition of NK activity at 1 mmol/l suggested that lysis of NK cells contributed little to the suppressive effect at this concentration. The disparity of the therapeutic efficacy and effects on NK activity of sulphasalazine and its derivatives in vitro may suggest that NK activity is not a major pathogenic mechanism in ulcerative colitis. Any inhibitory effect on cellular immune function of indomethacin does not necessarily reflect an effect of cyclo-oxygenase inhibition.

Allan A, Jewell DP. 1985. Effect of filtrate containing Clostridium difficile toxin on rectal mucosa maintained in organ culture. Digestion, 32 (1), pp. 25-29. | Show Abstract | Read more

Rectal biopsies were maintained in organ culture over a 24-hour culture period, with good preservation of histological architecture. A filtrate containing Clostridium difficile toxin significantly inhibited the rise in epithelial alkaline phosphatase activity normally seen during culture. This effect was abolished by pre-incubation of the filtrate with Clostridium sordellii antitoxin, or heat inactivation. This effect is most probably due to a toxin of C. difficile. The method provides a new quantitative approach to the study of luminal toxins as possible pathogenic agents in idiopathic inflammatory diseases of the colon.

Harper PH, Lee EC, Kettlewell MG, Bennett MK, Jewell DP. 1985. Role of the faecal stream in the maintenance of Crohn's colitis. Gut, 26 (3), pp. 279-284. | Show Abstract | Read more

The role of the faecal stream in the maintenance of the inflammation in Crohn's disease has been studied. Small bowel effluent and a sterile ultrafiltrate of it were reintroduced into the defunctioned colon of patients with Crohn's colitis treated by split ileostomy. The systemic effect of these challenges on the patients was assessed clinically and by laboratory tests, and the effect on the local disease was assessed by endoscopy, histology, and quantitative analysis of lamina propria plasma cell populations. There was little response to the ultrafiltrate challenge. In contrast the clinical responses to challenge with ileostomy effluent were marked in some patients. One patient relapsed and eight others had clinically detectable responses. On the other hand changes in laboratory, endoscopic, histological, and morphometric tests in response to the faecal challenge were less pronounced. The only significant changes in the laboratory results were a relative lymphopenia (p less than 0.05) and a raised ESR (p less than 0.02) after seven days challenge with the effluent. The plasma cell density also increased but not significantly. In conclusion, these results suggest that factors greater than 0.22 microns in the faecal stream are responsible for the maintenance and exacerbation of inflammation in Crohn's disease.

Cottone M, Bunce M, Taylor CJ, Ting A, Jewell DP. 1985. Ulcerative colitis and HLA phenotype. Gut, 26 (9), pp. 952-954. | Show Abstract | Read more

The distribution of HLA A, B, C, DR antigens was investigated in a British population with ulcerative colitis. Fifty six patients were typed for HLA, A, B, C and 46 additionally for DR. No association was found between the HLA phenotype and the presence or absence of ulcerative colitis. Serum from 52 patients was tested for the presence of the anticolon antibody. There was no relation between the presence of the antibody and the HLA phenotype. Finally, no correlation was found between the HLA phenotypes, the age of onset of the disease, the extent and the clinical course.

Hermanowicz A, Gibson PR, Jewell DP. 1985. The role of phagocytes in inflammatory bowel disease. Clin Sci (Lond), 69 (3), pp. 241-249. | Show Abstract | Read more

In recent years, almost all the emphasis in immunological studies of inflammatory bowel disease has been on specific, acquired immunity to various antigens. There is now increasing awareness that there is also a natural immune system composed of a family of natural effector cells. Natural reactivity appears spontaneously and plays a substantial role in resistance to disease. This review will present the function and role of granulocytes and monocytes/macrophages, important natural effector cells which may play a role in the pathogenesis of inflammatory bowel disease.

Rawcliffe PM, Giles P, Bartlett S, Jewell DP, Ross BD. 1984. Carnitine as a possible adjunct in parenteral feeding. Clin Nutr, 3 (3), pp. 141-145. | Show Abstract | Read more

Carnitine is necessary for the transport of fatty acids across the inner mitochondrial membrane, and depletion in response to Intralipid infusion has previously been demonstrated. This study investigates whether orally administered L-carnitine increases tolerance to a lipid load given intravenously. Eight patients with active inflammatory bowel disease, being treated with intravenous prednisolone, were studied. Intralipid was infused on two occasions. Triglycerides and ketone bodies rose in a reproducible manner. Carnitine did not influence these changes. Carnitine excretion rose after an oral dose indicating that carnitine was absorbed, but carnitine excretion was increased in the steroid-treated individuals and rose after oral prednisolone in two healthy subjects. It is concluded that under the conditions of this study oral carnitine is without demonstrable effect on the handling of an intravenous lipid load.

Jewell DP. 1984. Immunological defence mechanisms of the gastrointestinal tract. Neth J Med, 27 (7), pp. 242-248. | Show Abstract

The local immune system is highly complex. The distribution of T-cell subsets between epithelium and lamina propria is not random and may be determined by the micro-environment provided by the expression of the class I and II HLA antigens. Macrophages in the small intestine appear to have the characteristics of antigen-processing cells, whereas colonic macrophages may predominantly be phagocytic cells. Suppression of a systemic immune response by prior oral ingestion of antigen may be mediated by cellular and humoral mechanisms. The relation between these mechanisms and the anatomical distribution of lymphocytes within the mucosa is an interesting but unexplored field. The local humoral response is IgA. This is determined by the specific localization within the lamina propria of B-cells sensitized within Peyer's patches while already committed to IgA production. Modulation of this commitment to IgA synthesis may be mediated by a distinct subset of T-cells. In order to resist proteolysis, secretory IgA and IgM become bound to secretory component, which acts uniquely as a receptor and as a transporting protein through the enterocyte. All these mechanisms are presumably aimed at preventing antigen from stimulating injurious immune responses, either locally or systemically. Disturbances in regulation, function or numbers of the immune cell populations may have potential implications for human disease.

Gibson PR, Hermanowicz A, Jewell DP. 1984. Factors affecting the spontaneous cell-mediated cytotoxicity of intestinal mononuclear cells. Immunology, 53 (2), pp. 267-274. | Show Abstract

This study was performed to determine what factors related to the enzymatic isolation technique and assay conditions may influence the measurement of spontaneous cell-mediated cytotoxicity (SCMC) of mononuclear cells (MNC) isolated from human intestinal mucosa. In 18 studies, the SCMC of freshly isolated cells was 1.8 +/- 0.4% but increased to 12 +/- 3% following 24 hr culture without a change in the proportion of cells with the NK phenotype (Leu-7+). The SCMC tended to plateau with more prolonged culture. Culturing peripheral blood (PB) MNC for 24 hr did not alter SCMC nor the proportion of Leu-7+ cells. However, the suppression of the SCMC of PBMNC preincubated with the supernatant of the collagenase digestion of intestinal mucosa was completely reversed by 24 hr culture. Intestinal MNC were found to suppress the SCMC of autologous PBMNC in mixing experiments. However, 24 hr culture did not affect the degree of suppression and the proportion of T cells of the suppressor-cytotoxic phenotype (Leu-2a+) was also unchanged. It is concluded that the SCMC of intestinal MNC may be accurately assessed following 24 hr culture of the cells to allow recovery from the suppressive influences of the isolation process and that this does not introduce other artefactual problems. However, suppression of cytotoxicity within the assay may result in an underestimation of the SCMC of intestinal MNC when compared to that of PBMNC.

Biemond I, Selby WS, Jewell DP, Klasen EC. 1984. Alpha 1-antitrypsin serum concentration and phenotypes in ulcerative colitis. Digestion, 29 (2), pp. 124-128. | Show Abstract | Read more

96 unrelated patients suffering from ulcerative colitis were typed for the electrophoretic variants of alpha 1-antitrypsin (alpha 1-AT). None of the phenotypes showed a definite association with this condition. The serum concentration of alpha 1-AT was increased compared with healthy control subjects. There was a positive correlation between the serum concentration of alpha 1-AT and activity of the ulcerative colitis.

Selby WS, Bennett MK, Jewell DP. 1984. Topical treatment of distal ulcerative colitis with 4-amino-salicylic acid enemas. Digestion, 29 (4), pp. 231-234. | Show Abstract | Read more

Enemas of 4-amino-salicylic acid (4-ASA) have been compared with placebo enemas in a double-blind study for the treatment of distal ulcerative colitis of mild to moderate severity. 30 patients were randomised to receive enemas containing 1 g of 4-ASA or placebo, and 22 to receive 2-gram enemas of 4-ASA or placebo. For each dose of 4-ASA there was clinical and sigmoidoscopic improvement, which reached significance when all patients receiving 4-ASA enemas were compared with those receiving placebo enemas (Cochran's test: p less than 0.005). There was also a trend towards histological improvement, but this failed to reach the level of significance. These findings suggest that 4-ASA may provide a stable, inexpensive alternative to 5-ASA for the topical treatment of ulcerative colitis or for linking to carrier molecules for release in the colon.

Shepherd HA, Priddle JD, Jenkins WJ, Jewell DP. 1984. The preparation of human intrinsic factor-cobalamin complex from human gastric juice by immunoadsorption. Clin Chim Acta, 139 (2), pp. 155-165. | Show Abstract | Read more

Immune complexes of human intrinsic factor were prepared by mixing gastric juice saturated with vitamin B12, and sera from patients with pernicious anaemia that had a high proportion of binding (Type II) antibody. The complexes were isolated by sodium sulphate precipitation followed by Sephadex G-150 gel filtration. Acid conditions dissociated the immune complexes and allowed separation of specific antibody and purified antigen bound to vitamin B12 by Sephadex G-200 gel filtration. Specific antibody was covalently attached to Protein A Sepharose CL-4B by coupling with water soluble carbodiimide which allowed intrinsic factor-B12 complex to be purified directly from gastric juice. The intrinsic factor obtained after iodination, ran as a single band on SDS-polyacrylamide gel electrophoresis and was biologically active.

Makiyama K, Bennett MK, Jewell DP. 1984. Endoscopic appearances of the rectal mucosa of patients with Crohn's disease visualised with a magnifying colonoscope. Gut, 25 (4), pp. 337-340. | Show Abstract | Read more

The magnified endoscopic appearances of the rectum are described in 12 patients with Crohn's disease with apparent rectal sparing on sigmoidoscopy. Five of them had minor abnormalities on colonoscopy but the remaining seven had a normal rectum. After the application of 0.2% methylene blue, examination using a magnifying endoscope (Olympus CF-HM) revealed characteristic 'worm-eaten' appearances in 75% of the patients regardless of the activity of their disease. Histological examination of biopsy specimens from these lesions showed marked inflammatory changes, and granulomas or microgranulomas were found in 75%. Inflammatory changes were not seen in mucosa which appeared normal on magnifying colonoscopy although microgranuloma were found in three cases. These observations confirm the focal nature of Crohn's disease and may suggest that the early lesions are mucosal and frequently contain granulomata.

Khosla R, Willoughby CP, Jewell DP. 1984. Crohn's disease and pregnancy. Gut, 25 (1), pp. 52-56. | Show Abstract | Read more

Infertility and the outcome of pregnancy has been examined in 112 married women with Crohn's disease who were below the age of 45 years. Fifty four patients were available for study. The infertility rate (12%) was similar to that seen in the general population. Patients who had active disease at the time of conception continued to have symptoms and they mostly failed to go into satisfactory remission despite therapy. Furthermore, there was a high rate (35%) of spontaneous abortion in this group. In contrast, patients whose disease was in remission at the time of conception had a normal pregnancy and, in the majority, the Crohn's disease remained quiescent.

Gibson PR, Dow EL, Selby WS, Strickland RG, Jewell DP. 1984. Natural killer cells and spontaneous cell-mediated cytotoxicity in the human intestine. Clin Exp Immunol, 56 (2), pp. 438-444. | Show Abstract

Spontaneous cell-mediated cytotoxicity (SCMC) has been investigated in mononuclear cells (MNC) isolated from intestinal mucosa and autologous peripheral blood from human subjects. The proportion of cells with the NK-K phenotype (Leu 7+) were substantially lower in intestinal MNC than in autologous peripheral blood. SCMC of K-562 target cells when tested at an effector to target (E:T) ratio equivalent to that used for peripheral blood MNC was markedly deficient in intestinal MNC. This was not due to the effect of EDTA and collagenase used in the isolation process. However, at high E:T, ratios, significant cytotoxicity was demonstrated for most intestines examined probably reflecting a low proportion of effector cells within the intestinal MNC population. SCMC in both intestinal and autologous peripheral blood MNC were similarly related to the Leu 7+:T ratios used in the assay indirectly suggesting that the Leu 7+ cell may be responsible for the observed cytotoxicity. It is concluded that the apparent functional difference between similar cells derived from different sites may be largely related to differing proportions of effector cells. The findings indicate the need for specific definition of the effector cell and suggest that intestinal SCMC in health and various disease states requires re-appraisal.

Gibson PR, Verhaar HJ, Selby WS, Jewell DP. 1984. The mononuclear cells of human mesenteric blood, intestinal mucosa and mesenteric lymph nodes: compartmentalization of NK cells. Clin Exp Immunol, 56 (2), pp. 445-452. | Show Abstract

The proportions of T cell subsets and Leu 7+ cells and the spontaneous cell-mediated cytotoxicity (SCMC) of isolated mononuclear cells have been determined across the mesenteric vascular bed and along the intestinal mucosal-mesenteric lymph node (MLN) axis in patients undergoing abdominal surgery. Whereas the proportion of T4+ and T8+ cells were similar in simultaneously taken PVB and mesenteric venous blood (MVB), the proportion of Leu 7+ cells was higher in MVB in 16 of 17 studies (15.4 +/- 6.8%, 10.8 +/- 5.1%). Additional studies showed that the proportions of lymphocyte subsets in peripheral arterial blood are the same as those in PVB. Thus, an enrichment of Leu 7+ cells occurs across the mesenteric vascular bed. Isolated intestinal and MLN mononuclear cells contained similarly high proportions of T4+ and T8+ cells as in PVB but Leu 7+ cells made up a minority subpopulation in intestinal (1.3 +/- 0.8%) and MLN mononuclear cells (1.0 +/- 0.9%). The SCMC of intestinal and MLN mononuclear cells was low and paralleled the proportion of Leu 7+ cells. Despite the higher proportions of Leu 7+ cells in MVB, the SCMC was less than that of PVB in eight patients with inflamed intestine and not significantly different from PVB in seven patients with normal intestines. These paradoxical findings were at least in part due to inhibitory factors in mesenteric plasma. In conclusion, NK cells appear to be largely confined within the vascular system and the enrichment of Leu 7+ cells across the mesenteric vascular bed suggests that this compartmentalization may be due to differences in the traffic of lymphocyte subpopulations through the intestinal mucosa and MLN.

Selby WS, Janossy G, Bofill M, Jewell DP. 1984. Intestinal lymphocyte subpopulations in inflammatory bowel disease: an analysis by immunohistological and cell isolation techniques. Gut, 25 (1), pp. 32-40. | Show Abstract | Read more

Lymphocyte subpopulations in the intestinal mucosa of patients with ulcerative colitis or Crohn's disease have been studied using a double marker immunofluorescence technique. Analysis of tissue sections revealed that the majority of intraepithelial lymphocytes (IEL) were T cells (Hle-1+ HuTLA+ UCHT1+). Of these, over 80% were of suppressor-cytotoxic phenotype (OKT8+:83 +/- 10.2%) with a small population of helper type IEL (OKT4+). Only one third of OKT8+ IEL reacted with the T cell antibody, anti-Leu-1. IEL were also Tac-, C3b-receptor- (C3RT05-), and Ig-. Within the lamina propria, OKT4+ T cells predominated (ulcerative colitis 64 +/- 6.0%; Crohn's disease 63 +/- 6.0%). Less than half of the smaller OKT8+ population in the lamina propria was Leu-1+. These finding did not differ from those seen in histologically normal tissues from controls, and are similar to those reported in the small intestine. Mononuclear cells were also isolated from the intestinal lamina propria using an enzymatic technique. The majority of lymphocytes obtained were T cells (OKT3+), with populations of OKT4+ and OKT8+ cells. Comparison of the ratio of OKT4+ to OKT8+ lymphocytes determined by immunohistological analysis with that obtained in mucosal isolates, however, suggested that the isolation procedure may deplete OKT8+ cells. These findings indicate that an imbalance of mucosal immunoregulatory T cells, as defined by monoclonal antibodies, does not occur in inflammatory bowel disease. They also emphasize that functional studies of isolated intestinal mucosal cells should be combined with morphological studies of cell populations in situ.

Reed PI, Vincent-Brown A, Cook PJ, Colaco CB, Perks S, Baron JH, Jewell DP. 1983. Comparative study of carbenoxolone and cimetidine in the management of duodenal ulcer. Acta Gastroenterol Belg, 46 (9-10), pp. 459-468.

Teh LB, Stopard M, Anderson S, Grant A, Quantrill D, Wilkinson RH, Jewell DP. 1983. Assessment of fat malabsorption. J Clin Pathol, 36 (12), pp. 1362-1366. | Show Abstract | Read more

For the assessment of fat malabsorption, the standard method of measuring faecal fat excretion using a 5 day stool collection has been compared with the alternative methods: stool microscopy, a lipid tolerance test and a continuous marker technique for the estimation of fat content on a single stool sample. The lipid test, using an emulsion of arachis oil (Prosparol), was less reliable than had been expected with a sensitivity of 33% and a specificity of 45.4%. Stool microscopy using Oil Red O to stain fat globules had a sensitivity of 72.2% and a specificity of 95.4%. Fat estimation of a single stool sample using copper (1) thiocyanate showed a high correlation with that determined on a 5 day stool collection (p less than 0.001). It is concluded that lipid tolerance tests have little place in the estimation of fat absorption. In laboratories where faecal fats are not measured, microscopic examination of stool for fat globules provides a specific and relatively sensitive method for detecting steatorrhoea. The use of a continuous marker provides a method for assessing the degree of steatorrhoea on a single stool sample without the disadvantages of the conventional method of faecal fat analysis.

Jewell DP. 1983. Ulcerative enteritis. Br Med J (Clin Res Ed), 287 (6407), pp. 1740-1741. | Read more

Hosker JP, Jewell DP. 1983. Transient, selective factor X deficiency and acute liver failure following chest infection treated with erythromycin BP. Postgrad Med J, 59 (694), pp. 514-515. | Show Abstract | Read more

A 57-year-old man developed symptoms of a respiratory tract infection which was treated with erythromycin BP. He subsequently went into acute liver failure. Investigation of a very prolonged prothrombin time revealed a marked, selective factor X deficiency (1% of normal activity). He later recovered virtually normal liver function and completely normal factor X activity.

Rhodes JM, Jewell DP. 1983. Motility of neutrophils and monocytes in Crohn's disease and ulcerative colitis. Gut, 24 (1), pp. 73-77. | Show Abstract | Read more

Random motility and chemotaxis of peripheral blood neutrophils and monocytes from patients with Crohn's disease and ulcerative colitis have been measured using a modified Boyden Chamber filter assay. Increased random motility and chemotaxis of monocytes were found in patients with active ulcerative colitis. Monocyte motility was normal in Crohn's disease and no abnormality of neutrophil motility or chemotaxis was found in either disease. Drug therapy with prednisolone or sulphasalazine received in vivo was found to have no effect on the motility of the washed neutrophils and monocytes in vitro. This work adds to the evidence that monocytes are activated in ulcerative colitis but does not support the hypothesis that Crohn's disease is due to an inherent defect in phagocyte motility.

Allan A, Jewell DP. 1983. In vitro model for the assessment of luminal factors on rectal mucosa. Gut, 24 (9), pp. 812-817. | Show Abstract | Read more

An organ culture method for the maintenance of rectal biopsies over a period of 24 hours is described. Good preservation of histological architecture and continued crypt cell proliferation were shown over the culture period. The colonic enzyme alkaline phosphatase was found to rise over the period of culture. This rise was dependent upon continued protein synthesis by the cell. Changes in alkaline phosphatase activity during culture in biopsies from patients with ulcerative colitis and Crohn's disease are reported. This organ culture system and the measurement of alkaline phosphatase activity during culture provides a new approach to the assessment of luminal antigens as possible effectors of colonic epithelial cell damage.

Selby WS, Janossy G, Mason DY, Jewell DP. 1983. Expression of HLA-DR antigens by colonic epithelium in inflammatory bowel disease. Clin Exp Immunol, 53 (3), pp. 614-618. | Show Abstract

The expression of HLA-DR and HLA-A,B,C antigens by human colonic epithelium has been examined in tissue sections of patients with inflammatory bowel disease using an immunohistological technique. Colonic epithelial cells from all 21 control subjects with histologically normal colonic mucosa were HLA-DR-. In contrast, in nine of 13 patients with active ulcerative colitis and 11 of 12 with active Crohn's disease the epithelium of involved colonic mucosa was HLA-DR+. HLA-DR antigens were found on the epithelium of only one of six patients with ulcerative colitis in remission and one of three with inactive Crohn's disease. Moreover, these antigens were not present on the epithelium of non-inflamed colonic mucosa in two patients with Crohn's disease in whom adjacent involved mucosa showed strong epithelial reactivity. This difference between patients with active and those with inactive disease is highly significant (P less than 0.005). These findings provide further evidence of the importance of cell-mediated immune mechanisms in the pathogenesis of inflammatory bowel disease.

Strickland RG, Jewell DP. 1983. Immunoregulatory mechanisms in nonspecific inflammatory bowel disease. Annu Rev Med, 34 (1), pp. 195-204. | Show Abstract | Read more

Little is known of either the etiology or the pathogenesis of nonspecific inflammatory bowel disease (IBD). One hypothesis proposes the presence of a disorder of immune regulation as an initiating or perpetuating mechanism of continued bowel wall inflammation in these diseases. This chapter examines the basis for this proposal and reviews recent studies directed toward the demonstration of defective immunoregulatory mechanisms in IBD.

Selby WS, Janossy G, Bofill M, Jewell DP. 1983. Lymphocyte subpopulations in the human small intestine. The findings in normal mucosa and in the mucosa of patients with adult coeliac disease. Clin Exp Immunol, 52 (1), pp. 219-228. | Show Abstract

Lymphocyte subpopulations in human small intestinal mucosa have been studied using an immunofluorescence technique on tissue sections. In the normal intestine, the majority of intraepithelial lymphocytes (IEL) were of suppressor-cytotoxic phenotype (HuTLA+ UCHTI+ OKT8+ OKT4-; 84%). Only one-third of these OKT8+IEL reacted with anti-Leu-1, and antibody directed towards a 67,000 dalton antigen found on peripheral blood T cells. IEL failed to express the activation antigen, Tac, and also lacked detectable C3b receptor (C3RTO5-). The remaining T IEL, as well as the predominant lamina propria T lymphocytes (LPL), were OKT4+ OKT8-, helper type T cells. Most of the lamina propria OKT8+ cells were also Leu-1-. In patients with adult coeliac disease, the proportions of OKT8+ and OKT4+ lymphocytes in the epithelium were not altered. However, the proportion of OKT8+ Leu-1+TIEL was significantly increased (56 vs 32%; P less than 0.02). IEL were also HLA-DR-, Tac- and C3RTO5-. The proportion of OKT8+ cells in the lamina propria was slightly, but significantly, increased (40 vs 32%; P less than 0.005). Mucosal findings in treated patients did not differ from normal. Lymphocytes with the phenotype of natural killer cells (HNK-1) were rarely found in normal or diseased mucosa. No alterations in the proportions of circulating T lymphocytes or their subsets were found in patients with coeliac disease. These findings illustrate the heterogeneity of lymphocyte subpopulations in normal and in diseased small intestinal mucosa. The changes found in adult coeliac disease may reflect the increased traffic of IEL into the epithelium.

Harper PH, Truelove SC, Lee EC, Kettlewell MG, Jewell DP. 1983. Split ileostomy and ileocolostomy for Crohn's disease of the colon and ulcerative colitis: a 20 year survey. Gut, 24 (2), pp. 106-113. | Show Abstract | Read more

The clinical course of 140 patients who have had a split ileostomy for ulcerative colitis or colonic Crohn's disease over a 20 year period is reported. In 37 patients with ulcerative colitis there was no sustained improvement. In the 102 patients with Crohn's disease there was an immediate clinical improvement in 95, which was sustained in 65. Thirty patients have subsequently required a proctocolectomy for persistent inflammation, and 28 are still defunctioned. Bowel continuity was restored after 61 split ileostomies and in 44 patients intestinal continuity remains intact at the present time (mean follow up since closure = 62.5 months, range 0-231 months). It is concluded that a split ileostomy is a safe conservative operation producing at least temporary improvement in severely ill and malnourished patients with Crohn's colitis, and that if a subsequent resection becomes necessary it may be less extensive than was thought applicable at the initial operation. In 27 patients a resection has not been required.

Makiyama K, Selby WS, Jewell DP. 1983. E rosetting lymphocytes in inflammatory bowel disease. An analysis using monoclonal antibodies. Clin Exp Immunol, 52 (2), pp. 350-354. | Show Abstract

Lymphocytes rosetting with sheep red blood cells (SRBC) have been quantitated in the peripheral blood of patients with ulcerative colitis (UC) or Crohn's disease (CD) and the results compared with those from healthy control subjects. In contrast with previous studies, normal populations of total (SRBC: lymphocyte, 60:1) and avid (8:1) rosetting lymphocytes were found in the patient groups. Analysis of these cells, using monoclonal antibodies, showed that the proportions of OKT3+, OKT4+ and OKT8+ cells were similar in the two rosetting populations. However, for patients with UC, there was a significant increase in OKT4+ cells in the total rosette forming population when compared with healthy subjects. It is concluded that avid rosette forming cells are unlikely to form a functionally distinct population of T lymphocytes and this population, which is thymosin-dependent, is not deficient in patients with UC or CD.

Selby WS, Poulter LW, Hobbs S, Jewell DP, Janossy G. 1983. Heterogeneity of HLA-DR-positive histiocytes in human intestinal lamina propria: a combined histochemical and immunohistological analysis. J Clin Pathol, 36 (4), pp. 379-384. | Show Abstract | Read more

HLA-DR-positive histiocytes in the lamina propria of the human intestine have been characterised using combined histochemical and immunohistological techniques. In the small intestine, 80-90% of the HLA-DR+ histiocytes had irregular surfaces with stellate processes, and exhibited strong membrane adenosine triphosphatase (ATPase) activity, but weak acid phosphatase (ACP) and non-specific esterase (NSE) activities (HLA-DR+ ACP+/- NSA+/- ATP++; type 1 cell). In contrast, in the lamina propria of the colon the majority (60-70%) of HLA-DR+ cells were large, round cells with strong ACP and NSE activities but no detectable ATPase activity (HLA-DR+ ACP++ NSE++ ATP+/-; type 2 cell). The colon also contained a population of type 1 cells (30-40%). In active inflammatory bowel disease affecting the colon a third population of HLA-DR+ histiocytes was seen. These cells were irregular in outline, with many processes, and were ACP++ NSE+ ATP+/- (type 3 cell). The type 3 cells appeared to replace type 2 cells. After treatment, the appearances returned to normal. These findings suggest that the different populations of HLA-DR+ histiocytes in the human intestine may have several functions, reflecting the different forms of antigen present in the intestine. The alterations in inflammatory bowel disease may represent activation in response to an invading antigen.

Selby WS, Jewell DP. 1983. T lymphocyte subsets in inflammatory bowel disease: peripheral blood. Gut, 24 (2), pp. 99-105. | Show Abstract | Read more

Peripheral blood T lymphocytes and T lymphocyte subsets have been quantified in 28 patients with ulcerative colitis and 26 with Crohn's disease by an indirect immunofluorescence technique using monoclonal antibodies: OKT3, which detects all peripheral blood T lymphocytes; OKT4 (T cells of helper phenotype); and OKT8 (T cells of supressor-cytotoxic phenotype). Eighteen normal subjects and 16 patients with a variety of non-inflammatory gastrointestinal disorders were studied as controls. No significant differences were found between patient and control groups in the proportions of circulating T lymphocytes or their subsets. When compared with normal subjects, absolute numbers of T lymphocytes were reduced in patients with active ulcerative colitis or Crohn's disease (p less than 0.05). OKT4+ T cell numbers were reduced in ulcerative colitis, whether active (p less than 0.02) or inactive (p less than 0.05) and in active Crohn's disease (p less than 0.05) Numbers of OKT8+ T cells were reduced in active Crohn's disease (p less than 0.01). There were no differences in T lymphocyte numbers between the patient groups and the disease control subjects. The OKT4+:OKT8+ ratio in patients with inflammatory bowel disease did not differ from that in controls. No relation was found between any of the parameters studied and disease activity, site, or extent of disease, or treatment with sulphasalazine or corticosteroids. The presence of Ia-like, HLA-DR antigens on T cells was detected using a double marker immunofluorescence technique. In control subjects up to 7% of OKT3+ cells were HLA-DR+. In only three patients was the proportion of HLA-DR+ cells greater than in controls. These results indicate that the pathogenesis of ulcerative colitis or Crohn's disease does not depend upon an alteration in the proportion of circulating T lymphocytes nor upon an imbalance of T lymphocyte subsets as defined by monoclonal antibodies. The reduction in T lymphocyte numbers may result from mucosal infiltration. The findings also suggest that circulating T lymphocytes are not activated.

Agnew JE, Pocock DG, Jewell DP. 1982. Sacroiliac joint uptake ratios in inflammatory bowel disease: relationship to back pain and to activity of bowel disease. Br J Radiol, 55 (659), pp. 821-826. | Show Abstract | Read more

Sacroiliac uptake ratios based on 99Tcm methylene diphosphonate images were calculated in 14 patients with ankylosing spondylitis, 23 patients with non-specific backache, 33 patients with inflammatory bowel disease (ulcerative colitis 19, Crohn's disease 14) and 33 control subjects. Twenty-eight of the control subjects were patients referred from a breast cancer clinic. In the control subjects, and in 20 patients with inflammatory bowel disease who did not have back pain, sacroiliac ratios decreased significantly with increasing age (p less than 0.001 and p less than 0.01 respectively). Sacroiliac uptake ratios were significantly higher in ankylosing spondylitis than in patients with non-specific backache. Seven of the 14 patients with ankylosing spondylitis had higher sacroiliac ratios than any recorded in the control subjects. Eleven patients with inflammatory bowel disease had abnormally high sacroiliac uptake ratios; ten of these patients had back pain. Increased sacroiliac joint uptake in such patients may reflect early sacroiliitis. No relationship was detected between sacroiliac uptake and the activity of the bowel disease. Sacroiliac uptake ratios were significantly higher in the inflammatory bowel disease patients suffering from back pain than in age and sex matched patients with (a) inflammatory bowel disease but no back pain or (b) non-specific backache.

Brown DJ, Jewell DP. 1982. Cold-reactive lymphocytotoxins in Crohn's disease and ulcerative colitis. I. Incidence and characterization. Clin Exp Immunol, 49 (1), pp. 67-74. | Show Abstract

The incidence of cold-reactive lymphocytotoxins in the serum of patients with Crohn's disease or ulcerative colitis has been investigated. Twenty-seven percent of patients with Crohn's disease and twenty-two percent of those with ulcerative colitis had circulating lymphocytotoxins. This is significantly higher than the 4% found in a normal control population. The presence of lymphocytotoxins did not correlate with age or sex of the subjects studied nor with clinical parameters. As in previous studies, the lymphocytotoxin is an antibody of IgM class, is optimally effective at 15 degrees C in the presence of complement and reacts with both T and B lymphocytes. The lymphocytes from patients with active Crohn's disease or ulcerative colitis are poorly susceptible to lysis by lymphocytotoxins but lymphocytes from patients in remission are as susceptible as normal lymphocytes. This implies that the lymphocyte surface is altered during active disease although the pathogenetic significance of this is unclear.

Rhodes JM, Potter BJ, Brown DJ, Jewell DP. 1982. Serum inhibitors of leukocyte chemotaxis in Crohn's disease and ulcerative colitis. Gastroenterology, 82 (6), pp. 1327-1334. | Show Abstract

Studies were undertaken to determine the incidence and nature of serum chemotaxis inhibitors in patients with Crohn's disease and ulcerative colitis. Sera from patients with active Crohn's disease were shown to contain chemotactic factor-directed inhibitory activity. The molecular size of the inhibitor estimated by gel filtration is similar to the 7S gamma-globulins and it is precipitable by 40% ammonium sulfate. Less marked inhibitory activity is present in the same fractions of sera from patients with ulcerative colitis and from healthy controls, suggesting that it represents increased activity of one or more normal serum globulins. Leukocyte-directed serum inhibitors have also been demonstrated in patients with Crohn's disease and ulcerative colitis, particularly in patients with active disease. In Crohn's disease the presence of serum chemotactic factor inhibitors may explain the diminished chemotaxis of neutrophils into skin window chambers reported previously. The inhibitors are nonspecific and are probably secondary to the disease state but may have some bearing on the nature of the mucosal inflammation.

Rhodes JM, McLaughlin JE, Brown DJ, Nuttall LA, Jewell DP. 1982. Inhibition of leucocyte motility and prevention of immune-complex experimental colitis by hydroxychloroquine. Gut, 23 (3), pp. 181-187. | Show Abstract | Read more

The inhibitory effects of hydroxychloroquine on leucocyte motility have been compared with those of prednisolone. It has been shown to have similar potency to prednisolone as an inhibitor of human neutrophil and monocyte motility. Hydroxychloroquine has then been compared with placebo in the prevention of an immune-complex experimental colitis in rabbits. Rectal biopsies were taken from rabbits 24 hours after initiation of colitis, coded, and graded histologically. The summated gradings for acute inflammation and goblet cell depletion had worsened more in the control rabbits (mean grade +6.7) than in the treated rabbits (mean grade +1.8) P less than 0.05. There was no difference in the mononuclear cell infiltrate between the two groups. Hydroxychloroquine, which is a potent inhibitor of leucocyte motility, effectively prevents the acute inflammatory infiltrate in this experimental colitis model and therefore merits trial in human ulcerative colitis.

Jewell DP. 1982. Diagnosis and medical treatment of ulcerative colitis. Br J Hosp Med, 27 (5), pp. 456-462. | Show Abstract

Acute attacks of ulcerative colitis should be treated without delay and corticosteroids should be used systemically and topically. For patients with severe attacks, prognostic indicators and criteria for proceeding to urgent colectomy are well defined. In fact, with good medical management the surgeon should only rarely have to operate on a moribund patient, even when an emergency or urgent colectomy is indicated. The mortality rate in patients with severe attacks requiring surgery is low in specialist centres. When patients have gone into remission on corticosteroids, these should be tailed off and the patients maintained indefinitely on sulphasalazine. Currently there is considerable interest in the development of pro-drugs which will contain the 5-aminosalicylic acid moiety but not the sulphapyridine.

Selby WS, Jewell DP. 1982. Intestinal T-cell function. Gastroenterology, 82 (1), pp. 167.

Jewell DP, Berney JJ, Pettit JE. 1981. Splenic phagocytic function in patients with inflammatory bowel disease. Pathology, 13 (4), pp. 717-723. | Show Abstract | Read more

Splenic phagocytic function has been assessed in patients with inflammatory bowel disease. No Howell-Jolly bodies were found on blood film examination. Slow clearance times of heat damaged red cells were found in 13 of 16 patients with ulcerative colitis compared with 4 of 17 patients with Crohn's disease (P less than 0.01). For ulcerative colitis prolonged clearance times were strongly related to the length of history (r = 0.90; P less than 0.01). The prolongation of half-clearance times correlated poorly with splenic size suggesting a functional impairment of the reticuloendothelial system.

Jenkins WJ, Empson R, Jewell DP, Taylor KB. 1981. Subcellular localisation of vitamin B12 during absorption in the guinea-pig ileum. Gut, 22 (8), pp. 617-622. | Show Abstract | Read more

The subcellular distribution of vitamin B12 was studied during its absorption in the guinea-pig ileum. Animals were fed either (57Co) or (58Co) cyanocobalamin and killed two or four hours later. At two hours labelled cyanocobalamin was concentrated in brush border and lysosomal fractions of ileal homogenates, with some remaining in the sample layer. In contrast, at four hours labelled cyanocobalamin was concentrated predominantly in the cytosol with much smaller peaks in the brush border and lysosomal fractions. These findings are consistent with vitamin B12 absorption by receptor-mediated endocytosis. It is suggested that, after binding at the brush border, vitamin B12 is first sequestrated within lysosomes, and then released into the cytosol, from where it leaves the cell to enter the portal blood.

Rhodes JM, Bartholomew TC, Jewell DP. 1981. Inhibition of leucocyte motility by drugs used in ulcerative colitis. Gut, 22 (8), pp. 642-647. | Show Abstract | Read more

The effects on leucocyte motility of sulphasalazine (Salazopyrin) and its metabolites sulphapyridine and 5 amino-salicylic acid have been compared with those of prednisolone and indomethacin. Sulphasalazine, its active metabolite 5 amino-salicylic acid, and prednisolone are all potent inhibitors of leucocyte motility. Sulphapyridine and indomethacin are non-inhibitory. Inhibition of leucocyte motility may explain why sulphasalazine and 5 amino-salicylic acid are effective in ulcerative colitis while sulphapyridine is not. The lack of effect of indomethacin suggests that this action of sulphasalazine does not involve inhibition of prostaglandin synthesis.

Selby WS, Janossy G, Jewell DP. 1981. Immunohistological characterisation of intraepithelial lymphocytes of the human gastrointestinal tract. Gut, 22 (3), pp. 169-176. | Show Abstract | Read more

Intraepithelial lymphocytes (IEL) of the normal human stomach, small intestine, and large intestine have been characterised in tissue sections by a double marker immunofluorescent technique. A panel of reagents was used in combination, including antisera to T lymphocyte antigen (HuTLA), Ia-like (p28, 33) antigens and immunoglobulin subclasses, as well as a mouse monoclonal antibody to a human leucocyte antigen (HLe-1). In stomach and proximal small intestine over 95% of IEL were T lymphocytes (HLe-1+, HuTLA+). The proportion was slightly lower in the colon and rectum (85--95%). IEL rarely expressed Ia-like antigens. B lymphocytes were not seen within the epithelium of any of the tissues examined. The functions of IEL must be assessed in the light of the finding that they are predominantly T cells.

Jewell DP, Truelove SC. 1981. Disodium azodisalicylate in ulcerative colitis. Lancet, 2 (8256), pp. 1168-1169. | Read more

Harris A, Cook PJ, Jewell DP, James IM. 1981. Cimetidine and cerebral blood flow in elderly patients. Br J Clin Pharmacol, 11 (1), pp. 93-94. | Read more

Brown JJ, Jewell DP. 1981. Outpatient preparation for colonoscopy. Lancet, 2 (8248), pp. 695. | Read more

Willoughby CP, Bennett MK, Banerji A, Jewell DP. 1981. Gastrointestinal amyloidosis complicating psoriatic arthropathy. Postgrad Med J, 57 (672), pp. 663-667. | Show Abstract | Read more

A patient is described who developed gastrointestinal amyloidosis complicating psoriatic arthropathy. The presenting symptom was progressive dysphagia due to oesophageal involvement. Other clinical features included gastric ulceration with melaena, intestinal pseudo-obstruction and evidence of impaired renal function. The oesophageal symptoms improved after endoscopic dilatation of the cardia. Colchicine was used in an attempt to slow down progression of the condition. © 1981 The Fellowship of Postgraduate Medicine.

Selby WS, Janossy G, Goldstein G, Jewell DP. 1981. T lymphocyte subsets in human intestinal mucosa: the distribution and relationship to MHC-derived antigens. Clin Exp Immunol, 44 (3), pp. 453-458. | Show Abstract

T lymphocytes in the normal human intestinal tract have been analysed in tissue sections by a double-marker immunofluorescence technique, combining antiserum to T lymphocyte antigen (HuTLA) with a monoclonal antibody detecting T cells of suppressor-cytotoxic phenotype (OKT8). The distribution of HLA-A -B, -C and Ia-like antigens in intestinal mucosa was also examined by a similar method. In small and large intestine 67 to 90% (mean 70%) of intraepithelial T lymphocytes were of suppressor-cytotoxic phenotype (OKT8+). In contrast, only 27 to 56% (mean 39%) of lamina propria T cells were OKT8+. Intestinal epithelial cells demonstrated strong membrane staining for HLA-A, -B, -C antigens. Ia-like antigens were detected on the epithelial cells of small intestinal villi, but not on colonic epithelial cells. Lamina propria macrophages expressed both HLA-A, -B, -C and Ia-like antigens, the latter having strong membrane and cytoplasmic fluorescence. The distribution of T cells with suppressor-cytotoxic or inducer phenotype in the intestinal epithelium and lamina propria may be related to the differential expression of Ia-like and HLA-A, -B, -C antigens in intestinal mucosa.

Potter BJ, Brown DJ, Watson A, Jewell DP. 1980. Complement inhibitors and immunoconglutinins in ulcerative colitis and Crohn's disease. Gut, 21 (12), pp. 1030-1034. | Show Abstract | Read more

The serum concentrations of the complement inactivators C1INH, C3bINA and beta 1H have been determined in patients with ulcerative colitis and Crohn's disease and their correlation with C3 and properdin factor B examined. The incidence of immunoconglutinins (1K) in these patients was investigated. Raised serum concentrations of C1INH and C3bINA have been found in patients with active disease, but no significant alteration was found in serum concentration of beta 1H. An increasing incidence of positive 1K titres was found with increased length of disease history. These results suggest continuing complement activation in these diseases.

Mee AS, Berney J, Jewell DP. 1980. Monocytes in inflammatory bowel disease: absolute monocyte counts. J Clin Pathol, 33 (10), pp. 917-920. | Show Abstract | Read more

Using a cytochemical staining technique, peripheral blood monocytes have been precisely identified and enumerated in patients with inflammatory bowel disease and compared with healthy and disease control subjects. For ulcerative colitis there was a significant monocytosis, which was closely correlated with the total white cell count and with the activity of the disease. For patients with Crohn's disease, the peripheral blood monocyte count was also raised compared with that of the control groups, but the difference did not reach statistical significance. There was no correlation between the monocyte count in patients with Crohn's disease and the total white cell count or the disease activity. Some of the mechanisms that may influence the production and distribution of peripheral blood monocytes are discussed.

Mee AS, Szawatakowski M, Jewell DP. 1980. Monocytes in inflammatory bowel disease: phagocytosis and intracellular killing. J Clin Pathol, 33 (10), pp. 921-925. | Show Abstract | Read more

The ability of peripheral blood monocytes from patients with ulcerative colitis and Crohn's disease to phagocytose and kill a standard strain of Staphyloccus aureus has been studied. Using lysostaphin, a rapidly acting muralytic enzyme, phagocytosis could be accurately differentiated from intracellular killing. When compared with normal healthy individuals and patients with gastrointestinal diseases not thought to be immunologically mediated, monocytes from patients with inflammatory bowel disease showed a statistically significant increase in the number of bacteria phagocytosed in 2 hours. There was no difference, however, between patients with Crohn's disease and those with ulcerative colitis. For all groups studied, more than 95% of ingested organisms were killed, and there was no difference between groups. These results suggest that peripheral blood monocytes in patients with Crohn's disease and ulcerative colitis are activated. It is unlikely that the granulomata of Crohn's disease result from a defect in the microbicidal function of the monocyte/macrophage system.

Brown DJ, Khan JA, Copeland G, Jewell DP. 1980. Alpha 2-macroglobulin in patients with inflammatory bowel disease. J Clin Lab Immunol, 4 (1), pp. 53-57. | Show Abstract

Alpha 2-macroglobulin (alpha 2-M) has been investigated in patients with ulcerative colitis and Crohn's disease and compared with normal control subjects. During an active phase of either disease, serum concentrations of alpha 2-M fall but no other relationship with clinical features was found. The proportion of circulating mononuclear cells bearing alpha 2-M on their surface in patients with inflammatory bowel disease did not differ from normal controls. Alpha 2-M was not detected in rectal tissue from either the patients or control subjects. The fall in alpha 2-M in patients with active disease was unexpected. Protein loss from the inflamed intestine is unlikely to be the cause and metabolic studies will be needed to elucidate synthetic and catabolic rates.

Rhodes JM, Jewell DP, Janossy G. 1980. Alpha-chain disease diagnosed by rectal biopsy. Br Med J, 280 (6220), pp. 1043-1044. | Read more

Mee AS, Jewell DP. 1980. Monocytes in inflammatory bowel disease: monocyte and serum lysosomal enzyme activity. Clin Sci (Lond), 58 (4), pp. 295-300. | Show Abstract | Read more

1. The activity of a specific lysosomal marker enzyme N'-acetyl-beta-D-glucosaminidase has been determined fluorimetrically in the monocytes and in the serum of patients with Crohn's disease and ulcerative colitis and compared with results obtained from healthy and disease control subjects. 2. Enzyme activities were measured in a monocyte-enriched suspension from a Ficoll-Triosil gradient and in an adherent monocyte preparation. 3. The results indicate that enzyme activity is greater in both monocytes and sera of patients with Crohn's disease and ulcerative colitis than in those from control subjects (P less than 0.01). 4. Enzyme activity within monocytes correlated with disease activity (P less than 0.05). 5. Lysosomal enzymes may contribute to the pathogenesis of the mucosal inflammation in inflammatory bowel disease.

Mee AS, Nuttall L, Potter BJ, Jewell DP. 1980. Studies on monocytes in inflammatory bowel disease: factors influencing monocyte lysosomal enzyme activity. Clin Exp Immunol, 39 (3), pp. 785-791. | Show Abstract

The effect of endotoxin and immune complexes on monocyte lysosomal enzyme activity has been studied in patients with Crohn's disease and ulcerative colitis. Immune complexes made at equivalence or in antigen excess caused a rapid fall in intracellular activity of the enzyme N'acetyl-beta-D-glucosaminidase which was significantly greater than that seen when cells were incubated with medium alone. Endotoxin had no effect on intracellular enzyme activity but there was a significant elevation of activity in the supernatants. Cells from patients with inflammatory bowel disease were no different to cells from healthy control subjects in their response to either endotoxin or immune complexes.

Cook PJ, Vincent-Brown A, Lewis SI, Perks S, Jewell DP, Reed PI. 1980. Carbenoxolone (duogastrone) and cimetidine in the treatment of duodenal ulcer--a therapeutic trial. Scand J Gastroenterol Suppl, 65 pp. 93-101. | Show Abstract

A double-blind, double-dummy trial to compare carbenoxolone (Duogastrone) with cimetidine has been carried out in patients with duodenal ulcer. Sixty patients completed the six week trial period, 31 patients were treated with carbenoxolone and 29 with cimetidine. Both groups were comparable with respect to age, sex, smoking habits and alcohol intake. There were no significant differences between groups during the trial period with respect to symptomatic relief and antacid consumption. Endoscopy after six weeks of therapy showed healing in 61% of patients receiving carbenoxolone and 72% in those receiving cimetidine, a difference which is not significant. No serious side-effects occurred with either drug.

Potter BJ, Hodgson HJ, Mee AS, Jewell DP. 1979. Clq metabolism in ulcerative colitis and Crohn's disease. Gut, 20 (11), pp. 1012-1019. | Show Abstract | Read more

The metabolism of pure radioiodine labelled Clq has been observed in five patients with ulcerative colitis, five patients with Crohn's disease, and in five control subjects. Both the fractional catabolic rate and the synthesis rate of Clq were increased in the five patients with Crohn's disease and in four of the five patients with ulcerative colitis. The fifth patient was in remission and had a normal synthesis rate. These results support the hypothesis that complement activation plays a role in the pathogenesis of these disease states and that the increased complement activation is primarily via the classical pathway.

White MC, Gore M, Jewell DP. 1979. Endocrine function after cimetidine. N Engl J Med, 301 (9), pp. 502. | Read more

Mitchell CJ, Jewell DP, Lewin MR, McLaughlin JE, Moorhead JF. 1979. Gastric function and histology in chronic renal failure. J Clin Pathol, 32 (3), pp. 208-213. | Show Abstract | Read more

Gastric function and histology were investigated in 24 patients with untreated chronic renal failure. At endoscopy nine patients had oesophagitis, 12 patients were considered to have gastritis, and the duodenum appeared inflamed in 20 patients. Endoscopic biopsies were taken at standard sites in the stomach and duodenum; gastritis was found in all patients, and 17 patients had duodenitis. Stimulated acid secretion was impaired in seven out of 20 patients and acid hypersecretion was found in a further two patients. Pepsin output correlated well with acid output in these patients. Fasting serum gastrin levels were elevated in 12 of the 19 patients tested. Patients with atrophic gastritis had low acid outputs and hypergastrinaemia, and when extensive gastritis was present, the patients tended to have more severe renal failure and hyposecretion of acid. Three patients were studied again after regular haemodialysis or renal transplantation and were found to show marked endoscopic and histological improvement.

Rhodes JM, Middleton P, Jewell DP. 1979. The lactulose hydrogen breath test as a diagnostic test for small-bowel bacterial overgrowth. Scand J Gastroenterol, 14 (3), pp. 333-336. | Show Abstract | Read more

The lactulose hydrogen breath test has been evaluated as a diagnostic test for small-bowel bacterial overgrowth using the 14C-glycocholate breath test for comparison. Twenty-seven patients with suspected bacterial overgrowth and 37 control patients were studied. The lactulose test was positive in 8 out of 9 patients with Subsequently proven bacterial overgrowth, all of whom had positive 14C-glycocholate tests. However, 6 patients with ileal disease or resection had positive 14C-glycocholate tests but negative lactulose tests. subsequent bacteriological study of duodenal juice from these patients was negative. Negative results were obtained by both tests in the remaining 12 patients, none of whom were subsequently shown to have bacterial overgrowth. All 37 control subjects had negative lactulose tests. The lactulose breath test is a simple and promising diagnostic test for the detection of small-bowel bacterial overgrowth and, unlike the 14C-glycocholate test, has the advantage of being able to distinguish bacterial overgrowth from ileal disease.

Mee AS, McLaughlin JE, Hodgson HJ, Jewell DP. 1979. Chronic immune colitis in rabbits. Gut, 20 (1), pp. 1-5. | Show Abstract | Read more

A chronic colitis has been induced in rabbits having many of the histological features of human ulcerative colitis. Animals were first immunised with the common enterobacterial antigen of Kunin and haemagglutinating antibodies demonstrated in high titre. An immune complex colitis was then established by the injection of soluble immune complexes following mild irritation of the rectum with dilute formalin as previously described. The rabbits developed an acute colitis within the first week but, in contrast with unsensitised rabbits, the inflammation persisted and was still present at six months as assessed by proctoscopy and rectal biopsy. Kunin-sensitised rabbits receiving intravenous saline, antigen, or antibody alone did not develop a chronic colitis. It is suggested that hypersensitivity to colonic bacterial antigens may be one mechanism whereby an acute colitis becomes chronic.

Mee AS, Brown D, Jewell DP. 1979. Atopy in inflammatory bowel disease. Scand J Gastroenterol, 14 (6), pp. 743-746. | Show Abstract | Read more

Thirty-nine patients with ulcerative colitis and 35 with Crohn's disease have been investigated for evidence of reaginic hypersensitivity and compared with control subjects. There was no difference in the frequency of a personal or family history of atopy or in serum IgE levels. Similarly, no overall difference was noted in prick test responses to 21 allergens. However, further analysis of prick test responses showed that patients with inflammatory bowel disease responded more frequently to food allergens. This was highly significant when compared with healthy controls (p less than 0.001). The relevance of this finding to the aetiology of inflammatory bowel disease is discussed.

Mee AS, Jewell DP. 1978. Factors inducing relapse in inflammatory bowel disease. Br Med J, 2 (6140), pp. 801-802. | Read more

Hunt RH, Day RC, Jewell DP. 1978. Acquired double pylorus. Br Med J, 1 (6115), pp. 759. | Read more

Thomas HC, De Villiers D, Potter B, Hodgson H, Jain S, Jewell DP, Sherlock S. 1978. Immune complexes in acute and chronic liver disease. Clin Exp Immunol, 31 (2), pp. 150-157.

Hodgson HJ, Jewell DP. 1978. The humoral immune system in inflammatory bowel disease. II. Immunologlobulin levels. Am J Dig Dis, 23 (2), pp. 123-128. | Show Abstract | Read more

As there have been reports of differences in mean levels of serum immunoglobulins between patients with ulcerative colitis and Crohn's disease, serum IgG, IgA, and IgM were estimated in 158 patients with inflammatory bowel disease and the results correlated with the clinical features of the patients. Although a higher mean IgG level in ulcerative colitis compared to Crohn's disease was confirmed, no difference was found when the comparison was limited to patients with colonic Crohn's disease. Patients with either disease had higher mean IgM levels than controls, and the IgM levels were higher on treatment with corticosteroids and showed a tendency to rise in remission. IgG and IgM levels were also higher in both diseases if extraintestinal manifestations were present. It is concluded that if clinical features, particularly disease site, are taken into account, the overall immunoglobulin responses in these two diseases show no differences.

Johnson NM, Mee AS, Jewell DP, Clarke SW. 1978. Pulmonary function in inflammatory bowel disease. Digestion, 18 (5-6), pp. 416-418. | Show Abstract | Read more

Pulmonary function has been assessed in patients with ulcerative colitis and Crohn's disease and compared with a healthy population. No statistically significant differences were found in the measurements observed within the three groups.

Hodgson HJ, Potter BJ, Skinner J, Jewell DP. 1978. Immune-complex mediated colitis in rabbits. An experimental model. Gut, 19 (3), pp. 225-232. | Show Abstract | Read more

An experimental colitis in rabbits is described, following the intravenous injection of preformed immune complexes of human serum albumin (HSA) and anti-HSA into non-sensitised rabbits. Tissue damage was localised to the colon by the Auer technique of inducing local non-specific inflammation, by the rectal instillation of dilute formalin. Formalin alone gave transient changes that reverted to normal within 24 hours. In rabbits given intravenous immune complexes formed in antigen-excess, a severe colitis was initiated, with histological features including mucosal ulceration, mixed inflammatory cell infiltration in the lamina propria, and crypt abscess formation. It is possible that immune-complex damage may be one of the pathogenic mechanisms involved in human ulcerative colitis.

Hodgson HJ, Potter BJ, Jewell DP. 1977. Humoral immune system in inflammatory bowel disease: I. Complement levels. Gut, 18 (9), pp. 749-753. | Show Abstract | Read more

Serum levels of complement components Clq, C4, C3, and Properdin factor B, from the classical and alternative pathways of complement activation, have been estimated in patients with ulcerative colitis and Crohn's disease. C3, factor B, and to some extent C4 concentrations all increased when the disease was active. In remission the levels of these components did not differ from hospital control patients. There was no evidence for the preferential consumption of the proteins of either pathway of activation, even in those patients with evidence of circulating immune complexes.

Hodgson HJ, Potter BJ, Jewell DP. 1977. Immune complexes in ulcerative colitis and Crohn's disease. Clin Exp Immunol, 29 (2), pp. 187-196. | Show Abstract

Sera from 156 patients with ulcerative colitis and Crohn's disease were tested for the presence of immune complexes, by the detection of anti-complementary activity and 125I-labelled Clq precipitation. Using aggregated IgG, a comparison between the two tests indicated that the anti-complementary test was most sensitive to aggregates of 11S in size, while the 125I-labelled Clq test detected aggregates over 20S in size. Excess anti-complementary activity was common in patients with active bowel disease, and in those with extra-intestinal manifestations, particularly acute arthritis, ankylosing spondylitis and liver disease. Large complexes were only common in patients with liver disease. Immune complexes in the gut mucosa may play a role in the pathogenesis of these diseases, and the deposition of circulatory immune complexes may explain at least some of the extra-intestinal manifestations.

Hodgson HJ, Jewell DP. 1977. Selective IgA deficiency and Crohn's disease: report of two cases. Gut, 18 (8), pp. 644-646. | Show Abstract | Read more

Two patients are described with Crohn's disease and selective IgA deficiency. Serum IgA was undetectable in each case, and immunoperoxidase studies of the lamina propria showed a gross diminution of IgA-bearing plasma cells. Peripheral blood lymphocytes, however, showed normal numbers of IgA-bearing lymphocytes. The typical clinical course and histology in these two patients suggest that IgA-mediated responses in the mucosa are not involved in the pathogenesis of Crohn's disease.

Mitchell CJ, Jewell DP. 1977. The diagnosis of the site of upper gastrointestinal haemorrhage in patients with established portal hypertension. Endoscopy, 9 (3), pp. 131-135. | Show Abstract | Read more

Seventy-five endoscopies were performed in 60 patients known to have oesophageal varices presenting with further upper gastrointestinal haemorrhage during the previous 72 hours. A site of active bleeding was found at 50 of 75 examinations (67 percent) including all 21 patients endoscoped within three hours of the last haemorrhage. Variceal bleeding alone was seen in 40 of these 50 examinations (80%) and both varices and mucosal lesions were bleeding in 4 patients; mucosal lesions were an uncommon cause of haemorrhage and only 6 patients were bleeding from these alone. The adult GIF-D2 endoscope was used for 45 examinations. Variceal bleeding was restarted on three occasions and prolonged unconsciousness induced by intravenous diazepam in one patient. In contrast, the paediatric GIF-P endoscope (30 examinations) was easily tolerated with little or no sedation, did not impair diagnostic accuracy and was not associated with any complications.

Hodgson HJ, Potter BJ, Jewell DP. 1977. C3 metabolism in ulcerative colitis and Crohn's disease. Clin Exp Immunol, 28 (3), pp. 490-495. | Show Abstract

The metabolism of the third component of complement (C3) has been investigated in four patients with ulcerative colitis, three patients with Crohn's disease and seven control subjects, using radioiodinated C3 prepared from fresh human plasma. Both the fractional catabolic rate and synthesis rate of C3 were increased in the patients with inflammatory bowel disease, although the serum-C3 levels were normal or raised. The results suggest that complement activation may play a role in the pathogenesis of mucosal inflammation in these diseases.

Campbell AC, Skinner JM, Maclennan IC, Hersey P, Waller CA, Wood J, Jewell DP, Truelove SC. 1976. Immunosuppression in the treatment of inflammatory bowel disease. II. The effects of azathioprine on lymphoid cell populations in a double blind trial in ulcerative colitis. Clin Exp Immunol, 24 (2), pp. 249-258. | Show Abstract

Blood lymphocytes and rectal plasma cells have been studied in patients with ulcerative colitis taking part in a double-blind trial of treatment with azathioprine. Treatment for 1 year resulted in a modest fall in blood lymphocyte count, with little change in neutrophils or platelets. There was no major change in the proportions of circulating T and B lymphocytes, suggesting that the number of such cells per millilitre of blood fell in proportion to the change in lymphocyte count. The number of plasma cells in the rectal lamina propria was reduced to a mean less than half that of the control patient group. Blood K-cell cytotoxic activity fell at least 25-fold after 1 year's treatment. PHA-induced cytotoxicity was also reduced, but less consistently. Reduced K-cell activity is interpreted as reflecting depletion of effector cells from the circulation. The fall in lymphocyte count, K-cell activity and gut plasma cells was slow, indicating continuous inhibition of lymphopoiesis or differentiation throughout the trial period. Thus, azathioprine has some immunosuppressive effects which develop only after prolonged treatment. The clinical results of the trial did not show a major beneficial effect of azathioprine in the treatment of ulcerative colitis, nor were there clear correlations between the results of lymphocyte assays and clinical response in individual patients.

Hodgson HJ, Skinner JM, Potter BJ, Jewell DP. 1976. Proceedings: Immune complexes in ulcerative colitis--an experimental model. Gut, 17 (5), pp. 399.

Jewell DP, Katiyar VN, Rees C, Taylor KB, Wright JP. 1975. Isolation of parietal cells from guinea-pig gastric mucosa and the immunological characterization of their antigenic structure. Gut, 16 (8), pp. 603-612. | Show Abstract | Read more

A method is described for the isolation of parietal cells from the gastric mucosa of the guinea pig by enzymatic digestion with collagenase. A suspension was obtained that contained 70-80% parietal cells. About 80% of the cells were viable immediately after incubation, but viability dropped sharply after one hour. Parietal cells were identified by their morphology on light and electron microscopy, by their uptake of neutral red, by immunofluorescent staining and by carbonic anhydrase activity. Antibodies to four distinct parietal-cell antigens were obtained from rabbits immunized with the isolated parietal cells or fractions thereof. These antibodies were directed against the microsomal fraction of the parietal-cell cytoplasm, the plasma and nuclear membranes, the soluble proteins, and Castle's intrinsic factor. The antibody against the microsomal fraction, though reacting in the same way as the antibody to parietal cell canaliculi found in the serum of patients with pernicious anaemia, showed greater species specificity.

Jewell DP. 1975. Ulcerative colitis. Front Gastrointest Res, 1 pp. 125-141. | Read more

Hodgson HJ, Potter BJ, Jewell DP. 1975. Proceedings: Complement in inflammatory bowel disease. Gut, 16 (10), pp. 833-834.

Truelove SC, Jewell DP. 1974. Intensive intravenous regimen for severe attacks of ulcerative colitis. Lancet, 1 (7866), pp. 1067-1070. | Read more

Cited:

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Truelove SC, Jewell DP. 1974. INTENSIVE INTRAVENOUS REGIMEN FOR SEVERE ATTACKS OF ULCERATIVE COLITIS The Lancet, 303 (7866), pp. 1067-1070. | Show Abstract | Read more

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. © 1974.

Jewell DP, Truelove SC. 1974. Azathioprine in ulcerative colitis: final report on controlled therapeutic trial. Br Med J, 4 (5945), pp. 627-630. | Show Abstract | Read more

Eighty patients, all of whom were suffering from a frank clinical attack of ulcerative colitis, were admitted to the trial. The attack was treated with a standard course of corticosteroids and the patients were immediately placed on treatment with either azathioprine in a dose of 2.5 mg/kg body weight or dummy tablets. The trial tablets were continued for one year while the patients were maintained under regular clinical, sigmoidoscopic, histological, haematological, and biochemical surveillance. If a patient relapsed during such maintenance treatment he or she was treated with a further course of corticosteroids without interrupting maintenance treatment.In the treatment of an actual attack of ulcerative colitis the results in the attacks which brought the 80 patients into the trial show that no benefit came from the addition of azathioprine to a standard course of corticosteroid therapy.Patients admitted in their first attack of ulcerative colitis showed no benefit from the one-year maintenance treatment with azathioprine, the benefits of which were confined to patients admitted in a relapse of established disease. Even in these the difference between the treated group and the control group failed to reach statistical significance, but the difference was big enough to suggest that there is a prima facie case for regarding azathioprine as of some benefit in this group of patients.

Jewell DP. 1973. Proceedings: Etiology of ulcerative colitis. Proc R Soc Med, 66 (10), pp. 1031-1032.

Jewell DP, MacLennan IC. 1973. Circulating immune complexes in inflammatory bowel disease. Clin Exp Immunol, 14 (2), pp. 219-226. | Show Abstract

Evidence for circulating immune complexes in sera of patients with ulcerative colitis or Crohn's disease is described. Such sera produced significantly greater inhibition of antibody induced cytotoxicity mediated by lymphocytes than did sera from normal control subjects. Inhibitory activity of patients' sera showed a positive correlation with severity of disease, the height of the ESR and, in the case of ulcerative colitis, with the severity of inflammation as seen at sigmoidoscopy. Using gel filtration on Sepharose 6B, inhibitory activity was found in fractions of higher molecular weight than monomeric IgG but of lower molecular weight than IgM. These fractions were shown to contain IgG measured by immunodiffusion. Evidence that inhibition is not due to aggregated IgG molecules is provided by the fact that no correlation was found between inhibitory activity and total IgG concentration. A possible role of immune complexes in the pathogenesis of ulcerative colitis and Crohn's disease is proposed.

Jewell DP, Maclennan IC, Truelove SC. 1972. Circulating immune complexes in ulcerative colitis and Crohn's disease. Gut, 13 (10), pp. 839-840. | Read more

Jewell DP, Truelove SC. 1972. Circulating antibodies to cow's milk proteins in ulcerative colitis. Gut, 13 (10), pp. 796-801. | Show Abstract | Read more

Sera from patients with ulcerative colitis (51), Crohn's disease (30), hypolactasia (13), untreated adult coeliac disease (11), irritable colon syndrome (24), and sera from 38 healthy control subjects were tested for antibodies to the principal cow's milk proteins-casein, alpha-lactalbumin, and beta-lactoglobulin. The red-cell-linked antigen-antiglobulin reaction was used to determine the titres of direct agglutinating antibodies and IgA and IgG incomplete antibodies. Apart from patients with coeliac disease, direct agglutinating antibodies were found infrequently and then in low titres. Approximately 50% of subjects had low titres of IgA and IgG antibodies. However, the titres found in sera from patients with ulcerative colitis did not differ from those found in the control subjects or in patients with Crohn's disease, hypolactasia, or irritable colon syndrome. Patients with untreated coeliac disease frequently had high antibody titres to the milk proteins. In all subjects tested, incomplete antibodies of IgA or IgG immunoglobulin class occurred with equal frequency. The frequent occurrence in adults of low titres of antibodies to the milk proteins may be due to continued absorption of minute amounts of protein. Absorption of allergens may be facilitated by mucosal damage, such as that of coeliac disease, with stimulation of antibody production. At the present time, however, there is little evidence to suggest that milk allergy is a factor in the aetiology of ulcerative colitis.

Jewell DP, Truelove SC. 1972. Azathioprine in ulcerative colitis. Gut, 13 (4), pp. 323.

Jewell DP, Truelove SC. 1972. Azathioprine in ulcerative colitis: an interim report on a controlled therapeutic trial. Br Med J, 1 (5802), pp. 709-712. | Show Abstract | Read more

This interim report on a controlled therapeutic trial of azathioprine in ulcerative colitis deals with the first 40 patients to complete a one-year period of maintenance treatment with azathioprine or with dummy tablets. The patients all suffered from classical ulcerative colitis and were in an actual attack of the disease at the time of admission. The attack was treated with a standard corticosteroid regimen and the patients were assigned at random to maintenance treatment with real or dummy azathioprine tablets, using a stratified design. The treatment and control groups were closely similar at the beginning of the trial.The effect of treatment has been assessed on the basis of the number of relapses of the disease occurring during the one-year trial period, supplemented by an assessment of the sigmoidoscopic picture and of the histological findings on serial rectal biopsy. In the patients receiving azathioprine the disease ran a more favourable course than in the control group. After the attack had been treated 11 of the 20 patients on azathioprine were symptom-free throughout the rest of the one-year trial period compared with only 5 out of 20 in the control group. The only three patients classed as failures were all in the control group. These differences just fail to reach conventional levels of statistical significance.Azathioprine is not dramatically successful but may still be a useful addition to the medical treatment of ulcerative colitis, particularly if conventional medical treatment is ineffective and there are reasons for wishing to avoid radical surgery. In the dose used azathioprine was virtually free from undesirable side effects.

Jewell DP. 1972. Benign intracranial hypertension and ulcerative colitis. Am J Dig Dis, 17 (1), pp. 89-91. | Show Abstract | Read more

A case of benign intracranial hypertension, occurring in association with ulcerative colitis, is described. The pathogenesis of the intracranial hypertension is uncertain but it is possible that intracranial thrombosis affecting small venous radicles was the responsible mechanism. © 1972 Hoeber Medical Division • Harper & Row, Publishers, Incorporated.

Jewell DP, Truelove SC. 1972. Reaginic hypersensitivity in ulcerative colitis. Gut, 13 (11), pp. 903-906. | Show Abstract | Read more

Reaginic hypersensitivity in ulcerative colitis has been investigated in respect of a hypersensitivity to the cow's milk proteins and the frequency of atopic asthma, hay fever, and eczema. Intradermal tests were frequently positive, especially to casein, but the results did not differ from those found in healthy individuals and in groups of patients with Crohn's disease, hypolactasia, and the irritable colon syndrome. No circulating IgE-specific antibodies to the milk proteins were found. An increased frequency of atopic diseases was found in patients suffering from ulcerative colitis (15.7%) and Crohn's disease (13.3%) compared with the findings in a control group (1.2%). It is concluded that, if an allergy to milk proteins is a factor in the pathogenesis of ulcerative colitis, it is not mediated by reaginic antibodies. It is possible, however, that the frequent occurrence of atopy indicates a susceptibility to develop reaginic responses even though this mechanism does not apply to the milk proteins.

Herrlinger KR, Cummings JRF, Barnardo MCNM, Schwab M, Ahmad T, Jewell DP. 2005. The pharmacogenetics of methotrexate in inflammatory bowel disease. Pharmacogenet Genomics, 15 (10), pp. 705-711. | Show Abstract | Read more

OBJECTIVES: Methotrexate (MTX) is an effective immunosuppressive treatment in inflammatory bowel disease (IBD) but its use is limited by unpredictable toxicity and efficacy. MTX metabolism is complex involving a number of enzymes. An individual's response to MTX may in part be genetically determined by functional genetic variation in genes encoding these enzymes. We report a pharmacogenetic evaluation of MTX therapy in IBD. METHODS: We studied 102 IBD patients treated with MTX, and 202 patients with Crohn's disease (CD), 205 patients with ulcerative colitis (UC) and 189 healthy volunteers served as controls to assess allele frequencies in the disease and healthy populations. All subjects were genotyped for four polymorphisms: G80A in the reduced folate carrier (RFC1) gene, G452T in the gamma-glutamyl hydrolase (GGH) gene and C677T and A1298C in the methylenetetrahydrofolate reductase (MTHFR) gene. Three non-conservative SNPs in the RFC1 and the MTHFR gene could not be detected in our patient cohort. Genotype-phenotype associations were evaluated with respect to efficacy and toxicity of MTX therapy. RESULTS: No significant differences in the allele frequencies between CD, UC and healthy controls were detected. Overall 21% of patients experienced MTX side effects. Patients homozygous for the MTHFR 1298C allele were more likely to experience one or more side effects compared to patients with the wild-type 1298AA genotype (21.0 vs. 6.3%, P < 0.05). None of the genotyped SNPs or haplotypes, either alone or in combination, was associated with short-term efficacy or sustained response. CONCLUSIONS: Side effects of MTX in IBD are associated with a SNP in the MTHFR gene but response cannot be predicted by any of the investigated SNPs.

Jewell DP, Satsangi J, Lobo A, Probert C, Forbes A, Ghosh S, Shaffer J, Frenz M, Drummond H, Troy G et al. 2005. Infliximab use in Crohn's disease: impact on health care resources in the UK. Eur J Gastroenterol Hepatol, 17 (10), pp. 1047-1052. | Show Abstract | Read more

OBJECTIVE: To quantify the impact of infliximab therapy on health care resource utilization in the UK. METHODS: A retrospective audit was undertaken at seven centres in the UK, which reviewed patient notes for a period of 6 months before and 6 months after an initial infliximab infusion. Details of hospital admissions, outpatient visits, operations, diagnostic procedures, drug usage, and overall efficacy were collected. Results were compared for the two 6 month study periods. RESULTS: A total of 205 patients (62% female, median age 33 years) with moderate/severe Crohn's disease were audited. The majority of patients had chronic active disease (62%) and most received one infusion initially (72%). Clinicians rated 74% of responses as good to excellent and patients 72%. Most patients had concomitant immunosuppression (pre: 75%, post: 75%). Approximately half of the patients (45%) stopped taking steroids, with a further 34% having a dosage reduction. A fall of 1093 inpatient days was seen (1435 vs. 342) in the 6 months following infliximab administration. There were seven fewer operations, 33 fewer examinations under anaesthetic, and 99 fewer diagnostic procedures. Outpatient visits were similar pre- versus post- (555 vs. 534). The total reduction in direct costs amounted to an estimated pounds 591,006. Three hundred and fifty-three infliximab infusions were administered at an estimated cost of pounds 562,719. Thus, there was a net reduction of pounds 28,287 or pounds 137.98 per patient. CONCLUSIONS: Infliximab appears to be a potentially cost effective treatment for selected patients based on the reduced number of inpatient stays, examinations under anaesthetic, and diagnostic procedures over a 6 month period.

Meinzer U, Hugot J-P. 2005. Nod2 and Crohn's disease: many connected highways. Lancet, 365 (9473), pp. 1752-1754. | Read more

McGovern DPB, Hysi P, Ahmad T, van Heel DA, Moffatt MF, Carey A, Cookson WOC, Jewell DP. 2005. Association between a complex insertion/deletion polymorphism in NOD1 (CARD4) and susceptibility to inflammatory bowel disease. Hum Mol Genet, 14 (10), pp. 1245-1250. | Show Abstract | Read more

The identification of the role of genetic variants within NOD2 (CARD15) in Crohn's disease and ulcerative colitis susceptibility highlight the role of the innate immune system in inflammatory bowel disease (IBD) pathogenesis. NOD1 (CARD4) is located on chromosome 7p14.3, in a region of known linkage to IBD and encodes an intracellular bacterial pathogen-associated molecular pattern receptor that is closely related to NOD2. We have identified strong association between haplotypes in the terminal exons of NOD1 and IBD (multi-allelic P = 0.0000003) in a panel of 556 IBD trios. The deletion allele of a complex functional NOD1 indel polymorphism (ND(1) + 32656*1) was significantly associated with early-onset IBD (P = 0.0003) in unrelated cases and controls. ND1 + 32656*1 was also associated with extra-intestinal manifestations of IBD (P = 0.04). These findings in two independent populations provide strong evidence for a role for NOD1 variants in IBD susceptibility and reinforce the role of the innate immune system in IBD pathogenesis.

Armuzzi A, Ahmad T, Ling K-L, de Silva A, Cullen S, van Heel D, Orchard TR, Welsh KI, Marshall SE, Jewell DP. 2003. Genotype-phenotype analysis of the Crohn's disease susceptibility haplotype on chromosome 5q31. Gut, 52 (8), pp. 1133-1139. | Show Abstract | Read more

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 (p(c)=0.002; relative risk (RR) 2.0). Genotype-phenotype analyses demonstrated that this association was particularly strong in patients with perianal disease (p(c)=0.0005; RR 1.7), especially in individuals homozygous for this haplotype (p(c)=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.

Roussomoustakaki M, Koutroubakis I, Vardas EM, Dimoulios P, Kouroumalis EA, Baritaki S, Koutsoudakis G, Krambovitis E. 2003. NOD2 insertion mutation in a Cretan Crohn's disease population. Gastroenterology, 124 (1), pp. 272-273. | Read more

Orchard TR, Chua CN, Ahmad T, Cheng H, Welsh KI, Jewell DP. 2002. Uveitis and erythema nodosum in inflammatory bowel disease: clinical features and the role of HLA genes. Gastroenterology, 123 (3), pp. 714-718. | Show Abstract | Read more

BACKGROUND & AIMS: There are few systematic studies on the natural history or immunogenetic associations of erythema nodosum (EN) or ocular inflammation in inflammatory bowel disease (IBD), but they are reportedly more common in patients with other extraintestinal manifestations (EIMs), particularly arthritis. Immunogenetic associations have previously been described in IBD arthritis and in EN associated with sarcoidosis. This study examined the clinical features and HLA-B, DR, and tumor necrosis factor alpha (TNF-alpha) associations of ocular inflammation and EN and their clinical and immunogenetic relationship to arthritis in IBD. METHODS: Details of EN and ocular inflammation were gathered by case-note review and questionnaire in 976 ulcerative colitis patients and 483 Crohn's patients. Sequence-specific PCR typing for polymorphisms in HLA-B, DR, and TNF-alpha was performed in 39 EN and 40 ocular patients. Results were compared with 490 IBD controls without EIMs, 38 patients with type 1 and 31 with type 2 peripheral arthritis, and 16 AS patients. RESULTS: EN and ocular inflammation were more common in women, were associated with IBD relapse, and recurred in approximately 30% of patients. They occurred more commonly with arthritis and AS than expected by chance. Ocular inflammation was strongly associated with HLA-B*27, B*58, and HLA-DRB1*0103. There is a weak association between EN and HLA-B*15 but a strong association with the -1031 TNF-alpha. CONCLUSIONS: EN, uveitis, and arthritis associated with IBD occur together commonly. They are associated with genes in the HLA region, and linkage disequilibrium between these genes may account for the clinical picture of overlapping but independent clinical manifestations.

van Heel DA, Udalova IA, De Silva AP, McGovern DP, Kinouchi Y, Hull J, Lench NJ, Cardon LR, Carey AH, Jewell DP, Kwiatkowski D. 2002. Inflammatory bowel disease is associated with a TNF polymorphism that affects an interaction between the OCT1 and NF(-kappa)B transcription factors. Hum Mol Genet, 11 (11), pp. 1281-1289. | Show Abstract | Read more

Tumour necrosis factor-alpha (TNF) expression is increased in inflammatory bowel disease (IBD), and TNF maps to the IBD3 susceptibility locus. Transmission disequilibrium and case-control analyses, in two independent Caucasian cohorts, showed a novel association of the TNF(-857C) promoter polymorphism with IBD (overall P=0.001 in 587 IBD families). Further genetic associations of TNF(-857C) with IBD sub-phenotypes were seen for ulcerative colitis and for Crohn's disease, but only in patients not carrying common NOD2 mutations. The genetic data suggest a recessive model of inheritance, and we observed ex vivo lipopolysaccharide-stimulated whole-blood TNF production to be higher in healthy TNF(-857C) homozygotes. We show the transcription factor OCT1 binds TNF(-857T) but not TNF(-857C), and interacts in vitro and in vivo with the pro-inflammatory NF(-kappa)B transcription factor p65 subunit at an adjacent binding site. Detailed functional analyses of these interactions in gut macrophages, in addition to further genetic mapping of this gene-dense region, will be critical to understand the significance of the observed association of TNF(-857C) with IBD.

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