Ulcerative Colitis: Arnott ID

Hare NC, Arnott ID, Satsangi J. · Gastrointestinal Unit, Molecular Medicine Centre, University of Edinburgh, Western General Hospital, Crewe Road, Edinburgh, EH4 2XU, UK. · Expert Rev Gastroenterol Hepatol. · Pubmed #19072385 No free full text.

Abstract: Ulcerative colitis is a relapsing-remitting inflammatory disease affecting the colon and is associated with considerable morbidity. In acute severe attacks, there continues to be an associated mortality rate of 1-2%, even in specialist units. During an acute severe exacerbation, approximately two-thirds of patients will respond to intravenous corticosteroid therapy, the accepted first-line therapy in such cases. For steroid-refractory patients, options are limited to surgery (colectomy) or second-line agents, such as ciclosporin or infliximab, used in an attempt to salvage the colon. Considerable debate exists over the optimal management of such patients. During the last decade, an increased understanding of the pathogenesis of inflammatory bowel disease has led to the rapid development of other biological agents, such as basiliximab and visilizumab. Novel methods, such as leucopheresis, have been studied and other established immunomodulatory agents, such as tacrolimus, have also been suggested. The purpose of this review is to highlight some of the areas of recent development in the treatment of acute severe ulcerative colitis and review important safety data, with a particular emphasis on biological agents.

Probert CS, Hearing SD, Schreiber S, Kühbacher T, Ghosh S, Arnott ID, Forbes A. · University Division of Medicine, Bristol Royal Infirmary, Marlborough Street, Bristol BS2 8HW, UK. · Gut. · Pubmed #12801957 links to  free full text

Abstract: BACKGROUND: Tumour necrosis factor production is increased in the mucosa of patients with active ulcerative colitis. The benefits of infliximab in Crohn's disease are established. We investigated its efficacy in ulcerative colitis. METHODS: We conducted a randomised placebo controlled trial of infliximab (5 mg/kg) in the treatment of glucocorticoid resistant ulcerative colitis. Infusions were given at weeks 0 and 2. Disease activity and quality of life were recorded over eight weeks of follow up. Remission was defined as an ulcerative colitis symptom score (UCSS) of < or =2 and/or Baron score of 0 at week 6. Patients not in remission were offered open label infliximab 10 mg/kg and reviewed two weeks later. RESULTS: After two weeks, there was no statistically significant difference between the infliximab and placebo groups in the proportion of patients with a Baron score of 0 (13% (3/23) v 5% (1/19) (95% confidence interval (CI) -9% to 24%); p=0.74). After six weeks, remission (UCSS < or =2) rates were 39% (9/23) versus 30% (6/20) (95% CI -19 to 34%; p=0.76). The median improvement in UCSS was 3 for the infliximab group and 2.5 for the placebo group (p=0.82, Mann-Whitney U test). A Baron score of 0 was likely in either group (26% (6/23) v 30% (6/20) (95% CI -30% to 23%); p=0.96). Improvement in the IBDQ and EuroQol was not significantly different between the groups (p=0.22 and 0.3, respectively, Mann-Whitney U test). Twenty eligible patients were given open labelled infusions. Remission was achieved in 3/11 (27%) patients initially treated with infliximab and in 1/9 (11%) patients treated with placebo. CONCLUSION: These data do not support the use of infliximab in the management of moderately active glucocorticoid resistant ulcerative colitis.

Ho GT, Lee HM, Brydon G, Ting T, Hare N, Drummond H, Shand AG, Bartolo DC, Wilson RG, Dunlop MG, Arnott ID, Satsangi J. · Western General Hospital, University of Edinburgh, UK. · Am J Gastroenterol. · Pubmed #19262524 No free full text.

Abstract: OBJECTIVES: Calprotectin is a granulocyte neutrophil-predominant cytosolic protein. Fecal concentrations are elevated in intestinal inflammation and may predict relapse in quiescent inflammatory bowel disease. We aim to investigate fecal calprotectin (FC) as a biomarker in predicting the clinical course of acute severe ulcerative colitis (ASUC). METHODS: In 90 patients with ASUC requiring intensive in-patient medical therapy (January 2005-September 2007), we investigated the discriminant ability of FC to predict colectomy and corticosteroid and infliximab nonresponse. All patients received parenteral corticosteroids as first-line treatment; 21 (23.3%) were also treated with infliximab (5 mg/kg), after failure of corticosteroid therapy. RESULTS: Of 90 patients, 31 (34.4%) required colectomy, including 11 (52.4%) of those treated with infliximab. Overall FC was high (1,020.0 microg/g interquartile range: 601.5-1,617.5). FC was significantly higher in patients requiring colectomy (1,200.0 vs. 887.0; P=0.04), with a trend toward significance when comparing corticosteroid nonresponders and responders (1,100.0 vs. 863.5; P=0.08), as well as between infliximab nonresponders and responders (1,795.0 vs. 920.5; P=0.06). Receiver-operator characteristic curve analysis yielded an area under the curve of 0.65 to predict colectomy (P=0.04), with a maximum likelihood ratio of 9.23, specificity 97.4%, and sensitivity 24.0% at a cutoff point of 1,922.5 microg/g. Kaplan-Meier analyses showed that using 1,922.5 microg/g over a median follow-up of 1.10 years, 87% of patients will need subsequent colectomy. CONCLUSIONS: This is the first data set to demonstrate that FC levels are dramatically elevated in severe UC. These data raise the possibility that this biomarker can predict response to first or second-line medical therapy in this setting.

Russell RK, Ip B, Aldhous MC, MacDougall M, Drummond HE, Arnott ID, Gillett PM, McGrogan P, Weaver LT, Bisset WM, Mahdi G, Wilson DC, Satsangi J. · Department of Paediatric Gastroenterology, Yorkhill Hospital, UK. · J Pediatr Gastroenterol Nutr. · Pubmed #19179877 No free full text.

Abstract: OBJECTIVES: To determine anti-Saccharomyces cerevisiae antibodies (ASCA) status and its relation to disease phenotype in patients with inflammatory bowel disease (IBD). PATIENTS AND METHODS: A total of 301 Scottish patients with early-onset IBD-197 Crohn disease (CD), 76 ulcerative colitis (UC), 28 indeterminate colitis (IC)-and 78 healthy control individuals were studied. ASCA status (IgA, IgG) was determined by enzyme-linked immunosorbent assay. ASCA status was then analyzed in relation to CD phenotype. RESULTS: Patients with CD had a higher prevalence of ASCA than patients with UC and healthy controls: 82/197 versus 12/76, odds ratio (OR) 3.80 (1.93-7.50) and 82/197 versus 6/78, OR 8.56 (3.55-20.62), respectively. Univariate analysis showed that positive ASCA status was associated with oral CD (17/25 vs 59/153, OR 3.39 [1.38-8.34]), perianal CD (39/77 vs 38/108, OR 1.89 [1.04-3.44]) and the presence of granulomata (63/132 vs 15/52, OR 2.25 [1.13-4.48]) and also with markers of disease severity: raised C-reactive protein (44/90 vs 12/49, OR 2.95[1.36-6.37]), hypoalbuminemia (44/85 vs 20/74, OR 2.28[1.19-4.37]), and surgery (27/49 vs 54/147, OR 2.11 [1.10-4.06]). From multivariate analysis, the presence of oral disease (adjusted P = 0.001, OR 22.22 [3.41-142.86]) and hypoalbuminemia (adjusted P = 0.01, OR 4.78 [1.40-16.39]) was found to be independently associated with ASCA status. No association was demonstrated between ASCA and IBD candidate genes. CONCLUSIONS: Patients with CD had a higher prevalence of ASCA than did other patients with IBD. ASCA status described patients with CD who had a specific phenotype, showing an association with markers of disease severity and oral CD involvement.

Lees CW, Ali AI, Thompson AI, Ho GT, Forsythe RO, Marquez L, Cochrane CJ, Aitken S, Fennell J, Rogers P, Shand AG, Penman ID, Palmer KR, Wilson DC, Arnott ID, Satsangi J. · Gastrointestinal Unit, Western General Hospital, Edinburgh, UK. · Aliment Pharmacol Ther. · Pubmed #19132970 No free full text.

Abstract: BACKGROUND: Anti-TNF agents are now widely used in Crohn's disease (CD), and in ulcerative colitis (UC). AIM: To review the safety profile of anti-TNF agents in all patients treated with infliximab in Edinburgh from 1999 to 2007. METHODS: Complete data were available on 202/207 patients comprising 157 CD, 42 UC and three coeliac disease. Median follow-up was 2.4 years (1.0-4.9) with a total of 620 patient-years follow-up. About 19.1% of CD patients were subsequently treated with adalimumab. RESULTS: Seven deaths (3.3%) occurred in follow-up; only one death was <1 year post-infliximab (at day 72, from lung cancer). A total of six malignancies (three haematological, three bronchogenic) and six cases of suspected demyelination (three with confirmed neurological disease) were reported. In the 90 days following infliximab, 95 adverse events (36 serious) occurred in 58/202 (28.7%) patients. In all, 42/202 (20.8%) had an infectious event (22 serious) and 27/202 (13.4%) of patients had an infusion reaction: 19 acute (four serious) and eight delayed (three serious). CONCLUSIONS: Serious infections, malignancies and neurological disease complicate anti-TNF use in clinical practice. Although evidence for causality is unclear, potential mechanisms and predisposing factors need to be explored. In individual patients, the risk/benefit analysis needs to be carefully assessed and discussed prior to commencement of therapy.

Lees CW, Zacharias WJ, Tremelling M, Noble CL, Nimmo ER, Tenesa A, Cornelius J, Torkvist L, Kao J, Farrington S, Drummond HE, Ho GT, Arnott ID, Appelman HD, Diehl L, Campbell H, Dunlop MG, Parkes M, Howie SE, Gumucio DL, Satsangi J. · Gastrointestinal Unit, Molecular Medicine Centre, University of Edinburgh, Edinburgh, United Kingdom. · PLoS Med. · Pubmed #19071955 links to  free full text

Abstract: BACKGROUND: Ulcerative colitis (UC) and Crohn's disease (CD) are polygenic chronic inflammatory bowel diseases (IBD) of high prevalence that are associated with considerable morbidity. The hedgehog (HH) signalling pathway, which includes the transcription factor glioma-associated oncogene homolog 1 (GLI1), plays vital roles in gastrointestinal tract development, homeostasis, and malignancy. We identified a germline variation in GLI1 (within the IBD2 linkage region, 12q13) in patients with IBD. Since this IBD-associated variant encodes a GLI1 protein with reduced function and our expression studies demonstrated down-regulation of the HH response in IBD, we tested whether mice with reduced Gli1 activity demonstrate increased susceptibility to chemically induced colitis. METHODS AND FINDINGS: Using a gene-wide haplotype-tagging approach, germline GLI1 variation was examined in three independent populations of IBD patients and healthy controls from Northern Europe (Scotland, England, and Sweden) totalling over 5,000 individuals. On log-likelihood analysis, GLI1 was associated with IBD, predominantly UC, in Scotland and England (p < 0.0001). A nonsynonymous SNP (rs2228226C-->G), in exon 12 of GLI1 (Q1100E) was strongly implicated, with pooled odds ratio of 1.194 (confidence interval = 1.09-1.31, p = 0.0002). GLI1 variants were tested in vitro for transcriptional activity in luciferase assays. Q1100E falls within a conserved motif near the C terminus of GLI1; the variant GLI protein exhibited reduced transactivation function in vitro. In complementary expression studies, we noted the colonic HH response, including GLI1, patched (PTCH), and hedgehog-interacting protein (HHIP), to be down-regulated in patients with UC. Finally, Gli1(+/lacZ) mice were tested for susceptibility to dextran sodium sulphate (DSS)-induced colitis. Clinical response, histology, and expression of inflammatory cytokines and chemokines were recorded. Gli1(+/lacZ) mice rapidly developed severe intestinal inflammation, with considerable morbidity and mortality compared with wild type. Local myeloid cells were shown to be direct targets of HH signals and cytokine expression studies revealed robust up-regulation of IL-12, IL-17, and IL-23 in this model. CONCLUSIONS: HH signalling through GLI1 is required for appropriate modulation of the intestinal response to acute inflammatory challenge. Reduced GLI1 function predisposes to a heightened myeloid response to inflammatory stimuli, potentially leading to IBD.

Van Limbergen J, Russell RK, Drummond HE, Aldhous MC, Round NK, Nimmo ER, Smith L, Gillett PM, McGrogan P, Weaver LT, Bisset WM, Mahdi G, Arnott ID, Satsangi J, Wilson DC. · Gastrointestinal Unit, Molecular Medicine Centre, Western General Hospital, University of Edinburgh, Edinburgh, United Kingdom. · Gastroenterology. · Pubmed #18725221 No free full text.

Abstract: BACKGROUND & AIMS: Childhood-onset inflammatory bowel disease (IBD) might be etiologically different from adult-onset IBD. We analyzed disease phenotypes and progression of childhood-onset disease and compared them with characteristics of adult-onset disease in patients in Scotland. METHODS: Anatomic locations and behaviors were assessed in 416 patients with childhood-onset (276 Crohn's disease [CD], 99 ulcerative colitis [UC], 41 IBD type unclassified [IBDU] diagnosed before seventeenth birthday) and 1297 patients with adult-onset (596 CD, 701 UC) IBD using the Montreal classification. RESULTS: At the time of diagnosis in children, CD involved small bowel and colon (L3) in 51% (138/273), colon (L2) in 36%, and ileum (L1) in 6%; the upper gastrointestinal (GI) tract (L4) was also affected in 51%. In 39%, the anatomic extent increased within 2 years. Behavioral characteristics progressed; 24% of children developed stricturing or penetrating complications within 4 years (vs 9% at diagnosis; P < .0001; odds ratio [OR], 3.32; 95% confidence interval [CI], 1.86-5.92). Compared with adults, childhood-onset disease was characterized by a "panenteric" phenotype (ileocolonic plus upper GI [L3+L4]; 43% vs 3%; P < .0001; OR, 23.36; 95% CI, 13.45-40.59) with less isolated ileal (L1; 2% vs 31%; P < .0001; OR, 0.06; 95% CI, 0.03-0.12) or colonic disease (L2; 15% vs 36%; P < .0001; OR, 0.31; 95% CI, 0.21-0.46). UC was extensive in 82% of the children at diagnosis, versus 48% of adults (P < .0001; OR, 5.08; 95% CI, 2.73-9.45); 46% of the children progressed to develop extensive colitis during follow-up. Forty-six percent of children with CD and 35% with UC required immunomodulatory therapy within 12 months of diagnosis. The median time to first surgery was longer in childhood-onset than adult-onset patients with CD (13.7 vs 7.8 years; P < .001); the reverse was true for UC. CONCLUSIONS: Childhood-onset IBD is characterized by extensive intestinal involvement and rapid early progression.

Russell RK, Drummond HE, Wilson DC, Anderson NH, Arnott ID, Van Limbergen JE, Satsangi J, Nimmo ER. · Department of Paediatric Gastroenterology, Yorkhill Hospital, Glasgow, UK. · Genes Immun. · Pubmed #18563169 No free full text.

Abstract: The high incidence of Scottish Crohn's disease (CD) is not explained by the common three NOD2/CARD15 variants. We aimed to identify population-specific NOD2/CARD15 coding variants. A total of 1478 (320 inflammatory bowel disease patients <16 years, 343 adult CD patients, 542 parents and 273 controls). All NOD2/CARD15 exons were sequenced in 24 CD patients. Sequencing identified 18 single-nucleotide polymorphisms (SNPs) including 4 non-synonymous coding SNPs altering the structure of the Leucine-rich region--two were well established (1007-/C and 908G/R). Two other variants, valine955isoleucine (955V/I) and methionine863valine (863M/V), were genotyped in all subjects. 863M/V carriage was not significantly higher in CD patients vs controls (1.35 vs 0.37%, P=0.27). 955V/I carriage was no higher in CD or ulcerative colitis patients (12.8 and 15.8%, respectively) compared to controls (16.2%). Transmission disequilibrium test analysis was negative. 955V/I carriage was higher in indeterminate colitis patients (n=29) compared to controls (41.4 vs 16.2%, P=0.001, OR=3.6 (1.6-8.2)). Population-specific NOD2/CARD15 exonic variants do not account for the high-CD prevalence in Scotland.

Noble CL, Abbas AR, Cornelius J, Lees CW, Ho GT, Toy K, Modrusan Z, Pal N, Zhong F, Chalasani S, Clark H, Arnott ID, Penman ID, Satsangi J, Diehl L. · Gastrointestinal Unit, Molecular Medicine Centre, Western General Hospital, Edinburgh, EH4 2XU, UK. · Gut. · Pubmed #18523026 No free full text.

Abstract: OBJECTIVE: To investigate differential intestinal gene expression in patients with ulcerative colitis and in controls. DESIGN: Genome-wide expression study (41,058 expression sequence tags, 215 biopsies). SETTING: Western General Hospital, Edinburgh, UK, and Genentech, San Francisco, USA. PATIENTS: 67 patients with ulcerative colitis and 31 control subjects (23 normal subjects and 8 patients with inflamed non-inflammatory bowel disease biopsies). INTERVENTIONS: Paired endoscopic biopsies were taken from 5 specific anatomical locations for RNA extraction and histology. The Agilent microarray platform was used and confirmation of results was undertaken by real time polymerase chain reaction and immunohistochemistry. RESULTS: In healthy control biopsies, cluster analysis showed differences in gene expression between the right and left colon. (chi(2) = 25.1, p<0.0001). Developmental genes, homeobox protein A13 (HOXA13), (p = 2.3x10(-16)), HOXB13 (p<1x10(-45)), glioma-associated oncogene 1 (GLI1) (p = 4.0x10(-24)), and GLI3 (p = 2.1x10(-28)) primarily drove this separation. When all ulcerative colitis biopsies and control biopsies were compared, 143 sequences had a fold change of >1.5 in the ulcerative colitis biopsies (0.01>p>10(-45)) and 54 sequences had a fold change of <-1.5 (0.01>p>10(-20)). Differentially upregulated genes in ulcerative colitis included serum amyloid A1 (SAA1) (p<10(-45)) the alpha defensins 5 and 6 (DEFA5 and 6) (p = 0.00003 and p = 6.95x10(-7), respectively), matrix metalloproteinase 3 (MMP3) (p = 5.6x10(-10)) and MMP7 (p = 2.3x10(-7)). Increased DEFA5 and 6 expression was further characterised to Paneth cell metaplasia by immunohistochemistry and in situ hybridisation. Sub-analysis of the inflammatory bowel disease 2 (IBD2) and IBD5 loci, and the ATP-binding cassette (ABC) transporter genes revealed a number of differentially regulated genes in the ulcerative colitis biopsies. CONCLUSIONS: Key findings are the expression gradient in the healthy adult colon and the involvement of novel gene families, as well as established candidate genes in the pathogenesis of ulcerative colitis.

Lees CW, Maan AK, Hansoti B, Satsangi J, Arnott ID. · GI Unit, University of Edinburgh, Edinburgh, UK. · Aliment Pharmacol Ther. · Pubmed #17988235 No free full text.

Abstract: BACKGROUND: Azathioprine intolerance is a common clinical problem, requiring drug withdrawal in up to 30% of patients. The successful use of mercaptopurine is described, but data to support this strategy are needed. AIMS: To assess the tolerability of mercaptopurine in inflammatory bowel disease patients previously intolerant of azathioprine, and identify predictive factors. METHODS: Sixty-one azathioprine-intolerant patients (31 males, median age at diagnosis 32 years, 31 with Crohn's disease, 30 with ulcerative colitis) who had been treated with mercaptopurine were identified. Intolerances included nausea and vomiting, flu-like illness, neutropenia, hepatotoxicity and pancreatitis. RESULTS: Mercaptopurine was tolerated by 59% (36 of 61) of azathioprine-intolerant patients (median dose 1.0 mg/kg), 61% (17 of 28) in patients with azathioprine-related nausea and vomiting, 61% (11 of 18) with flu-like illness, 33% (three of nine) with hepatotoxicity, 100% (one of one) with neutropenia, 100% (three of three) with rash and 0% (zero of one) with pancreatitis. Mercaptopurine intolerance was frequently for a different adverse event. Those intolerant of mercaptopurine were younger (28.4 years vs. 37.0 years; P = 0.014) and more frequently female (14/30 vs. 2/29, P = 0.027). Mercaptopurine tolerability was not affected by diagnosis, location, behaviour, surgery, smoking, family history or extra-intestinal manifestations. CONCLUSION: Mercaptopurine may be tolerated in up to 60% of azathioprine-intolerant patients, and treatment should be considered, particularly if intolerance was due to nausea, vomiting, flu-like illness or rash.

Lees CW, Heys D, Ho GT, Noble CL, Shand AG, Mowat C, Boulton-Jones R, Williams A, Church N, Satsangi J, Arnott ID, Anonymous00089. · Gastrointestinal Unit, Western General Hospital, Edinburgh, UK. · Aliment Pharmacol Ther. · Pubmed #17635376 No free full text.

Abstract: BACKGROUND: Forty per cent of patients with acute severe ulcerative colitis will not respond to intravenous corticosteroids and require second-line medical therapy or colectomy. A recent controlled trial has suggested that infliximab may be effective as rescue therapy. AIM: To assess the value of infliximab as rescue therapy for acute severe colitis in a retrospective cohort of ulcerative colitis patients in Scotland. METHODS: All patients satisfied Truelove and Witts criteria on admission, failed to respond to intravenous corticosteroids and received infliximab (5 mg/kg) as rescue therapy. Response was defined as need for colectomy at hospital discharge and by 90 days. RESULTS: A total of 39 patients (median age 31.7 years) were treated. 26/39 (66%) responded, avoiding colectomy during the acute admission, and were followed up for a median of 203 days (Interquartile range = 135.5-328.5). Hypoalbuminaemia was a consistent predictor of non-response on univariate and multivariate analysis. At day 3 of intravenous steroids, 9/18 (50.0%) with serum albumin <34 g/L had urgent colectomy vs. 1/13 (7.7%) >or=34 g/L (P = 0.02, OR = 12.0, C.I. 1.28-112.7). Two serious adverse events occurred - one death due to Pseudomonas pneumonia, and one post-operative fungal septicaemia. CONCLUSIONS: Infliximab represents a moderately effective rescue therapy for patients with acute severe ulcerative colitis. Serious adverse events, including death, do occur and should be discussed with patients prior to therapy.

Van Limbergen J, Nimmo ER, Russell RK, Drummond HE, Smith L, Anderson NH, Davies G, Arnott ID, Wilson DC, Satsangi J. · Gastrointestinal Unit, Western General Hospital, University of Edinburgh, UK. · Hum Mol Genet. · Pubmed #17613538 links to  free full text

Abstract: Both NOD1/CARD4 and NOD2/CARD15 are intracellular pattern-recognition receptors involved in the innate immune response. Germline NOD2/CARD15 variation has a definite effect on susceptibility to Crohn's disease (CD) and phenotype, although this contribution is weak in Scotland and Scandinavia. The NOD1/CARD4 gene lies within the putative inflammatory bowel disease (IBD) locus at 7p14.3. We have assessed, in detail, the influence of germline NOD1/CARD4 variation on IBD susceptibility and phenotype in the Scottish population. Two thousand two hundred and ninety-six subjects, including 356 children with IBD, were involved in parallel case-control and family-based association studies. Nine tagging single-nucleotide polymorphisms (SNPs) were selected based on HapMap data spanning the whole of the NOD1/CARD4 gene. Our case-control SNP analysis was powered to detect an effect size with OR 1.5 for IBD and OR 1.6 for CD. No significant associations were observed between any of nine the NOD1/CARD4 SNPs studied and IBD, CD or ulcerative colitis (UC) (P > 0.05 for all). Haplotype case-control analysis was also negative (P > 0.05 in IBD, CD and UC). Multimarker transmission disequilibrium testing analysis was negative (P > 0.05 in IBD, CD and UC). NOD2/CARD15 variant carriage had no influence on NOD1/CARD4 effect on IBD susceptibility. This study represents the first application of a gene -wide haplotype-tagging approach to assess, in detail, the contribution of NOD1/CARD4 in IBD.

Aldhous MC, Drummond HE, Anderson N, Baneshi MR, Smith LA, Arnott ID, Satsangi J. · Gastrointestinal Unit, Molecular Medicine Centre, School of Molecular and Clinical Medicine, University of Edinburgh, Western General Hospital, Edinburgh, Scotland, UK. · Am J Gastroenterol. · Pubmed #17338737 No free full text.

Abstract: INTRODUCTION: Cigarette smoking affects susceptibility to ulcerative colitis (UC), but its effects on age at diagnosis, disease extent, and need for surgery are less well defined. We examined these parameters in a detailed retrospective analysis of a large cohort of well-characterized UC patients. METHODS: 499 UC patients (254 male, median age 34.3 yr) were studied. Data were collected on smoking habits, smoking load (pack-years), age at recruitment, age at diagnosis, surgery, and disease extent. Colonoscopic and histological data at both diagnosis and follow-up (median follow-up time 4.6 yr) were available on 349 patients. RESULTS: Ex-smokers were older at diagnosis than current or nonsmokers, (46.5 yr vs 31.1 or 29.4 yr, respectively, P < 0.001). Before diagnosis, ex-smokers had a higher smoking load than current smokers (13.0 vs 6.94 pack-years, P < 0.001). A Cox model for age at diagnosis, with smoking as a time-dependent covariate, showed that at any age, ex-smokers were significantly more likely to develop UC than current smokers (hazard ratio 1.8, 95% CI 1.41-2.44, P < 0.001). For current smokers at latest colonoscopy, those with extensive disease were the lightest smokers (median 0.320 pack-years), whereas those with healthy colons were the heaviest smokers (median 9.18 pack-years, P= 0.006). At 5 yr, regression of extensive disease was more frequent in current than ex-smokers or nonsmokers (30% current smokers vs 8% nonsmokers and 5% ex-smokers, chi(2)= 30.4, P < 0.001) but these differences were not maintained over a longer time period. CONCLUSIONS: Smoking habit influences the age at diagnosis and changes in disease extent in UC. Mechanisms are likely to be complex and require further investigation.

Van Limbergen J, Russell RK, Nimmo ER, Törkvist L, Lees CW, Drummond HE, Smith L, Anderson NH, Gillett PM, McGrogan P, Hassan K, Weaver LT, Bisset WM, Mahdi G, Arnott ID, Sjöqvist U, Lördal M, Farrington SM, Dunlop MG, Wilson DC, Satsangi J. · Gastrointestinal Unit, Molecular Medicine Centre, Western General Hospital, University of Edinburgh, Edinburgh, UK. · Inflamm Bowel Dis. · Pubmed #17285593 links to  free full text

Abstract: BACKGROUND: NOD1/CARD4 and NOD2/CARD15 are both intracellular pattern-recognition receptors. The NOD1/CARD4 gene lies within a previously described inflammatory bowel disease (IBD) locus (7p14). An association has been suggested between the NOD1/CARD4+32656 deletion*1 variant of a complex deletion*1/insertion*2 polymorphism and IBD in 1 recent study in Europe. Our aim was to assess the influence of NOD1/CARD4+32656 on disease susceptibility and phenotype in the Scottish and Swedish IBD populations. METHODS: A total of 3,962 individuals (1,791 IBD patients, 522 parents, 1,649 healthy controls) from 2 independent populations (Scotland and Sweden) were genotyped for NOD1/CARD4+32656 A/C by TaqMan and direct sequencing. Case-control, Transmission Disequilibrium Testing (TDT) and detailed genotype-phenotype (Montreal) analyses were performed. The case-control analysis had 80% power to detect an effect size of odds ratio (OR) 1.21 for IBD. RESULTS: In case-control analyses in Scottish and Swedish patients, none of the genotypes studied in IBD, Crohn's disease (CD) or ulcerative colitis (UC), differed significantly from controls (deletion*1 allelic frequency 73.9%, 73.6%, 73.9%, and 73.6%, respectively: all P > 0.8). No epistatic interaction with NOD2/CARD15 was seen for CD susceptibility. TDT analysis in our Scottish early onset cohort was negative. CONCLUSIONS: This variant allele of NOD1/CARD4+32656 is not associated with a strong effect on susceptibility to IBD in children and adults in Northern Europe. A gene-wide haplotype-based approach may be preferable to analysis of individual variants to assess the contribution of the NOD1/CARD4 gene to IBD.

Ho GT, Chiam P, Drummond H, Loane J, Arnott ID, Satsangi J. · Gastrointestinal Unit, Western General Hospital, Edinburgh, UK. · Aliment Pharmacol Ther. · Pubmed #16842459 No free full text.

Abstract: BACKGROUND: Corticosteroids remain the mainstay of first-line therapy in active inflammatory bowel disease. AIMS: To determine the clinical outcome after the first corticosteroid-therapy and to identify factors which predict response/failure. METHODS: 216 (136 ulcerative colitis and 80 Crohn's disease) patients were identified in this 5-year inception cohort. The outcomes of early (30 days) and late (1 year) responses were used. Multivariate analyses were performed to identify factors associated with outcome. RESULTS: 86 (63%) and 60 (75%) ulcerative colitis and Crohn's disease required corticosteroid therapy, respectively. In ulcerative colitis, at 30 days, 69 (51%), 42 (31%) and 25 (18%) patients demonstrated complete response, partial response and no response, respectively. For Crohn's disease, these outcomes were observed in 32 (40%), 28 (35%) and 20 (25%). After 1 year, 75 (55%), 23 (17%) and 29 (21%) patients with ulcerative colitis demonstrated prolonged response, corticosteroid-dependence or required surgery, respectively. For Crohn's disease, these outcomes were observed in 30 (38%), 19 (24%) and 27 (35%) patients. Extensive ulcerative colitis was a predictor of surgery (P = 0.001, OR: 15.2). In Crohn's disease, inflammatory disease behaviour was negatively associated with surgery (P = 0.02, OR: 0.13). CONCLUSION: Although corticosteroids are effective, dependence/resistance remains common. Patients with extensive ulcerative colitis and fistulizing/stricturing Crohn's are most at risk of failing corticosteroid therapy.

Lees CW, Shand AG, Penman ID, Satsangi J, Arnott ID. · No affiliation provided · Inflamm Bowel Dis. · Pubmed #16633056 links to  free full text

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Noble CL, Nimmo ER, Drummond H, Ho GT, Tenesa A, Smith L, Anderson N, Arnott ID, Satsangi J. · Gastrointestinal Unit, Western General Hospital, University of Edinburgh, Edinburgh, Scotland. · Gastroenterology. · Pubmed #16344054 No free full text.

Abstract: BACKGROUND & AIMS: Recent data suggest that polymorphisms in the organic cation transporter (OCTN) genes OCTN1 (SLC22A4) and OCTN2 (SLC22A5) represent disease-causing mutations within the IBD5 locus (chromosome 5q31). We investigated associations with disease susceptibility, phenotype, and evidence for epistasis with CARD15 in 679 patients with Crohn's disease (CD) or ulcerative colitis (UC). METHODS: A total of 374 patients with CD, 305 patients with UC, and 294 healthy controls (HCs) were studied. Genotyping for single nucleotide polymorphisms IGR2096, IGR2198, and IGR2230, OCTN1 variant (SLC22A4 1672C-->T), and OCTN2 variant (SLC22A5 -207G-->C) was performed using the TaqMan system. RESULTS: The IBD5 OCTN1 and OCTN2 polymorphisms were in strong linkage disequilibrium (D', >0.959). IGR2198 variant allele frequency (49.1% vs 40.8%; P = .0046) and homozygosity (21% vs 14.8%; P = .044) were associated with CD versus HCs. Variant allelic frequency of OCTN1 (53.6% vs 43%; P = .0008) and OCTN2 (56.1% vs 48.4%; P = .0092) polymorphisms and homozygosity for the OCTN1/2-TC haplotype (28.4% vs 16%; P = .0042) were associated with CD versus HCs. IGR2198 homozygosity and TC homozygosity were associated with stricturing/penetrating disease at follow-up (P = .011 and P = .011, respectively) and disease progression (P = .038 and P = .049, respectively) on univariate analysis and with need for surgery on multivariate analysis (P = .016 and P = .004, respectively). In the absence of the IBD5 risk haplotype, no association of OCTN1/2 variants with CD was detected. No associations were seen with UC. CONCLUSIONS: The IBD5 locus influences susceptibility, progression, and need for surgery in CD. However, the contribution of OCTN1/2 variants is not independent of the IBD5 haplotype; a causative role for these genes remains plausible but is not yet proven. Further genetic, functional, and expression data are now required.

Silverberg MS, Satsangi J, Ahmad T, Arnott ID, Bernstein CN, Brant SR, Caprilli R, Colombel JF, Gasche C, Geboes K, Jewell DP, Karban A, Loftus Jr EV, Peña AS, Riddell RH, Sachar DB, Schreiber S, Steinhart AH, Targan SR, Vermeire S, Warren BF. · Mount Sinai Hospital, Toronto, Canada. · Can J Gastroenterol. · Pubmed #16151544 No free full text.

Abstract: 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.

Noble CL, Nimmo ER, Drummond H, Smith L, Arnott ID, Satsangi J. · Gastrointestinal Unit, Western General Hospital, Edinburgh, UK. · Gut. · Pubmed #15843420 links to  free full text

Abstract: INTRODUCTION: Recent data have suggested that specific haplotypic variants of the DLG5 gene on chromosome 10q23 may be associated with susceptibility to inflammatory bowel disease (IBD) in Germany. Haplotype D, notably characterised by the presence of a G-->A substitution at nucleotide 113, was associated with susceptibility to Crohn's disease (CD) whereas an extended haplotype A conferred protection. AIMS: Association of DLG5 haplotypic variants with disease susceptibility, genotype-phenotype relationships, and epistasis with CARD15 was investigated in the Scottish population. PATIENTS AND METHODS: A total of 374 CD, 305 ulcerative colitis (UC), and 294 healthy controls (HC) were studied. Genotyping for the variants rs1248696 (113A, representing haplotype D) and the single nucleotide polymorphism tag rs2289311 (representing haplotype A) were typed using the Taqman system. RESULTS: On analysis of the DLG5 variant 113A, there were no associations with IBD when allelic frequency (11.4% IBD v 13.2% HC; p = 0.30) and carrier frequency (19.2% IBD v 24.6% HC; p = 0.069) were analysed. No associations were observed between 113A variant allelic frequency (p = 0.37), carrier frequency (p = 0.057), and CD. In fact, 113A heterozygosity rates were lower in CD (16%) and IBD (16.9%) than in HC (23%) (p = 0.029 and p = 0.033, respectively). No associations between DLG5 and UC were observed. Haplotype A was not protective and there was no evidence of epistasis between DLG5 and CARD15. CONCLUSIONS: The present data contrast strongly with previous data from Germany. DLG5 113A is not associated with disease susceptibility and haplotype A does not confer resistance. Further work is required to evaluate the significance of DLG5 in other populations from geographically diverse regions.

Ho GT, Nimmo ER, Tenesa A, Fennell J, Drummond H, Mowat C, Arnott ID, Satsangi J. · Gastrointestinal Unit, Western General Hospital, Edinburgh, Scotland, UK. · Gastroenterology. · Pubmed #15685540 No free full text.

Abstract: BACKGROUND AND AIMS: The MDR1 gene encodes P-glycoprotein 170, an efflux transporter that is highly expressed in intestinal epithelial cells. The MDR1 exonic single nucleotide polymorphisms (SNPs) C3435T and G2677T have been shown to correlate with activity/expression of P-glycoprotein 170. METHODS: This was a case-control analysis of MDR1 C3435T and G2677T SNPs in a large well-characterized Scottish white cohort (335 with ulcerative colitis [UC], 268 with Crohn's disease [CD], and 370 healthy controls). We conducted 2-locus haplotype and detailed univariate and multivariate genotypic-phenotypic analyses. RESULTS: The MDR1 3435 TT genotype (34.6% vs 26.5%; P = .04; odds ratio [OR], 1.60; 95% confidence interval [95% CI], 1.04-2.44) and T-allelic frequencies (58.2% vs 52.8%; P = .02; OR, 1.28; 95% CI, 1.03-1.58) were significantly higher in patients with UC compared with controls. No association was seen with CD. The association was strongest with extensive UC (TT genotype: 42.4% vs 26.5%; P = .003; OR, 2.64; 95% CI, 1.34-4.99; and T allele: 63.9% vs 52.8%; P = .009; OR, 1.70; 95% CI, 1.24-2.29), and this was also confirmed on multivariate analysis ( P = .007). The G2677T SNP was not associated with UC or CD. These 2 SNPs lie in linkage disequilibrium in our population (D', .8-.9; r 2 , .7-.8). Two-locus haplotypes showed both positive (3435T/G2677 haplotype: P = .03; OR, 1.44) and negative (C3435/2677T haplotype: P = .002; OR, .35) associations with UC. Homozygotes for the haplotype 3435T/G2677 were significantly increased in UC ( P = .017; OR, 8.88; 95% CI, 1.10-71.45). CONCLUSIONS: Allelic variations of the MDR1 gene determine disease extent as well as susceptibility to UC in the Scottish population. The present data strongly implicate the C3435T SNP, although the 2-locus haplotype data underline the need for further detailed haplotypic studies.

Walker LJ, Aldhous MC, Drummond HE, Smith BR, Nimmo ER, Arnott ID, Satsangi J. · Gastrointestinal Unit, University of Edinburgh School of Clinical and Molecular Medicine, Western General Hospital, Edinburgh, UK. · Clin Exp Immunol. · Pubmed #15008984 links to  free full text

Abstract: Anti-Saccharomyces cerevisiae antibodies (ASCAs) have been proposed as serological markers, which may differentiate Crohn's disease (CD) from ulcerative colitis (UC) and predict disease phenotype. Their importance in pathogenesis is unproven. We investigated the relationship between ASCAs, disease phenotype and NOD2/CARD15 genotype in CD and whether ASCAs were related to antibodies to other fungal proteins. Serum from 228 patients [143 CD, 75 UC, 10 with indeterminate colitis (IC)] and 78 healthy controls (HC) were assayed for ASCA. Antibodies (IgA, IgG) to other fungal proteins (Fusarium species ATC20334, Mycoprotein) were measured in the same samples using an in-house enzyme-linked immunosorbent assay (ELISA) assay. ASCAs were present in 57% of CD, 19% of UC, 30% of IC and 8% of HCs. ASCA-positive status was a predictor for CD with sensitivity of 57%, specificity of 87%, positive predictive value of 78% and negative predictive value of 68%. ASCA was associated with proximal (gastroduodenal and small bowel involvement) rather than purely colonic disease (P < 0.001) and with a more severe disease phenotype and requirement for surgery over a median follow-up time of 9 years (P < 0.0001). No associations with NOD2/CARD15 mutations were seen. There was no association between ASCA and antibodies to MP (IgA or IgG). These data implicate ASCA as a specific marker of disease location and progression in CD, emphasizing the heterogeneity within IBD.

Arnott ID, Drummond HE, Ghosh S. · University Department of Medical Sciences, Western General Hospital, Edinburgh, UK. · Eur J Gastroenterol Hepatol. · Pubmed #11293442 No free full text.

Abstract: BACKGROUND: Clinical differences between small- and large-bowel Crohn's disease have been demonstrated. Neutrophil migration and degranulation are important effector mechanisms in gut damage. Granulocyte elastase, a neutrophil-bound enzyme, interleukin 8 and 1beta can be detected in whole-gut lavage fluid. We aimed to assess differences between large- and small-bowel Crohn's disease. METHODS: A total of 167 patients with active inflammatory bowel disease (118 Crohn's disease, 49 ulcerative colitis) underwent whole-gut lavage with a polyethylene glycol electrolyte solution. Granulocyte elastase was assayed using an enzyme substrate reaction, IL-8 and IL-1beta by ELISA. RESULTS: Twenty-seven of 36 patients with isolated colonic Crohn's disease had detectable granulocyte elastase (median 0.259 pKat/l, range < 0.039-2.742 microKat/l), whereas 3 of 15 with small-bowel involvement alone had detectable granulocyte elastase (median < 0.039 microKat/l, range < 0.039-0.266 microKat/l; P < 0.0001). Granulocyte elastase levels were significantly higher in patients with ileocolonic disease and post-ileocaecal resection compared with small-bowel disease alone. IL-8 (P< 0.0001) and IL-1beta (P < 0.04) levels differed between colonic and ileal distributions. No variations were seen in ulcerative colitis. CONCLUSIONS: Neutrophil migration to the gut lumen in Crohn's disease is a feature of colonic disease irrespective of associated ileal lesions. This suggests that bacterial-derived chemo-attractants may play a role. High levels of IL-8 in colonic disease are consistent with this hypothesis.