Ulcerative Colitis: Lees CW

Noble CL, McCullough J, Ho W, Lees CW, Nimmo E, Drummond H, Bear S, Hannan J, Millar C, Ralston SH, Satsangi J. · Gastrointestinal Unit, Molecular Medicine Centre, University of Edinburgh, Western General Hospital, Edinburgh, UK. · Aliment Pharmacol Ther. · Pubmed #18194505 No free full text.

Abstract: BACKGROUND: Osteoporosis is a recognized complication of inflammatory bowel disease (IBD). Aim To investigate the role of environmental factors and vitamin D receptor (VDR) variants on the prevalence of osteoporosis. METHODS: DEXA scans and case note review were performed on 440 IBD patients from 1997 to 2006. All the IBD patients and 240 healthy controls were genotyped for VDR variants Taq-1 and Apa-1 using PCR-RFLP. RESULTS: Osteoporosis and osteopenia rates were 15% and 18% for IBD, 16% and 18% for Crohn's disease (CD) and 13% and 19% for ulcerative colitis, respectively. On univariate analysis of the CD patients, low body mass index (BMI, <18.5) and smoking status (P = 0.008 and 0.005 respectively) were associated with osteoporosis and osteopenia. Low BMI was also associated with osteoporosis on multivariate analysis in CD (P = 0.021, OR 5.83, CI 1.31-25.94). No difference was observed between Taq-1 and Apa-1 VDR polymorphisms in IBD, CD, ulcerative colitis and healthy controls. However, CD males were more likely to carry the variant Taq-1 polymorphism than healthy controls males (P = 0.0018, OR 1.94, CI 1.28-2.92) and female CD patients (P = 0.0061, OR 1.60, CI 1.17-2.44). CONCLUSIONS: In this well-phenotyped cohort of IBD patients, a relatively low prevalence of osteoporosis was observed. Low BMI was the only independent risk factor identified to be associated with osteoporosis.

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.

Anderson CA, Massey DC, Barrett JC, Prescott NJ, Tremelling M, Fisher SA, Gwilliam R, Jacob J, Nimmo ER, Drummond H, Lees CW, Onnie CM, Hanson C, Blaszczyk K, Ravindrarajah R, Hunt S, Varma D, Hammond N, Lewis G, Attlesey H, Watkins N, Ouwehand W, Strachan D, McArdle W, Lewis CM, Anonymous00026, Lobo A, Sanderson J, Jewell DP, Deloukas P, Mansfield JC, Mathew CG, Satsangi J, Parkes M. · Genetic and Genomic Epidemiology Unit, Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford, UK. · Gastroenterology. · Pubmed #19068216 links to  free full text

Abstract: 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.

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.

Fisher SA, Tremelling M, Anderson CA, Gwilliam R, Bumpstead S, Prescott NJ, Nimmo ER, Massey D, Berzuini C, Johnson C, Barrett JC, Cummings FR, Drummond H, Lees CW, Onnie CM, Hanson CE, Blaszczyk K, Inouye M, Ewels P, Ravindrarajah R, Keniry A, Hunt S, Carter M, Watkins N, Ouwehand W, Lewis CM, Cardon L, Anonymous00021, Lobo A, Forbes A, Sanderson J, Jewell DP, Mansfield JC, Deloukas P, Mathew CG, Parkes M, Satsangi J. · Department of Medical and Molecular Genetics, King's College London School of Medicine, 8th Floor Guy's Tower, Guy's Hospital, London SE1 9RT, UK. · Nat Genet. · Pubmed #18438406 links to  free full text

Abstract: 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.

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, 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.

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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