Temporal Trends in Surgical Resection Rates and Biologic Prescribing in Crohn's Disease: A Population-based Cohort Study.

BACKGROUND: The use of biologic therapy for Crohn's disease [CD] continues to evolve, however, the effect of this on the requirement for surgery remains unclear. We assessed changes in biologic prescription and surgery over time in a population-based cohort. METHODS: We performed a retrospective cohort study of all 1753 patients diagnosed with CD in Lothian, Scotland, between January 1, 2000 and December 31, 2017, reviewing the electronic health record of each patient to identify all CD-related surgery and biologic prescription. Cumulative probability and hazard ratios for surgery and biologic prescription from diagnosis were calculated and compared using the log-rank test and Cox regression analysis stratified by year of diagnosis into cohorts. RESULTS: The 5-year cumulative risk of surgery was 20.4% in cohort 1 [2000-2004],18.3% in cohort 2 [2005-2008], 14.7% in cohort 3 [2009-2013], and 13.0% in cohort 4 [2014-2017] p <0.001. The 5-year cumulative risk of biologic prescription was 5.7% in cohort 1, 12.2% in cohort 2, 22.0% in cohort 3, and 44.9% in cohort 4 p <0.001. CONCLUSIONS: The increased and earlier use of biologic therapy in CD patients corresponded with a decreasing requirement for surgery over time within our cohort. This could mean that adopting a top-down or accelerated step-up treatment strategy may be effective at reducing the requirement for surgery in newly diagnosed CD.

Real-world Effectiveness and Safety of Vedolizumab for the Treatment of Inflammatory Bowel Disease: The Scottish Vedolizumab Cohort.

BACKGROUND & AIMS: Vedolizumab is an anti-a4b7 monoclonal antibody that is licensed for the treatment of moderate to severe Crohn's disease and ulcerative colitis. The aims of this study were to establish the real-world effectiveness and safety of vedolizumab for the treatment of inflammatory bowel disease. METHODS: This was a retrospective study involving seven NHS health boards in Scotland between June 2015 and November 2017. Inclusion criteria included: a diagnosis of ulcerative colitis or Crohn's disease with objective evidence of active inflammation at baseline (Harvey-Bradshaw Index[HBI] ≥5/Partial Mayo ≥2 plus C-reactive protein [CRP] >5 mg/L or faecal calprotectin ≥250 µg/g or inflammation on endoscopy/magnetic resonance imaging [MRI]); completion of induction; and at least one clinical follow-up by 12 months. Kaplan-Meier survival analysis was used to establish 12-month cumulative rates of clinical remission, mucosal healing, and deep remission [clinical remission plus mucosal healing]. Rates of serious adverse events were described quantitatively. RESULTS: Our cohort consisted of 180 patients with ulcerative colitis and 260 with Crohn's disease. Combined median follow-up was 52 weeks (interquartile range [IQR] 26-52 weeks). In ulcerative colitis, 12-month cumulative rates of clinical remission, mucosal healing, and deep remission were 57.4%, 47.3%, and 38.5%, respectively. In Crohn's disease, 12-month cumulative rates of clinical remission, mucosal healing, and deep remission were 58.4%, 38.9%, and 28.3% respectively. The serious adverse event rate was 15.6 per 100 patient-years of follow-up. CONCLUSIONS: Vedolizumab is a safe and effective treatment for achieving both clinical remission and mucosal healing in ulcerative colitis and Crohn's disease.

Predicting outcome in acute severe ulcerative colitis: comparison of the Travis and Ho scores using UK IBD audit data.

BACKGROUND: Acute severe ulcerative colitis is categorised using the Truelove & Witts criteria. The Travis and the Ho scores are calculated following 72 h of steroid treatment to identify patients at risk of failing steroid therapy who require colectomy or second-line medical therapy. AIM: To compare the Travis and the Ho scores in a large unselected cohort to determine which might be more clinically relevant. METHODS: We analysed 3049 patients with ulcerative colitis from the 2010 round of the UK IBD audit of which 984 had acute severe ulcerative colitis. 420 patients had sufficient data for analysis. Patients were allocated into either a Travis high- or low-risk group and either a Ho high-, intermediate- or low-risk group. We assessed whether further medical or surgical intervention and outcomes varied between groups. RESULTS: High-risk patients in Travis and the Ho groups, when compared to lower risk groups, were more likely to fail steroid therapy: 64.5% (131/203) vs. 38.7% (84/217) (P < 0.0001) for Travis and 66.2% (96/145) vs. 46.7% (85/182) vs. 36.6% (34/93) (P < 0.0001) for Ho. They were also more likely to undergo surgery 34.0% (69/203) vs. 9.7% (21/217) for Travis and 33.1% (48/145) vs. 17.0% (31/182) vs. 11.8% (11/93) (P < 0.0001) for Ho. Travis high patients were more likely to be refractory to second-line medical therapy: 44.6% (37/83) vs. 20.0% (9/45) (P = 0.01). CONCLUSIONS: Patients identified as high risk using the Travis or the Ho scoring systems are more likely to be resistant to IV steroids and require surgery. Risk of surgery in both high-risk populations is lower than previously reported.

Diverticular disease in Scotland: 2000-2010.

AIM: Symptomatic diverticular disease (DD) may be increasing in incidence in western society particularly in younger age groups. This study aimed to describe hospital admission rates and management for DD in Scotland between 2000 and 2010. METHOD: Data were obtained from the Scottish Morbidity Records (SMR01). The study cohort included all patients with a hospital admission and a primary diagnosis of DD of the large intestine (ICD-10 primary code K57). RESULTS: Scottish NHS hospitals reported 90 990 admissions for DD (in 87 314 patients) from 2000 to 2010. The annual number of admissions increased by 55.2% from 6591 in 2000 to 10,228 in 2010, an average annual increase per year of 4.5%. Most of the increase attributable to DD was due to elective day cases (3618 in 2000; 6925 in 2010) a likely consequence of a greater proportion of the population accessing colonoscopy over that time period. There was an 11% increase in inpatient admissions (2973-3303), 60% of these patients being women. Admissions in younger age groups increased proportionally in the later years of the study, and there was an association between DD admissions and greater deprivation. Despite an increase in complicated DD from 22.9% in 2000 to 27.1% in 2010 and a 16.8% increase in emergency inpatient admissions, the rate of surgery fell during the period of study. CONCLUSION: This report supports findings of other population-based studies of western countries indicating that DD is an increasing burden on health service resources, particularly in younger age groups.

Thiopurine withdrawal during sustained clinical remission in inflammatory bowel disease: relapse and recapture rates, with predictive factors in 237 patients.

BACKGROUND: Thiopurines (azathioprine and mercaptopurine) remain integral to most medical strategies for maintaining remission in Crohn's disease (CD) and ulcerative colitis (UC). Indefinite use of these drugs is tempered by long-term risks. While clinical relapse is noted frequently following drug withdrawal, there are few published data on predictive factors. AIM: To investigate the success of planned thiopurine withdrawal in patients in sustained clinical remission to identify rates and predictors of relapse. METHODS: This was a multicentre retrospective cohort study from 11 centres across the UK. Patients included had a definitive diagnosis of IBD, continuous thiopurine use ≥3 years and withdrawal when in sustained clinical remission. All patients had a minimum of 12 months follow-up post drug withdrawal. Primary and secondary end points were relapse at 12 and 24 months respectively. RESULTS: 237 patients were included in the study (129 CD; 108 UC). Median duration of thiopurine use prior to withdrawal was 6.0 years (interquartile range 4.4-8.4). At follow-up, moderate/severe relapse was observed in 23% CD and 12% UC patients at 12 months, 39% CD and 26% UC at 24 months. Relapse rate at 12 months was significantly higher in CD than UC (P = 0.035). Elevated CRP at withdrawal was associated with higher relapse rates at 12 months for CD (P = 0.005), while an elevated white cell count was predictive at 12 months for UC (P = 0.007). CONCLUSION: Thiopurine withdrawal in the context of sustained remission is associated with a 1-year moderate-to-severe relapse rate of 23% in Crohn's disease and 12% in ulcerative colitis.

Systematic review: The use of thiopurines or anti-TNF in post-operative Crohn's disease maintenance--progress and prospects.

BACKGROUND: Post-operative recurrence of Crohn's disease is an important management challenge, with 2-year recurrence rates defined by clinical, endoscopic and radiological parameters of up to 77%, 64% and 49%. Clinical and severe endoscopic recurrence vary widely in controlled trials from 13% to 36% and 22% to 56% with thiopurine treatment or 0% and 9% with infliximab treatment respectively at 1 year. AIMS: To provide a review of the evidence for thiopurine or anti-TNF use in post-operative Crohn's disease, and to assess the ability to identify those patients at highest risk of recurrent disease. METHODS: A literature search was undertaken using Medline, Embase and Cochrane databases to identify studies using search terms 'thiopurine', 'azathioprine', 'mercaptopurine', 'Infliximab', 'adalimumab', 'Anti-TNF', 'Crohn's disease', 'post-operative' and 'recurrence'. RESULTS: Trials to examine this important area have proved difficult to execute, with recruitment and retention of patients posing major challenges to randomised clinical trials. There have been four RCTs of 433 patients of thiopurine therapy (with three meta-analyses of these data), and one of anti-TNF therapy involving 24 patients. Overall the efficacy data for thiopurine use in this setting are inconclusive, and other than smoking, there are no consistent predictors of post-operative relapse. CONCLUSIONS: At present, evidence for routine use of thiopurine treatment in post-operative Crohn's disease is heterogeneous and unconvincing. Stratification by risk of relapse emerges as a key challenge in post-operative management that needs to be addressed, using clinical parameters and emerging biomarkers. The evidence for prophylactic anti-TNF use is limited though promising, with its routine use guided by early assessment of relapse.

A trial of mercaptopurine is a safe strategy in patients with inflammatory bowel disease intolerant to azathioprine: an observational study, systematic review and meta-analysis.

BACKGROUND: Thiopurines maintain remission and modify disease course in inflammatory bowel disease. Use is limited by intolerance and subsequent drug withdrawal in approximately 17% of patients treated with azathioprine. Previous case series have addressed the success rates of re-treatment with mercaptopurine in these individuals. AIMS: To determine the rate of tolerance when trialling mercaptopurine in azathioprine-intolerant patients and the factors predictive of success, and to perform a systematic review and meta-analysis of these data with other published data sets. METHODS: A retrospective observational study of 149 patients with IBD (82 with Crohn's disease and 67 with ulcerative colitis) previously intolerant of azathioprine subsequently treated with mercaptopurine was performed. A meta-analysis was undertaken of all published studies of mercaptopurine use in azathioprine-intolerant patients (455 patients in 11 included studies). RESULTS: Mercaptopurine was tolerated by 58% of azathioprine-intolerant patients in the Edinburgh cohort. In the meta-analysis, 68% tolerated mercaptopurine. A higher proportion of those in the meta-analysis with GI toxicity (62%) or hepatotoxicity (81%) were able to tolerate mercaptopurine than those with flu-like illness (36%). Among those patients who ceased mercaptopurine for further adverse effects, 59% experienced the same adverse effect as they had with azathioprine. CONCLUSIONS: This meta-analysis shows that switching to mercaptopurine is a safe therapeutic strategy for over two-thirds of azathioprine-intolerant patients and may help optimise immunomodulatory therapy in inflammatory bowel disease. A trial of mercaptopurine should be attempted in IBD patients (except those with acute pancreatitis or bone marrow aplasia) before considering thiopurine intolerance.

Outcomes of rescue therapy in acute severe ulcerative colitis: data from the United Kingdom inflammatory bowel disease audit.

BACKGROUND: Approximately one third of patients with acute severe ulcerative colitis (ASUC) fail response to steroids. Ciclosporin and anti-TNFα are proven second-line therapies, but evidence of their efficacy has come mainly from tertiary centres and/or selective clinical trial recruitment. AIM: To assess ASUC outcomes in a large unselected cohort. METHODS: UK-wide audits of IBD care were conducted in 2008 (209 hospital sites) and 2010 (198 hospital sites), covering >87% of admitting hospitals. Each site entered data from 20 consecutive UC admissions onto a web-based proforma. Admissions included 852 (2008) and 984 (2010) with ASUC, accounting for 35% and 39% of UC admissions, respectively. RESULTS: ASUC in-hospital mortality was 1.2% in 2008; 0.7% in 2010 (P = 0.22). Response to first-line steroid therapy was 61% (2008); 58% (2010) and mortality was higher in non-responders: 2008: 2.9% (9/315) vs. 0.19% (1/537; P < 0.001); 2010: 1.8% (7/391) vs. 0.0% (0/593; P = 0.002). In 2010, more patients (56%) received second-line medical therapy than in 2008 (47%, P = 0.02). In-hospital mortality was similar to second-line medical therapy vs. surgery without further medical therapy; 2008: 2.7% vs. 2.8%, P = 0.99; 2010: 0.9% vs. 3.1%, P = 0.17. Second-line therapy response was more frequently observed with anti-TNFα than ciclosporin: (2008: 76% vs. 46%, P < 0.001; 2010: 80% vs. 58%, P < 0.001). CONCLUSIONS: Mortality in acute severe ulcerative colitis was low, but higher in steroid non-responders. Patients treated with second-line medical therapies had no higher risk of in-hospital mortality than those undergoing surgery. Second-line 'rescue' medical therapy usage is increasing; however, ciclosporin response rates were relatively low.

Magnetic resonance follow-through imaging for evaluation of disease activity in ileal Crohn's disease: an observational, retrospective cohort study.

BACKGROUND: Magnetic resonance follow-through (MRFT) is a new cross-sectional imaging modality with the potential to accurately stage ileal Crohn's disease (CD), while avoiding ionizing radiation and the discomfort associated with enteroclysis. We aimed to assess the reliability of this technique in assessing the extent and activity of ileal CD, and to assess its influence on subsequent management. METHODS: Out of a total of 342 patients undergoing MRFT between 2004 and 2008, 221 were performed in 191 patients with confirmed CD. Case notes were reviewed in detail with documentation of all investigations pre- and post-MRFT. Agreement between inflammatory markers, histopathology, and MRFT findings was determined. RESULTS: Overall, 116/221 (52.5%) of MRFTs showed active ileal CD, and 76/221 (34.4%) quiescent CD, while 29/221 (13.1%) were suboptimal. Overall, 66 strictures and 18 fistulae were identified. There was substantial agreement between active ileal CD on MRFT and histopathology (n = 59; kappa = 0.66; P = 0.0006; sensitivity 85.1%, specificity 85.7%) and fecal calprotectin (n = 14; kappa = 0.72; P = 0.047), while C-reactive protein (CRP) showed moderate agreement (n = 107; kappa = 0.402; P = 0.00028). Management was influenced by MRFT reports following active (52/84, 62% treated medically) or quiescent (48/62, 77.4% managed conservatively) disease. Fibrotic strictures were predominantly treated surgically (7/14, 50%). In all, 13/32 (40.6%) patients with inflammatory ileal strictures required surgery, mostly due to steroid-resistant disease. Overall, 75 MR findings were documented in 221 MRFTs, including 1 renal cancer. CONCLUSIONS: MRFT provides accurate information on ileal CD activity, with close agreement to inflammatory markers and histopathology. It represents a substantial advance in the staging of CD, while avoiding painful enteroclysis and radiation exposure in young patients.

Lack of association between cervical dysplasia and IBD: a large case-control study.

BACKGROUND: It has been variously reported that women with inflammatory bowel disease (IBD) have an increased risk of cervical dysplasia. We aimed to assess in a large, accurately phenotyped, case-controlled population whether women with IBD had increased rates of abnormal cervical smears and if this was affected by immunosuppressant therapy or disease phenotype. METHODS: Women with IBD diagnosed prior to the age of 60 were studied at a single tertiary referral center in Scotland. Full cervical smear histories were available on 411 women (204 Crohn's disease, 207 ulcerative colitis, median age at diagnosis 28.4 years, median current age 44.1 years). All the cases were matched 1:4 to healthy controls (n = 1644) from the same geographical location. RESULTS: There was no difference in rates of abnormal smears between patients with IBD (80.5% negative, 10.5% low-grade, and 9.0% high-grade dysplasia) and controls (85.4%, 7.7%, and 6.9%, P = 0.37). The use of immunosuppressant therapy had no impact on rates of cervical dysplasia or neoplasia. Furthermore, there was no effect of disease location, behavior, or oral contraceptive use. However, there were significantly more abnormal cervical smears in IBD patients who were current smokers compared with exsmokers and those who had never smoked (27.4% versus 11.4%, P = 0.001, odds ratio = 2.95, 95% confidence interval = 1.55-5.50). CONCLUSIONS: Women with IBD are not at increased risk of abnormal cervical smears unless they smoke. These data suggest that young women with IBD should be managed as per the background population; attending for regular smear testing, and undergoing vaccination against cervical cancer when available.

Fecal calprotectin predicts the clinical course of acute severe ulcerative colitis.

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.

Efficacy and complications of adalimumab treatment for medically-refractory Crohn's disease: analysis of nationwide experience in Scotland (2004-2008).

BACKGROUND: Adalimumab is a second generation humanized anti-tumour necrosis factor (TNF) monoclonal antibody with established efficacy in Crohn's disease (CD). AIMS: To evaluate the efficacy and safety of adalimumab on a nationwide clinical setting. METHODS: We used the Scottish Society of Gastroenterology network to identify and follow up the clinical outcomes of patients with CD treated with adalimumab over a 4-year period (2004-2008). RESULTS: A total of 98 patients received adalimumab - 100.5 patient follow-up years were recorded (64.3% females; median age at diagnosis of 20.7 years; 88.8% treated with 80/40 mg induction regimen. Eighty eight (89.8%) had previous infliximab with 29 (32.9%) primary nonresponders; 32 (32.6%) were corticosteroid-dependent; 47 (47.9%) were intolerant/resistant to most immunosuppressive therapies (two or more). In all, 60% of patients were in clinical remission at 1-year follow-up, with 30% and 55% requiring dose escalation to weekly therapy at 1-and 2-year follow-up respectively. Overall, 29 (29.6%) patients developed complications with eight nonfatal serious (8.2%) adverse events and 2 (2.0%) case fatalities (sepsis following perforation and disseminated colorectal cancer, respectively). CONCLUSIONS: Adalimumab is efficacious in severe and refractory CD in the clinical setting, although there remain significant therapy- and disease-related risks of serious complications.

Anti-Saccharomyces cerevisiae antibodies status is associated with oral involvement and disease severity in Crohn disease.

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.

The safety profile of anti-tumour necrosis factor therapy in inflammatory bowel disease in clinical practice: analysis of 620 patient-years follow-up.

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.

Detailed assessment of NOD2/CARD15 exonic variation in inflammatory bowel disease in Scotland: implications for disease pathogenesis.

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.

Regional variation in gene expression in the healthy colon is dysregulated in ulcerative colitis.

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.