C Lees

A retrospective analysis of the efficacy and safety of infliximab as rescue therapy in acute severe ulcerative colitis

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.

Characterization of Intestinal Gene Expression Profiles in Crohn's Disease by Genome-wide Microarray Analysis

Background: Genome‐wide microarray expression analysis creates a comprehensive picture of gene expression at the cellular level. The aim of this study was to investigate differential intestinal gene expression in patients with Crohns disease (CD) and controls with subanalysis of confirmed CD susceptibility genes, associated pathways, and cell lineage. Methods: In all, 172 biopsies from 53 CD and 31 control subjects were studied. Paired endoscopic biopsies were taken at ileocolonoscopy from five specific anatomical locations including the terminal ileum (TI) for RNA extraction and histology. The 41,058 expression sequence tags were analyzed using the Agilent platform. Results: Analysis of all CD biopsies versus controls showed 259 sequences were upregulated and 87 sequences were downregulated. Upregulated genes in CD included SAA1 (fold change [FC] +7.5, P = 1.47 × 10−41) and REGL (FC +7.3, P = 2.3 × 10−16), whereas cellular detoxification genes including‐SLC14A2 (FC‐2.49, P = 0.00002) were downregulated. In the CD TI biopsies diubiquitin (FC+11.3, P < 1 × 10−45), MMP3 (FC+7.4, P = 1.3 × 10−11), and IRTA1 (FC‐11.4, P = 4.7 × 10−12) were differentially expressed compared to controls. In the colon SAA1 (FC+6.3, P = 5.3 × 10−8) was upregulated and thymic stromal lymphopoietin (TSLP) (FC‐2.3, P = 2.7 × 10−6) was downregulated comparing noninflamed CD and control biopsies, and the colonic inflammatory CD signature was characterized by downregulation of the organic solute carriers‐SLC38A4, SLC26A2, and OST alpha. Of CD susceptibility genes identified by genome‐wide association scan IL‐23A, JAK2, and STAT3 were upregulated in the CD group, confirming the dysregulation of Th17 signaling. Conclusions: These data characterize the dysregulation of a series of specific inflammatory pathways highlighting potential pathogenic mechanisms as well as areas for translation to therapeutic targets. (Inflamm Bowel Dis 2010)

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

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.

Contribution of the NOD1/CARD4 insertion/deletion polymorphism +32656 to inflammatory bowel disease in Northern Europe

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, Crohns 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. (Inflamm Bowel Dis 2007)

Systematic review: the use of thiopurines or anti‐TNF in post‐operative Crohn's disease maintenance – progress and prospects

Post‐operative recurrence of Crohns 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.

Letter: European Medicines Agency recommendations for allergic reactions to intravenous iron-containing medicines.

*CIBEREHD, Hospital Cl inico Universitario Lozano Blesa, Zaragoza, Spain. Rambam Health Care Campus, Haifa, Israel. Humanitas Clinical and Research Center, Milan, Italy. Agaplesion Markus Hospital, Frankfurt, Germany. Herlev Hospital, University of Copenhagen, Copenhagen, Denmark. **Semmelweis University, Budapest, Hungary. Western General Hospital, Edinburgh, UK. University Hospital Skane, University of Lund, Malm€o, Sweden. ISCARE Lighthouse and 1st Medical Faculty, Charles University, Prague, Czech Republic. Evangelismos Hospital, Athens, Greece. ***Lausanne University Medical Center, Lausanne, Switzerland. Oslo University Hospital, University of Oslo, Oslo, Norway. University Hospital of Nancy, Universit e Henri Poincar e 1, Vandoeuvre-l es-Nancy, France. Ankara University School of Medicine, Ankara, Turkey. Erasmus University Medical Center, Rotterdam, The Netherlands. ****Clinical Immunology and Infectious Diseases, Medical University of Innsbruck, Innsbruck, Austria. Ismar Healthcare, Lier, Belgium. Department Internal Medicine III, Medical University of Vienna, Vienna, Austria. E-mails: fgomollon@gmail.com, fgomollon@me.com

P349 Serum calprotectin: a novel biomarker to predict outcome in acute severe ulcerative colitis?

Reference(s) [1] Stephane Paul, Emilie Del Tedesco, Hubert Marotte, et al. (2013), Therapeutic Drug Monitoring of Infliximab and Mucosal Healing in Inflammatory Bowel Disease: A Prospective Study, Inflammatory Bowel Disease. [2] Filip Baert, Maja Noman, Severine Vermeire, et al. (2003), Influence of Immunogenicity on the Long-Term Efficacy of Infliximab in Crohn’s Disease, The New England Journal of Medicine.

Letter: azathioprine‐induced pancreatitis and subsequent tolerance of mercaptopurine – authors' reply

SIRS, We read with interest the paper by Kennedy et al. describing patients with inflammatory bowel disease (IBD) who had been intolerant of azathioprine and had subsequently been trialled with mercaptopurine. It was an interesting article, but it did not highlight some recent data that indicate that the development of azathioprine-induced pancreatitis is not necessarily a strict contraindication to subsequent use of mercaptopurine. Thiopurine-induced pancreatitis occurs in up to 5% of patients and is an idiosyncratic drug reaction. In our study published earlier this year, we described 64 patients with IBD over 10 years of whom 23 were intolerant to azathioprine, seven of whom developed acute pancreatitis. In all seven patients, the pancreatitis was mild and resolved within a few days of withdrawal of azathioprine. Three of these seven patients with azathioprine-related pancreatitis then went on to tolerate mercaptopurine. Ledder et al. also recently described a case series of four paediatric patients with IBD who developed azathioprine-induced pancreatitis. The subsequent trial of mercaptopurine was tolerated in all four patients, leading to the conclusion that the results called into question that azathioprine-induced pancreatitis is an absolute contraindication to the use of mercaptopurine and is most relevant in those with an aggressive phenotype where long-term immunosuppression is required. Azathioprine-induced pancreatitis should not be considered a strict contraindication to the subsequent use of mercaptopurine in patients with IBD. Introduction of mercaptopurine following azathioprine-induced pancreatitis in a controlled setting should be considered.

AODWE-007 Real world data on the effectiveness and safety of vedolizumab in the treatment of crohn’s disease and ulcerative colitis: the edinburgh experience

Introduction The GEMINI clinical trials programme has demonstrated the efficacy and safety of vedolizumab in the induction and maintenance of Crohn’s disease and ulcerative colitis. 2 years after licensing and subsequent approvals (eg. NICE/SMC), there is great interest in real world effectiveness and safety data from early adopters. Here, we present the short and medium term outcomes from a single centre cohort of IBD patients treated with vedolizumab. Method The following were prospectively collected for all patients at each infusion: observations, routine haematology, biochemistry and inflammatory markers, clinical disease activity score, faecal calprotectin (FC) and adverse events. Clinical effectiveness was evaluated by assessing changes in HBI and SCCAI at 12–14 weeks and 26 weeks. Clinical remission was defined as a HBI <5 and SCCAI <3. Response was defined as a change in disease activity ≥3. Changes in CRP/FC were also analysed. Results By the end of November 2016, 94 patients had received vedolizumab treatment. 63/94 (27 CD, 33 UC, 3 IBDU) had completed 12–14 week follow-up and are included in the primary analysis of clinical efficacy. Median disease duration was 7.9 years (IQR 4–15) with 36/63 (57%) patients previously exposed to anti-TNF therapy. Median HBI and SCCAI at baseline were 4 (IQR 2–7) and 5 (IQR 2–6) respectively. At 12–14 weeks median HBI was 3 (IQR 1–7) (p=0.37) with SCCAI dropping to 1 (IQR 1–3) (p=0.004). At 26 weeks median HBI fell to 2 (IQR 0.5–3, n=15) (p=0.02) and SCCAI remained at 1 (IQR 0–1, n=26) (p=0.0001). 23/63 (37%) patients were in clinical remission at baseline (59% on steroids) with 42/63 (67%) at 12–14 weeks (24% on steroids) and 35/41 (85%) at 26 weeks (12% on steroids). Clinical response and remission rates of those patients with clinically active disease at baseline were 61% and 53% at week 12–14 (n=36), and 78% for both at week 26 (n=24). Median FC was 730 µg/g (IQR 215–858, n=50) at baseline, 170 µg/g (IQR 60–465, n=36) at week 12–14 (p=0.00018) and 70 µg/g (IQR 30–180, n=29) at week 26 (p=0.00001). No significant drug related complications were observed. Arthralgia was the most commonly reported side effect (12/94). 7/94 (7%) patients underwent surgery within 30 weeks of starting vedolizumab. 2 pregnancies and 1 colorectal cancer were reported in our cohort. Conclusion Our experience further supports the clinical effectiveness and safety data for the use of vedolizumab. We demonstrate a clear benefit in clinical/biochemical disease activity in a cohort of IBD patients many of which had complex and previously refractory disease. Disclosure of Interest None Declared

OC-009 Withdrawal of anti-tnf following sustained remission for inflammatory bowel disease: a systematic review and meta-analysis

Introduction UK regulators mandate reassessment of disease activity after 12 months of anti-TNF therapy for Crohn’s disease (CD), with consideration of withdrawal of treatment. There is a need for more data to establish the rates of relapse following treatment cessation. We have therefore analysed an expanded retrospective cohort of patients from the UK and performed a systematic review and a meta-analysis of all available literature. Method Our original cohort of 80 UK IBD patients1was expanded to 161 accurately phenotyped subjects (142 CD, 19 ulcerative colitis [UC]/IBD unclassified). Searches were conducted of PubMed and EMBASE to identify all other published studies or conference abstracts that described outcomes after drug withdrawal for sustained clinical remission. Studies were excluded where patients had not had maintenance therapy for ≥12 months or where it was not possible to ascertain the relapse rate at 12 months. Data regarding relapse rates and response to retreatment were extracted and combined using a random-effects meta-analysis. Results After removal of duplicates, 2371 studies were identified with initial searches. 12 studies were included in the final meta-analysis with 697 CD patients and 132 UC/IBDU. For CD, the estimated 1-year relapse rate was 0.38 (95% confidence interval [CI] 0.34–0.43); see forest plot in Figure 1. Heterogeneity was low. Data on retreatment with anti-TNF was available for 188 patients. The estimated chance of retreatment success was 0.95 (95% CI 0.92–0.98). For UC/IBDU, the estimated 1-year relapse rate was 0.34 (95% CI 0.26–0.42) and retreatment success was estimated as 0.92 (95% CI 0.86–0.98).Abstract OC-009 Figure 1 Conclusion Remarkably consistent data has now emerged that supports relapse rates in CD and UC of just over a third by one year after discontinuation of anti-TNF maintenance for sustained remission. Although some indicators show promise, prediction of relapse remains challenging. Disclosure of interest None Declared. Reference Kennedy NA, Warner B, Johnston E, et al. OC-001 Anti-tnf withdrawal in Ibd: initial results from a pan-UK study. Gut 2014;63:A1