Alan G. Shand

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 μg/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 μg/g. Kaplan–Meier analyses showed that using 1,922.5 μg/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.

Use of methotrexate in refractory Crohn's disease: The Edinburgh experience

Background: In the two benchmark controlled trials in Crohns disease (CD) supporting its use, methotrexate (MTX) was used as the immunosuppressant of choice in immunomodulatory‐naive patients. However, in daily clinical practice MTX is used generally after thiopurine analogs have failed. Methods: The data are reported using intramuscular (IM) MTX (25 mg/week) in the induction of remission and oral MTX (15 mg/week) in 39 CD patients with a median age of 32 years, assessed retrospectively. In all, 97% patients had failed azathioprine and/or mercaptopurine therapy due to lack of efficacy in 14 (36%) and side effects in 24 (61%) patients; 21 patients (53%) were steroid‐dependent with a median dose of 27.5 mg prednisolone/day for over a year. Results: In all, 72% of patients tolerated an induction regimen of 25 mg/week of IM MTX; 10% managed a reduced dose and 18% were intolerant. Remission was achieved in 71% of patients at 16 weeks. In the patients taking corticosteroids, withdrawal was achieved in 26% of patients and reduction in 47% at 16 weeks. Oral MTX therapy was continued in 22 patients after induction. In this group the probability of relapse was 78% at 50 weeks of oral therapy. Conclusions: Parenteral MTX therapy is efficacious in inducing remission in steroid‐dependent CD patients, although its use is limited by side effects in ≈30% of patients. Low‐dose oral therapy does not maintain long‐term remission and is not a suitable alternative.

564 Elevated Faecal Calprotectin Predicts Disease Progression in Crohn's Disease

Introduction Historical cohort studies have clearly demonstrated that over time the majority of patients with Crohn’s disease (CD) will progress from inflammatory (B1) to stricturing (B2) or fistulating (B3) disease. Emerging data suggest that more intensive treatment targeted towards mucosal healing will help to prevent disease progression. Faecal calprotectin (FC) is an established surrogate biomarker for endoscopic mucosal healing. It has yet to be established whether tailoring therapy to FC levels prevents disease progression. In the present study we aimed to determine whether FC levels in patients with established CD were predictive of disease progression. Methods The Edinburgh Faecal Calprotectin Registry (EFCR) comprises data on 22,130 FC assays in 16,278 patients from 2005–2012. Detailed phenotypic information was obtained on patients with CD by retrospective casenote review. Data collected included demographics, disease location, disease behaviour over time, CD-related surgery, investigations, hospitalisations and drug therapy. Patients were included in the main analysis if they had at least 12 months’ follow-up since first FC. The a priori primary endpoint was a composite of progression in Montreal luminal behaviour, hospitalisation for flare and resectional surgery. Results There were 881 CD patients identified with at least one FC, of which 723 had at least one year’s follow-up, with median follow-up time 40 months (IQR 25–60). The median age was 28y (IQR 20–42) at diagnosis and 40y (28–53) at time of first FC. 239 patients (33%) reached the primary endpoint, of whom 68 had had progression of their Montreal behaviour from B1 to B2 or B3, or from B2 to B3. The median of the earliest FC was significantly higher in the group that reached the primary endpoint at 586 µg/g (IQR 210–1235) vs. 289 (75–1001) in those that did not (p Conclusion This large single-centre study presents compelling evidence that measurement of FC can be used to predict disease course, which creates the opportunity for physicians to intervene earlier and perhaps alter the disease course. Disclosure of Interest None Declared

PTU-123 Acute severe ulcerative colitis: the last 12 years in Edinburgh

Introduction Acute severe ulcerative colitis (ASUC) remains a common reason for urgent colectomy, yet there are relatively few large cohort studies exploring prognosis and outcome.1–3 This study aims to examine presentation and management of ASUC in the Western General Hospital, a tertiary referral centre in Edinburgh and to identify prognostic factors. Methods Patients were identified from a large database of participants in genetic studies in Edinburgh, as well as from two previous small cohorts of ASUC studied in Edinburgh. More recent cases were found from minutes of a weekly IBD meeting. Cases were included if they met the standard clinical, radiological and pathological criteria for ulcerative colitis and required an admission for 3 days or more requiring intravenous corticosteroids and/or colectomy. Two cohorts were analysed, one with full clinical detail (97 admissions in 86 patients) and one with more basic detail (444 admissions in 323 patients). Results Overall colectomy rate was 31.8%. Haemoglobin, C reactive protein and albumin at days 0 and 3 were significant predictors of colectomy in both cohorts (p<0.05 in each case), while in the detailed cohort day 3 but not day 0 stool frequency was predictive (p<0.001 and 0.81 respectively). A simple score was derived to predict colectomy at admission based on disease extent, albumin and CRP. Scores of 0, 1, 2 and 3 corresponded to risks for colectomy of 10%, 31%, 61% and 75%. For day 3 parameters, both the Edinburgh acute colitis (Ho) score (Abstract PTU-123 figure 1) and Travis criteria performed well.Abstract PTU-123 Figure 1 Conclusion ASUC remains an important cause of colectomy. This study confirms the prognostic value of the Ho score and Travis criteria at day 3, but also indicates that day 0 CRP and albumin are strong predictors of outcome. Competing interests None declared. References 1. Dinesen LC, et al. J Crohns Colitis 2010;4:431–7. 2. Ho GT, et al. Aliment Pharmacol Ther 2004;19:1079–87. 3. Turner D, et al. Clin Gastroenterol Hepatol 2007;5:103–10.

Higher Adalimumab Drug Levels During Maintenance Therapy for Crohn’s Disease Are Associated With Biologic Remission

BACKGROUND Adalimumab is an established treatment for Crohns disease. Limited data are available regarding the relationship between adalimumab drug levels and serum/fecal markers of gut inflammation. We therefore aimed to characterize the relationship between adalimumab levels and biologic remission during maintenance therapy. METHODS A single-center prospective cross-sectional study was undertaken on Crohns disease patients who had received adalimumab therapy for a minimum of 12 weeks after induction. Data on clinical activity (Harvey-Bradshaw Index), C-reactive protein (CRP), adalimumab drug and antibody levels, and fecal calprotectin were collected. Biologic remission was defined as a CRP <5 mg/L and fecal calprotectin <250 µg/g. Adalimumab drug and antibody levels were processed using the Immundiagnostik monitor enzyme-linked immunosorbent assay. RESULTS One hundred fifty-two patients had drug and antibody samples matched with CRP and fecal calprotectin. Patients in biologic remission had significantly higher adalimumab levels compared with others (12.0 µg/mL vs 8.0 µg/mL, P < 0.0001). Receiver operating characteristic curve analysis demonstrated an optimal adalimumab level of >8.5 µg/mL (sensitivity, 82.2%; specificity, 55.7%; likelihood ratio, 1.9) for predicting biologic remission. Multivariable logistic regression revealed that adalimumab levels >8.5 µg/mL were independently associated with biologic remission (odds ratio, 5.27; 95% confidence interval, 2.43-11.44; P < 0.0001). CONCLUSIONS Higher adalimumab levels are associated with biologic remission. An optimal level of >8.5 µg/mL was identified.

1128 A Trial With Mercaptopurine Following Azathioprine Intolerance is a Safe Treatment Strategy for the Majority of Patients With IBD

Introduction Azathioprine intolerance (AZA-I) leads to withdrawal of therapy in up to 30% of patients with IBD. Smaller case series demonstrated that mercaptopurine (MP) could be a well tolerated alternative in selected patients. 1 This study aims to further assess its tolerability, in a larger cohort of AZA-I patients, over a longer period of time, and to re-evaluate potential factors predictive of tolerance. Methods A retrospective audit was made of 137 patients with IBD (78 women, median age at diagnosis 32 years, 78 with CD, 59 with UC) who had been intolerant of AZA and then subsequently treated with MP. Results MP was tolerated by 58% of AZA-I patients (median follow-up 937 days, median dose 0.91 mg/kg). Tolerance was highest in patients with AZA related gastrointestinal intolerance (66%) and hepatotoxicity (61%), and lowest in patients with AZA related flu-like illness (40%). The number of patients with AZA induced neutropenia and pancreatitis were too small to draw firm conclusions (see Abstract PTU-122 table 1). Age at diagnosis was significantly associated with tolerability. Patients intolerant of MP were younger (28 vs 33 yro; p=0.024) and of those under the age of 40 only 55% tolerated MP compared with 69% of those aged 40 years or over (p=Azathioprine-intolerant patients, subsequently treated with mercaptopurine (AZA-I/MP) grouped by azathioprine intolerance Conclusion Consistent with previous data, this, the largest series to date, with substantial follow- up, has shown that MP is a safe alternative for up to 60% of AZA-I patients, including some with a previous major intolerance. Patients with previous gastrointestinal intolerance or hepatotoxicity may be more likely to tolerate a trial of MP. Competing interests None declared. Reference 1. Lees , et al. Aliment Pharmacol & Ther 2007; 27 :220–7.

Sa1241 Acute Severe Ulcerative Colitis: the Last Twelve Years in Edinburgh

Background Acute severe ulcerative colitis (ASUC) remains a common reason for urgent colectomy, yet there are relatively few large cohort studies exploring prognosis and outcome. This study aims to examine presentation and management of ASUC in the Western General Hospital, a tertiary referral centre in Edinburgh, UK and to identify prognostic factors. Methods Patients were identified from a large database of participants in genetic studies in Edinburgh, as well as from two previous small cohorts of ASUC studied in Edinburgh. More recent cases were found from minutes of a weekly IBD meeting. Cases were included if they met the standard clinical, radiological and pathological criteria for ulcerative colitis and required an admission for 3 days or more requiring intravenous corticosteroids and/or colectomy. Two cohorts were analysed, one with full clinical detail (97 admissions in 86 patients) and one with more basic detail (444 admissions in 323 patients). Results Overall colectomy rate was 31.8%. Haemoglobin, C-reactive protein and albumin at days 0 and 3 were significant predictors of colectomy in both cohorts (p<0.05 in each case), while in the detailed cohort day 3 but not day 0 stool frequency was predictive (p<0.001 and 0.81 respectively). A simple score was derived to predict colectomy at admission based on disease extent, albumin and CRP. Scores of 0, 1, 2 and 3 corresponded to risks for colectomy of 10%, 31%, 61% and 75%. For day 3 parameters, both the Edinburgh acute colitis (Ho) score (figure 1) and Travis criteria performed well. Conclusions ASUC remains an important cause of colectomy. This study confirms the prognostic value of the Ho score and Travis criteria at day 3, but also indicates that day 0 CRP and albumin are strong predictors of outcome.