Amy L. Hamilton

Crohn's disease management after intestinal resection: a randomised trial.

BACKGROUND Most patients with Crohns disease need an intestinal resection, but a majority will subsequently experience disease recurrence and require further surgery. This study aimed to identify the optimal strategy to prevent postoperative disease recurrence. METHODS In this randomised trial, consecutive patients from 17 centres in Australia and New Zealand undergoing intestinal resection of all macroscopic Crohns disease, with an endoscopically accessible anastomosis, received 3 months of metronidazole therapy. Patients at high risk of recurrence also received a thiopurine, or adalimumab if they were intolerant to thiopurines. Patients were randomly assigned to parallel groups: colonoscopy at 6 months (active care) or no colonoscopy (standard care). We used computer-generated block randomisation to allocate patients in each centre to active or standard care in a 2:1 ratio. For endoscopic recurrence (Rutgeerts score ≥i2) at 6 months, patients stepped-up to thiopurine, fortnightly adalimumab with thiopurine, or weekly adalimumab. The primary endpoint was endoscopic recurrence at 18 months. Patients and treating physicians were aware of the patients study group and treatment, but central reading of the endoscopic findings was undertaken blind to the study group and treatment. Analysis included all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, number NCT00989560. FINDINGS Between Oct 13, 2009, and Sept 28, 2011, 174 (83% high risk across both active and standard care groups) patients were enrolled and received at least one dose of study drug. Of 122 patients in the active care group, 47 (39%) stepped-up treatment. At 18 months, endoscopic recurrence occurred in 60 (49%) patients in the active care group and 35 (67%) patients in the standard care group (p=0.03). Complete mucosal normality was maintained in 27 (22%) of 122 patients in the active care group versus four (8%) in the standard care group (p=0.03). In the active care arm, of those with 6 months recurrence who stepped up treatment, 18 (38%) of 47 patients were in remission 12 months later; conversely, of those in remission at 6 months who did not change therapy recurrence occurred in 31 (41%) of 75 patients 12 months later. Smoking (odds ratio [OR] 2.4, 95% CI 1.2-4.8, p=0.02) and the presence of two or more clinical risk factors including smoking (OR 2.8, 95% CI 1.01-7.7, p=0.05) increased the risk of endoscopic recurrence. The incidence and type of adverse and severe adverse events did not differ significantly between patients in the active care and standard care groups (100 [82%] of 122 vs 45 [87%] of 52; p=0.51) and (33 [27%] of 122 vs 18 [35%] of 52; p=0.36), respectively. INTERPRETATION Treatment according to clinical risk of recurrence, with early colonoscopy and treatment step-up for recurrence, is better than conventional drug therapy alone for prevention of postoperative Crohns disease recurrence. Selective immune suppression, adjusted for early recurrence, rather than routine use, leads to disease control in most patients. Clinical risk factors predict recurrence, but patients at low risk also need monitoring. Early remission does not preclude the need for ongoing monitoring. FUNDING AbbVie, Gutsy Group, Gandel Philanthropy, Angior Foundation, Crohns Colitis Australia, and the National Health and Medical Research Council.

Efficacy of thiopurines and adalimumab in preventing Crohn's disease recurrence in high‐risk patients – a POCER study analysis

Crohns disease recurs in the majority of patients after intestinal resection.

Microbial Factors Associated with Postoperative Crohn’s Disease Recurrence

Background and Aims: The intestinal microbiota is a key antigenic driver in Crohn’s disease [CD]. We aimed to identify changes in the gut microbiome associated with, and predictive of, disease recurrence and remission. Methods: A total of 141 mucosal biopsy samples from 34 CD patients were obtained at surgical resection and at colonoscopy 6 and/or 18 months postoperatively; 28 control samples were obtained: 12 from healthy patients [healthy controls] and 16 from hemicolectomy patients [surgical controls]. Bacterial 16S ribosomal profiling was performed using the Illumina MiSeq platform. Results: CD was associated with reduced alpha diversity when compared with healthy controls but not surgical controls [p < 0.001 and p = 0.666, respectively]. Beta diversity [composition] differed significantly between CD and both healthy [p < 0.001] and surgical [p = 0.022] controls, but did not differ significantly between those with and without endoscopic recurrence. There were significant taxonomic differences between recurrence and remission. Patients experiencing recurrence demonstrated elevated Proteus genera [p = 0.008] and reduced Faecalibacterium [p< 0.001]. Active smoking was associated with elevated levels of Proteus [p = 0.013] postoperatively. Low abundance of Faecalibacterium [< 0.1%] and detectable Proteus in the postoperative ileal mucosa was associated with a higher risk of recurrence (odds ratio [OR] 14 [1.7–110], p = 0.013 and 13 [1.1–150], p = 0.039, respectively) when corrected for smoking. A model of recurrence comprising the presence of Proteus, abundance of Faecalibacterium, and smoking status showed moderate accuracy (area under the curve [AUC] 0.740, 95% confidence interval [CI] [0.69–0.79]). Conclusions: CD is associated with a microbial signature distinct from health. Microbial factors and smoking independently influence postoperative CD recurrence. The genus Proteus may play a role in the development of CD.

Visceral adiposity predicts post‐operative Crohn's disease recurrence

Excessive visceral adipose tissue has been associated with poorer outcomes in patients with inflammatory bowel disease.

Effect of intestinal resection on quality of life in Crohn's disease.

INTRODUCTION Patients with Crohns disease have poorer health-related quality of life [HRQoL] than healthy individuals, even when in remission. Although HRQoL improves in patients who achieve drug-induced or surgically induced remission, the effects of surgery overall have not been well characterised. METHODS In a randomised trial, patients undergoing intestinal resection of all macroscopically diseased bowel were treated with postoperative drug therapy to prevent disease recurrence. All patients were followed prospectively for 18 months. C-reactive protein [CRP], Crohns Disease Activity Index [CDAI], and faecal calprotectin [FC] were measured preoperatively and at 6, 12, and 18 months. HRQoL was assessed with a general [SF36] and disease-specific [IBDQ] questionnaires at the same time points. RESULTS A total of 174 patients were included. HRQoL was poor preoperatively but improved significantly [p < 0.001] at 6 months postoperatively. This improvement was sustained at 18 months. Females and smokers had a poorer HRQoL when compared with males and non-smokers, respectively. Persistent endoscopic remission, intensification of drug treatment at 6 months, and anti-tumour necrosis factor therapy were not associated with HRQoL outcomes different from those when these factors were not present. There was a significant inverse correlation between CDAI, [but not endoscopic recurrence, CRP, or FC] on HRQoL. CONCLUSION Intestinal resection of all macroscopic Crohns disease in patients treated with postoperative prophylactic drug therapy is associated with significant and sustained improvement in HRQoL irrespective of type of drug treatment or endoscopic recurrence. HRQoL is lower in female patients and smokers. A higher CDAI, but not direct measures of active disease or type of drug therapy, is associated with a lower HRQoL.

Comparison of Fecal Inflammatory Markers in Crohn's Disease.

Background:Fecal biomarkers are used increasingly to monitor Crohns disease (CD). However, the relative accuracy of different markers in identifying inflammation has been poorly evaluated. We evaluated fecal calprotectin (FC), lactoferrin (FL), and S100A12 (FS) using endoscopic validation in a prospective study of the progression of CD after intestinal resection. Methods:Data were collected from 135 participants in a prospective, randomized, controlled trial aimed at preventing postoperative CD recurrence. Three hundred nineteen stool samples were tested for FC, FL, and FS preoperatively and 6, 12, and 18 months after resection. Colonoscopy was performed at 6 and/or 18 months. Endoscopic recurrence was assessed blindly using the Rutgeerts score. C-reactive protein (CRP) and Crohns Disease Activity Index (CDAI) were assessed. Results:FC, FL, and FS concentrations were elevated preoperatively (median: 1347, 40.9, and 8.4 &mgr;g/g, respectively). At 6 months postoperatively, marker concentrations decreased (166, 3.0, 0.9 &mgr;g/g) and were higher in recurrent disease than remission (275 versus 72 &mgr;g/g, P < 0.001; 5.7 versus 1.6 &mgr;g/g, P = 0.007; 2.0 versus 0.8 &mgr;g/g, P = 0.188). FC > 135 &mgr;g/g, FL > 3.4 &mgr;g/g, and FS > 10.5 &mgr;g/g indicated endoscopic recurrence (score ≥ i2) with a sensitivity, specificity, and negative predictive value (NPV) of 0.87, 0.66, and 91%; 0.70, 0.68, and 81%; 0.91, 0.12, and 71%, respectively. FC and FL correlated significantly with the presence and severity of endoscopic recurrence, whereas FS, CRP and CDAI did not. Conclusions:FC was the optimal fecal marker for monitoring disease activity in postoperative CD and was superior to CRP and CDAI. FL offered modest sensitivity for detecting recurrent disease, whereas S100A12 was sensitive but had low specificity and NPV.

Su2092 Clinical Risk Stratification Predicts Development of Endoscopic Recurrence After Crohn's Disease Surgery: Early Results From the POCER Study

G A A b st ra ct s ulcerations at ileocolonoscopy and a history of positive clinical response followed by secondary failure and/or intolerance to at least one TNFα antagonist. Patients randomized in the TNF-K group were receiving TNF-K at days 0, 7, 28, 84 and placebo at days 91 and 112. Patients randomized in the control group were receiving placebo at days 0, 7, 28, and TNFK at days 84, 91 and 112. TNF-K was injected intramuscularly at the dose of 180 mcg per injection. The primary end point was CDAI clinical remission (CDAI≤150) at week 8. Other efficacy end-points included mucosal healing at week 12 and evolution of calprotectin and C-reactive protein. Immune responses were evaluated through titration of anti-TNFα and anti-KLH antibodies. Results: All patients have been recruited. Fewmild or moderate transient local and systemic reactions have been recorded following immunizations. The only serious adverse event reported by the investigator as potentially related to the study drug was a deterioration of CD one month following administration of blinded treatment. There were no other safety concerns. Full analysis is ongoing. Conclusions: Active immunization with TNF-K in patients with Crohns disease is safe. Full immunogenicity and clinical efficacy results will be presented.

Serologic antibodies in relation to outcome in postoperative Crohn's disease

Disease recurs frequently after Crohns disease resection. The role of serological antimicrobial antibodies in predicting recurrence or as a marker of recurrence has not been well defined.

P342 Adalimumab prevents post-operative Crohn's disease recurrence and is superior to thiopurines: Early results from the prospective POCER study

unaffected by TPMT (30.8 vs 33.0 pmol/hb/ml, p = 0.16), site of disease, behaviour, family history, smoking, surgery or, extraintestinal manifestations. Conclusions: 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.

DOP064 Faecal calprotectin is superior to faecal lactoferrin and S100A12

DOP064 Faecal calprotectin is superior to faecal lactoferrin and S100A12 E.K. Wright1 *, P.P. De Cruz1, M.A. Kamm1, A.L. Hamilton1, K.J. Ritchie1, E.O. Krejany1, S.T. Leach2, J.I. Keenan2, A. Gorelik1, D. Liew1, L. Prideaux1, I.C. Lawrance1, J.M. Andrews1, P.A. Bampton1, M.P. Sparrow1, T.H. Florin1, P.R. Gibson1, H.S. Debinski1, F.A. Macrae1, R.W. Leong1, I.J. Kronborg1, G.L. Radford-Smith1, W.S. Selby1, M.J. Johnson1, R.J. Woods1, P.R. Elliott1, S.J. Bell1, S.J. Brown1, W.R. Connell1, A.S. Day2, R.B. Gearry2, P.V. Desmond1. 1St Vincent’s Hospital & University of Melbourne, Gastroenterology, Melbourne, Australia, 2Christchurch Hospital, Gastroenterology, Christchurch, New Zealand