Ruth Prosser

Crohn's disease and smoking: Is it ever too late to quit?

BACKGROUND Smoking increases CD risk. The aim was to determine if smoking cessation at, prior to, or following, CD diagnosis affects medication use, disease phenotypic progression and/or surgery. METHODS Data on CD patients with disease for ≥5 yrs were collected retrospectively including the Montreal classification, smoking history, CD-related abdominal surgeries, family history, medication use and disease behaviour at diagnosis and the time when the disease behaviour changed. RESULTS 1115 patients were included across six sites (mean follow-up-16.6 yrs). More non-smokers were male (p=0.047) with A1 (p<0.0001), L4 (p=0.028) and perianal (p=0.03) disease. Non-smokers more frequently received anti-TNF agents (p=0.049). (p=0.017: OR 2.5 95%CI 1.18-5.16) and those who ceased smoking prior to diagnosis (p=0.045: OR 2.3 95%CI 1.02-5.21) progressed to complicated (B2/B3) disease as compared to those quitting at diagnosis. Patients with uncomplicated terminal ileal disease at diagnosis more frequently developed B2/B3 disease than isolated colonic CD (p<0.0001). B2/B3 disease was more frequent with perianal disease (p<0.0001) and if i.v. steroids (p=0.004) or immunosuppressants (p<0.0001) were used. 49.3% (558/1115) of patients required at least one intestinal surgery. More smokers had a 2nd surgical resection than patients who quit at, or before, the 1st resection and non-smokers (p=0.044: HR=1.39 95%CI 1.01-1.91). Patients smoking >3 cigarettes/day had an increased risk of developing B2/B3 disease (p=0.012: OR 3.8 95%CI 1.27-11.17). CONCLUSION Progression to B2/B3 disease and surgery is reduced by smoking cessation. All CD patients regardless of when they were diagnosed, or how many surgeries, should be strongly encouraged to cease smoking.

Infliximab vs. adalimumab in Crohn's disease: results from 327 patients in an Australian and New Zealand observational cohort study

Maintenance anti‐tumour necrosis factor‐α (anti‐TNFα) treatment for Crohns disease is the standard of care for patients with an inadequate response to corticosteroids and immunomodulators.

Inter-observer agreement for Crohn's disease sub-phenotypes using the Montreal Classification: How good are we? A multi-centre Australasian study

BACKGROUND Crohns disease (CD) exhibits significant clinical heterogeneity. Classification systems attempt to describe this; however, their utility and reliability depends on inter-observer agreement (IOA). We therefore sought to evaluate IOA using the Montreal Classification (MC). METHODS De-identified clinical records of 35 CD patients from 6 Australian IBD centres were presented to 13 expert practitioners from 8 Australia and New Zealand Inflammatory Bowel Disease Consortium (ANZIBDC) centres. Practitioners classified the cases using MC and forwarded data for central blinded analysis. IOA on smoking and medications was also tested. Kappa statistics, with pre-specified outcomes of κ>0.8 excellent; 0.61-0.8 good; 0.41-0.6 moderate and ≤0.4 poor, were used. RESULTS 97% of study cases had colonoscopy reports, however, only 31% had undergone a complete set of diagnostic investigations (colonoscopy, histology, SB imaging). At diagnosis, IOA was excellent for age, κ=0.84; good for disease location, κ=0.73; only moderate for upper GI disease (κ=0.57) and disease behaviour, κ=0.54; and good for the presence of perianal disease, κ=0.6. At last follow-up, IOA was good for location, κ=0.68; only moderate for upper GI disease (κ=0.43) and disease behaviour, κ=0.46; but excellent for the presence/absence of perianal disease, κ=0.88. IOA for immunosuppressant use ever and presence of stricture were both good (κ=0.79 and 0.64 respectively). CONCLUSION IOA using MC is generally good; however some areas are less consistent than others. Omissions and inaccuracies reduce the value of clinical data when comparing cohorts across different centres, and may impair the ability to translate genetic discoveries into clinical practice.

PACSIN2 Does Not Influence Thiopurine-Related Toxicity In Patients With Inflammatory Bowel Disease

PACSIN2 Does Not Influence Thiopurine-Related Toxicity In Patients With Inflammatory Bowel Disease

High Vitamin D-Binding Protein Concentration, Low Albumin, and Mode of Remission Predict Relapse in Crohn's Disease

Background:Vitamin D (25(OH)D) deficiency occurs in active Crohns disease (CD) and may be secondary to reduced sunlight exposure and oral intake. Vitamin D–binding protein (VDBP) levels, however, fluctuate less with season and sunlight. The aim, therefore, was to examine patients with CD in remission and determine any associations between VDBP, serum 25(OH)D, and the calculated free 25(OH)D concentrations with the risk of disease flare. Methods:Subjects were identified from prospectively maintained inflammatory bowel disease databases at 3 teaching hospitals in Australia. Patients were in steroid-free clinical remission at the time of blood draw and were followed for at least 12 months. Total and epimer-25(OH)D3, VDBP concentrations, and genotypes were determined. Results:A total of 309 patients with CD (46% men) met the inclusion criteria. A disease flare occurred in 100 (32.4%). Serum 25(OH)D3 was deficient (<50 nmol/L) in 36 (12%) and insufficient (50–75 nmol/L) in 107 (35%) patients. Total, free, and epimer-25(OH)D3 serum levels did not predict disease flare. Higher VDBP concentrations, however, significantly correlated with increased risk of disease flare (hazard ratio 1.2, 95% CI, 1.0–1.5). On multivariate analysis, VDBP concentration, low albumin, and medication-induced remission were significantly more associated with disease flare. VDBP genotypes were significantly associated with 25(OH)D and VDBP concentrations but not disease flare. Conclusions:Vitamin D deficiency was uncommon in our patients with CD in remission, and serum 25(OH)D3 did not predict disease flare, whereas higher VDBP concentrations were significantly associated with disease flare. Further investigations to explore the possible mechanisms for this association are warranted.

Colon cancer surveillance in inflammatory bowel disease: unclear gain but no psychological pain?

Surveillance for colorectal neoplasia in inflammatory bowel disease (IBD) is widely practised despite a lack of convincing mortality reduction. The psychological impact of this approach is largely unexplored.

Nonsynonymous Polymorphism in Guanine Monophosphate Synthetase Is a Risk Factor for Unfavorable Thiopurine Metabolite Ratios in Patients With Inflammatory Bowel Disease

Background Up to 20% of patients with inflammatory bowel disease (IBD) who are refractory to thiopurine therapy preferentially produce 6-methylmercaptopurine (6-MMP) at the expense of 6-thioguanine nucleotides (6-TGN), resulting in a high 6-MMP:6-TGN ratio (>20). The objective of this study was to evaluate whether genetic variability in guanine monophosphate synthetase (GMPS) contributes to preferential 6-MMP metabolizer phenotype. Methods Exome sequencing was performed in a cohort of IBD patients with 6-MMP:6-TGN ratios of >100 to identify nonsynonymous single nucleotide polymorphisms (nsSNPs). In vitro assays were performed to measure GMPS activity associated with these nsSNPs. Frequency of the nsSNPs was measured in a cohort of 530 Caucasian IBD patients. Results Two nsSNPs in GMPS (rs747629729, rs61750370) were detected in 11 patients with very high 6-MMP:6-TGN ratios. The 2 nsSNPs were predicted to be damaging by in silico analysis. In vitro assays demonstrated that both nsSNPs resulted in a significant reduction in GMPS activity (P < 0.05). The SNP rs61750370 was significantly associated with 6-MMP:6-TGN ratios ≥100 (odds ratio, 5.64; 95% confidence interval, 1.01-25.12; P < 0.031) in a subset of 264 Caucasian IBD patients. Conclusions The GMPS SNP rs61750370 may be a reliable risk factor for extreme 6MMP preferential metabolism.

Corrigendum: PACSIN2 Does Not Influence Thiopurine-Related Toxicity in Patients With Inflammatory Bowel Disease.

Corrigendum: PACSIN2 Does Not Influence Thiopurine-Related Toxicity in Patients With Inflammatory Bowel Disease

S1118 Pregnancy, Disease Activity and IBD Medication: This Two-Edged Sword from a Patient Perspective

Background: Ileal pouch anal anastomosis (IPAA) is the surgical treatment of choice for ulcerative colitis (UC) patients. The procedure is safe and effective but is also associated with long term complications such as pouch inflammation (pouchitis) reported in up to 60% of patients. The reasons for pouch inflammation are vague and prediction of pouchitis is still impossible. Normal pouch status is usually defined clinically and there is lack of longitudinal studies investigating the processes occurring in a “normal” pouch. Aim: To evaluate the clinical, laboratory, endoscopic and histologic characteristics of normal pouches longitudinally. Methods: UC Patients undergoing IPAA were prospectively followed up at a pouch clinic. Clinical, laboratory, endoscopic and histologic evaluation was performed at least yearly. Normal pouch status was defined at first visit as no previous episodes of pouchitis and pouch disease activity index (based on clinical, endoscopic and histologic scores, maximum 6 points each)<7 for the first two years of follow up without antibiotic or anti inflammatory treatment. Patients were used as their own controls, thus only patients with≥2 follow up visits were included. Results: Out of 167 pouch patients 25 (15%, 12 males, average age 47.4 ±14.6 years) were recruited to the “normal pouch” cohort. Time since surgery was 8±6.3 (range 3-14). Average number of bowel movements: 6.2±2/day. Fifteen (66%) patients had an elevated ESR or CRP and the average ESR and CRP were 36±21.4 and 6.5±7.8, respectively. Fourteen patients (56%) had an endoscopic score ≥2 and 8 (32%)≥3; Ten patients (40%) had a histologic score≥2 in at least one endoscopy. Moreover, in 9 patients (36%) endoscopic or histologic scores increased over a 5 year follow up. Four patients (16%) developed an episode of pouchitis within 5 years of follow up. Interestingly, in a control group of familial adenomatous polyposis pouch patients, increased inflammatory indices, endoscopic or histologic scores were not observed, and no episodes of pouchitis were reported. Conclusions: An ileal pouch in UC patients is an inflammatory condition per se. Subclinical inflammation exists in the majority of clinically “normal pouch” patients and tends to increase over time. Overt pouchitis developed at a rate of 16%/ five years. The lack of correlation between clinical, endoscopic and histologic scores necessitates their combined use for patient follow up. Anti inflammatory therapeutic interventions may be advised.