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.

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 Crohn's 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.

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.

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

BACKGROUND: Crohn's 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.

Anti-tumour necrosis factor-alpha treatment for perianal Crohn's disease in Australia.

OBJECTIVE: To examine the prevalence of perianal Crohn's disease (PCD) and the eligibility of PCD patients to access anti-tumour necrosis factor-alpha (anti-TNFalpha) treatment under current Australian Pharmaceutical Benefits Scheme (PBS) guidelines. DESIGN, SETTING AND PARTICIPANTS: A retrospective study of patients with Crohn's disease (CD) and PCD attending four large adult inflammatory bowel disease (IBD) centres in Australia between January 2004 and May 2008. Patients for whom anti-TNFalpha therapy was clinically indicated were assessed to determine whether they satisfied PBS criteria for subsidised medication. MAIN OUTCOME MEASURES: Prevalence of CD and PCD in patients attending different IBD centres; eligibility of PCD patients for PBS-subsidised anti-TNFalpha medication. RESULTS: Data were available on 3589 patients, representing about 6% of all patients with IBD in Australia. Of the 1815 patients with CD, 310 (17%) had PCD. Anti-TNFalpha therapy was deemed clinically indicated for 166 patients with PCD (54%), of whom 49 (30%) did not qualify for PBS-funded therapy. CONCLUSION: Thirty per cent of patients with clinically significant PCD currently do not have access to PBS-subsidised optimal medical treatment. We believe that PBS criteria should be extended to include this subgroup of IBD patients.

Female gender and surgery impair relationships, body image, and sexuality in inflammatory bowel disease: patient perceptions.

BACKGROUND: There is a paucity of literature on the impact of inflammatory bowel disease (IBD) on relationships, body image, and sexual function from a patient perspective. This study sought to describe patients' perceptions of these issues. METHODS: In all, 347 patients, age 18-50 years, from a hospital-based IBD database were surveyed by post. Quantitative and qualitative data were obtained on demographics, relationships, quality of life (QoL), body image, and sexual function. Comparisons were made by diagnosis, gender, and operative status. Univariate and multivariable analyses and logistic regressions were performed; P < 0.05 was regarded as significant. RESULTS: The response rate was 62.5%. Overall, 88.5% reported impaired QoL; 50.2% a negative effect on relationship status; and 66.8% impaired body image (females 74.8% versus males 51.4%, P = 0.0007; operated 81.4% versus nonoperated 51.3%, P = 0.0003). A greater proportion of women reported decreased frequency of sexual activity, as did operated subjects (female 66.3% versus male 40.5%, P < 0.0001; operated 68.5% versus nonoperated 50.4%, P = 0.0113). Women and operated subjects also more often reported decreased libido (female 67.1% versus male 41.9% P = 0.0005; operated 67.4% versus nonoperated 52.6%, P = 0.035). 9.7% omitted medication because of perceived negative effect(s) on sexual function. Logistic regression revealed that female gender negatively affected body image, libido, and sexual activity, while limited resection surgery negatively affected body image (all P < 0.005). CONCLUSIONS: A large proportion of patients perceive IBD to negatively affect many aspects of sexuality. Females and operated subjects more frequently perceived these negative effects. These findings are important in overall clinical care of patients with IBD and should be addressed.

Fear and fertility in inflammatory bowel disease: a mismatch of perception and reality affects family planning decisions.

BACKGROUND: Smaller family size and voluntary childlessness has been reported in IBD; however, the disease-related reasons for this from a patient viewpoint are not described. The aims were to 1) determine whether IBD patients' perceptions of the issues surrounding IBD, pregnancy, and childbearing influence their reproductive behavior, and 2) describe these specific perceptions and concerns related to fertility and pregnancy. METHODS: All contactable subjects between 18-50 years of age from a hospital-based IBD database were surveyed by postal questionnaire. Data were obtained regarding age, gender, IBD diagnosis and treatment, body image and sexual relationships, as well as both objective and subjective data regarding fertility and pregnancy. Comparisons were made to community norms where data were available. Contingency tables with Fisher's exact test were used. RESULTS: Of 365 subjects, 255 responded (70%). The mean age was 35.5 years overall, 34.7 years for women. In all, 34% of participants were male, 127 had Crohn's disease (CD), 85 ulcerative colitis (UC), and 5 indeterminate colitis (IC). The average fertility rate was no different between women with CD and UC (1.0 and 1.2 births/woman, respectively; P = 0.553), compared with 1.81 for all Australian women. Although 42.7% of IBD patients reported a fear of infertility, patients only sought medical fertility advice at the same rate as the general population. Fear of infertility was most evident in women, those with CD, and those reporting previous surgery. Specific patient concerns, which appear to have decreased patients' family size, included IBD heritability, the risk of congenital abnormalities, and medication teratogenicity. CONCLUSIONS: The unusually high response rate indicates the centrality of reproductive issues to IBD patients. "Voluntary" childlessness in this group appears to result from concerns about adverse reproductive outcomes that may not be justified. Patients require accurate counseling addressing fertility and pregnancy outcomes in IBD to assist in their decision making.