Early thiopurine maintenance is associated with reduced proximal disease progression and colectomy rate in ulcerative colitis.

BACKGROUND: Thiopurines effectively maintain remission in ulcerative colitis patients. Whether early initiation of thiopurines after ulcerative colitis diagnosis decreases proximal disease progression and colectomy rates is not known. METHODS: We conducted a cohort study of ulcerative colitis subjects recruited from 1970 to 2009. Early thiopurine maintenance was defined as commencement of azathioprine or mercaptopurine within 5 years of diagnosis and maintenance for at least 6 months. Propensity score matching was conducted to correct for confounders influencing early thiopurine introduction. Outcomes of interest were colectomy rate and endoscopic proximal disease extension. RESULTS: 982 consecutive ulcerative colitis subjects (12 879 patient-years) were recruited with 116 requiring colectomy. Thiopurines initiation and maintenance increased over time with median time to thiopurine commencement decreasing from 23 years in the first decade to 2 years in the last decade (P < 0.0001). Multivariate analysis showed that early thiopurine maintenance significantly decreased the need for colectomy [hazard ratio, 0.13; 95% confidence interval (CI):0.03-0.55; P = 0.006]. The number of subjects needed to be treated to reduce one colectomy at 5 and 10 years was 18 (95% CI, 16- 36) and 12 (95% CI, 11-25). After propensity score matching, early thiopurine maintenance was significantly associated with decreased colectomy (hazard ratio, 0.10; 95% CI, 0.03-0.43; P = 0.002) and proximal progression of disease extent (hazard ratio, 0.26; 95% CI, 0.10-0.78; P = 0.015). CONCLUSION: Early thiopurine maintenance for >6 months is significantly associated with reduced colectomy and proximal progression of disease extent in ulcerative colitis.

Comorbidities Rather Than Age Are Associated With the Use of Immunomodulators in Elderly-onset Inflammatory Bowel Disease.

BACKGROUND AND AIM: The use of immunomodulators (IMs) is often avoided in elderly patients with inflammatory bowel disease (IBD) due to concerns about complications. Our aim is to compare the use of IMs in elderly and younger patients with Crohn's disease (CD) or ulcerative colitis (UC) and identify markers that predict their use. METHODS: In this retrospective cohort study, patients diagnosed with IBD from 1970 to 2009 were recruited from the "Sydney IBD Cohort." Patients diagnosed at age 60 years old or older and between 16 and old 40 years were classified as "elderly-onset" and "young-onset" respectively. RESULTS: A total of 255 elderly-onset patients (115 CD, 140 UC) and 1244 young-onset patients (657 CD, 587 UC) were recruited. Most elderly-onset patients had colonic CD (61.4%), whereas young-onset patients had predominantly ileocolonic CD (42.8%, P < 0.0001). Left-sided UC was the most common disease localization for both elderly-onset (52.1%) and young-onset patients (42.2%, P = 0.013). The cumulative probability of IM exposure at 5 years post-diagnosis was significantly less in elderly-onset patients compared with young-onset patients for CD (20.0% vs 33.4%, P = 0.0002) and UC (7.8% vs 13.4%, P = 0.0007). Age at diagnosis was not associated with the time to IMs introduction. Charlson Comorbidity Index was shown to delay IM introduction in CD (hazard ratio [HR] 0.863; 95% CI, 0.787-0.946; P = 0.002) and UC (HR 0.807; 95% CI, 0.711-0.917; P = 0.001). Early IM use was associated with reduced need for abdominal and perianal surgery in CD (HR 0.177; 95% CI, 0.089-0.351; P < 0.0001). CONCLUSIONS: Comorbidity and not age at diagnosis is associated with IM introduction. Early IM is associated with reduced surgery in both young- and elderly-onset CD but not UC.

Pediatric-to-adult Transition and Medication Adherence in Patients with Inflammatory Bowel Disease.

BACKGROUND: Medication nonadherence is common in inflammatory bowel disease and is associated with poor outcomes. There has been no study on pediatric-to-adult transition as a risk factor for nonadherence in inflammatory bowel disease, which has been demonstrated in other diseases. We aimed to assess whether transitioned (TR) patients have higher nonadherence rates than young adults (YAs) diagnosed in adulthood. METHODS: Consecutive ambulatory subjects were prospectively recruited and completed the validated Medication Adherence Reporting Scale (MARS), with the primary outcome being adherence differences between group age-matched TR and YA groups. Pediatric subjects were taken as the control group. Perceptions of medication-related necessity and concerns were assessed with the Beliefs about Medicines Questionnaire (BMQ). Nonadherers (defined as MARS ≤16) received the Inflammatory Bowel Diseases Pharmacist Adherence Counselling (IPAC) intervention and adherence change was reassessed after 6 months as a secondary outcome. RESULTS: Adherence in TR patients (n = 38, mean age 20.4, 13.2% nonadherent) was noninferior to and numerically better than YAs diagnosed in adulthood (n = 41, mean age 21.2, 24.4%). Nonadherence in the pediatric control group (n = 50, mean age 14.7) was 8.0%. YAs had significantly higher medication-related concerns (14.6 versus 11.9, P = 0.02) than the pediatric group. The IPAC intervention reduced nonadherence rates by 60% (P = 0.004). CONCLUSIONS: TR patients did not have worse adherence than YAs diagnosed in adulthood. Protective factors may include previous treatment in pediatric centers and the salient symptomatology of inflammatory bowel disease, whereas increasing concerns over medications contribute to nonadherence in YAs. Pharmacist-led counselling improves adherence in these patients.

A prospective evaluation of levofloxacin-based triple therapy for refractory Helicobacter pylori infection in Australia.

BACKGROUND: First-line Helicobacter pylori eradication failure is a common and challenging problem. AIM: To assess the efficacy of salvage levofloxacin-based triple therapy in Australia. METHODS: Prospective patients referred after prior treatment failure(s) were prescribed esomeprazole 40 mg, amoxicillin 1 g and levofloxacin 500 mg each twice daily for 10 days. All patients received detailed written and verbal adherence support. Outcome assessment was by 13 C-urea breath test and/or histology and urease test. RESULTS: In 150 consecutive, evaluable patients (66% female, mean age 54 ± 14 years; six smokers), the main indications for treatment were peptic ulcer disease (17%), increased gastric cancer risk (20%), symptoms (35%) and other risk reduction (28%). The median number of previous treatments was 2 (range 1-7). Eradication of H. pylori was achieved in 90% (intention to treat (ITT)) and 91% (per-protocol (PP)) of patients. The eradication rate did not differ according to the type or number of prior treatments: 93% when ≤2 (n = 107) compared with 84% after three or more prior treatments (n = 43; P = 0.13) or with age, ethnicity or indication for treatment but it was higher in females (ITT 94 vs 82%, P = 0.04). Adherence was excellent (95%). No serious adverse effects were observed; mild adverse effects were reported in 11%. No primary levofloxacin resistance was observed in 20 concurrent cases. CONCLUSION: The efficacy and safety of this levofloxacin-based triple therapy suggests it should be used as a salvage regimen in this region. Randomised comparative trials are unlikely to be done but these data compare favourably with local data for other salvage therapies.

Full-Spectrum Endoscopy Improves Surveillance for Dysplasia in Patients With Inflammatory Bowel Diseases.

BACKGROUND & AIMS: Inflammatory bowel diseases (IBDs) increase the risk of colorectal cancer. Surveillance colonoscopy with chromoendoscopy is recommended, but conventional forward-viewing colonoscopy (FVC) detects dysplasia with low levels of sensitivity. Full-spectrum endoscopy (FUSE) incorporates 2 additional lateral cameras to the forward camera of the colonoscope, allowing endoscopists to view behind folds and in blind spots, which might increase dysplasia detection. We compared FUSE vs FVC in the detection of dysplasia in patients with IBDs. METHODS: We performed a prospective, randomized, cross-over, tandem colonoscopy study comparing FVC vs FUSE in 52 subjects with IBD undergoing surveillance for neoplasia in Australia (23 with Crohn's colitis, 29 with ulcerative colitis; median age, 45.0 y; 60% male; mean IBD duration, 16.4 y). All subjects met national IBD surveillance inclusion criteria; 27 were assigned randomly to groups that underwent FVC followed by FUSE, and 25 were assigned to groups that underwent FUSE followed by FVC. All procedures were performed from February 2014 through December 2015. Random biopsy specimens were collected and visible lesions were collected; all were analyzed histologically. The primary end point was dysplasia missed by the first colonoscopy detected by the second colonoscopy. Dysplasia was diagnosed by an expert gastrointestinal pathologist blinded to the colonoscope allocation in consensus with a second expert pathologist. RESULTS: FVC missed 71.4% of dysplastic lesions per lesion whereas FUSE missed 25.0% per lesion (P = .0001); FVC missed 75.0% of dysplastic lesions per subject and FUSE missed 25.0% per subject (P = .046). FUSE identified a mean of 0.37 dysplastic lesions and FVC identified a mean of 0.13 dysplastic lesions (P = .044). The total colonoscopy times were similar (21.2 min for FUSE vs 19.1 min for FVC; P = .32), but withdrawal time was significantly longer for FUSE (15.8 min) than for FVC (12.0 min) (P = .03). Correcting for per-unit withdrawal time, the mean dysplasia miss rate per subject was significantly lower for FUSE (0.19) than for FVC (0.83; P < .0001). Targeted tissue acquisition identified significantly more dysplastic lesions than random biopsies (P < .0001). CONCLUSIONS: In a prospective cross-over study of IBD patients undergoing surveillance colonoscopy, we found panoramic views obtained by full-spectrum endoscopy increased the number of dysplastic lesions detected, compared with conventional forward-viewing colonoscopy. Trial no: ACTRN12616000047493.

Early use of thiopurines or methotrexate reduces major abdominal and perianal surgery in Crohn's disease.

BACKGROUND: Earlier introduction of immunomodulators (IM) thiopurine or methotrexate is advocated to improve Crohn's disease (CD) outcomes, but whether abdominal surgery can be prevented remains controversial. METHODS: A specialist-referred cohort of CD was recruited from 1970 to 2009. Early IM use was defined as commencement of azathioprine or methotrexate within 3 years of CD diagnosis and adherence of at least 6 months. Propensity score matching was conducted to correct for confounders influencing early IM introduction. Outcomes of interest were rates of initial and recurrent major abdominal surgery for CD and their predictive factors. RESULTS: A total of 1035 consecutive patients with CD (13,061 patient-years) were recruited. The risk of first and recurrent major abdominal surgery at 1, 5, and 10 years were 17.5%, 28.4%, and 39.5% and 5.9%, 19.0%, and 33.3%, respectively. Early IM use increased over time from 1.3% to 55.3% (P < 0.0001) and was a significant independent predictor of lower rates of initial abdominal surgery (hazard ratio [HR], 0.45; 95% confidence interval [CI], 0.35-0.69), recurrent abdominal surgery (HR, 0.44; 95% CI, 0.25-0.79) and perianal surgery (HR, 0.30; 95% CI, 0.16-0.56). Using propensity score matching, early IM significantly reduced surgical rates (HR, 0.54; 95% CI, 0.37-0.79). Number needed to treat to prevent a surgical event at 5 years from diagnosis and after initial surgery was 6.99 (95% CI, 5.34-11.95) and 8.59 (95% CI, 6.26-23.93), respectively. CONCLUSIONS: Early IM use with thiopurines or methotrexate was significantly associated with the reduced need for abdominal and perianal surgery in CD.

The value of age and medical history for predicting colorectal cancer and adenomas in people referred for colonoscopy.

BACKGROUND: Colonoscopy is an invasive and costly procedure with a risk of serious complications. It would therefore be useful to prioritise colonoscopies by identifying people at higher risk of either cancer or premalignant adenomas. The aim of this study is to assess a model that identifies people with colorectal cancer, advanced, large and small adenomas. METHODS: Patients seen by gastroenterologists and colorectal surgeons between April 2004 and December 2006 completed a validated, structured self-administered questionnaire prior to colonoscopy. Information was collected on symptoms, demographics and medical history. Multinomial logistic regression was used to simultaneously assess factors associated with findings on colonoscopy of cancer, advanced adenomas and adenomas sized 6 -9 mm, and ≤ 5 mm. The area under the curve of ROC curve was used to assess the incremental gain of adding demographic variables, medical history and symptoms (in that order) to a base model that included only age. RESULTS: Sociodemographic variables, medical history and symptoms (from 8,204 patients) jointly provide good discrimination between colorectal cancer and no abnormality (AUC 0.83), but discriminate less well between adenomas and no abnormality (AUC advanced adenoma 0.70; other adenomas 0.67). Age is the dominant risk factor for cancer and adenomas of all sizes. Having a colonoscopy within the last 10 years confers protection for cancers and advanced adenomas. CONCLUSIONS: Our models provide guidance about which factors can assist in identifying people at higher risk of disease using easily elicited information. This would allow colonoscopy to be prioritised for those for whom it would be of most benefit.

Most bowel cancer symptoms do not indicate colorectal cancer and polyps: a systematic review.

BACKGROUND: Bowel symptoms are often considered an indication to perform colonoscopy to identify or rule out colorectal cancer or precancerous polyps. Investigation of bowel symptoms for this purpose is recommended by numerous clinical guidelines. However, the evidence for this practice is unclear. The objective of this study is to systematically review the evidence about the association between bowel symptoms and colorectal cancer or polyps. METHODS: We searched the literature extensively up to December 2008, using MEDLINE and EMBASE and following references. For inclusion in the review, papers from cross sectional, case control and cohort studies had to provide a 2×2 table of symptoms by diagnosis (colorectal cancer or polyps) or sufficient data from which that table could be constructed. The search procedure, quality appraisal, and data extraction was done twice, with disagreements resolved with another reviewer. Summary ROC analysis was used to assess the diagnostic performance of symptoms to detect colorectal cancer and polyps. RESULTS: Colorectal cancer was associated with rectal bleeding (AUC 0.66; LR+ 1.9; LR- 0.7) and weight loss (AUC 0.67, LR+ 2.5, LR- 0.9). Neither of these symptoms was associated with the presence of polyps. There was no significant association of colorectal cancer or polyps with change in bowel habit, constipation, diarrhoea or abdominal pain. Neither the clinical setting (primary or specialist care) nor study type was associated with accuracy.Most studies had methodological flaws. There was no consistency in the way symptoms were elicited or interpreted in the studies. CONCLUSIONS: Current evidence suggests that the common practice of performing colonoscopies to identify cancers in people with bowel symptoms is warranted only for rectal bleeding and the general symptom of weight loss. Bodies preparing guidelines for clinicians and consumers to improve early detection of colorectal cancer need to take into account the limited value of symptoms.

Non-invasive estimation of liver fibrosis in non-alcoholic fatty liver disease using the 13 C-caffeine breath test.

BACKGROUND AND AIM: Fibrotic progression in non-alcoholic fatty liver disease (NAFLD) is associated with impaired hepatic function. The (13) C-caffeine breath test (CBT) is a non-invasive, quantitative test of liver function. We sought to determine the utility of the CBT in detecting hepatic fibrosis in NAFLD. METHODS: The CBT was applied to 48 patients with NAFLD. CBT results were compared to clinical, biochemical and histological data. Twenty-four healthy subjects served as controls. RESULTS: Patients with simple steatosis had similar CBT values (2.28 ± 0.71 Δ‰ per 100 mg caffeine) to controls (2.31 ± 0.85, P = 1.0). However, CBT was significantly reduced in patients with non-alcoholic steatohepatitis (1.59 ± 0.65, P = 0.005) and cirrhosis (1.00 ± 0.73, P < 0.001). CBT significantly correlated with Brunt's fibrosis score (r = -0.49, P < 0.001) but not with steatosis (P = 0.23) or inflammation (P = 0.08). CBT also correlated with international normalized ratio (r = -0.61, P < 0.001), albumin (r = 0.37, P = 0.009), aspartate aminotransferase/alanine aminotransferase (r = -0.34, P = 0.018) and platelets (r = 0.31, P = 0.03). On multivariate analysis, age (odds ratio 1.12, 95% confidence interval 1.042-1.203, P = 0.002) and CBT (OR 0.264, 95% CI 0.084-0.822, P = 0.02) were independent predictors of significant fibrosis (F ≥ 2). CBT yielded an area under the receiver operating characteristic curve of 0.86 for the diagnosis of cirrhosis. CONCLUSIONS: The CBT reflects the extent of hepatic fibrosis in NAFLD and represents a non-invasive predictor of fibrosis severity in this condition.

Prevention of peptic ulcers with esomeprazole in patients at risk of ulcer development treated with low-dose acetylsalicylic acid: a randomised, controlled trial (OBERON).

OBJECTIVE: To determine whether once-daily esomeprazole 40 mg or 20 mg compared with placebo reduces the incidence of peptic ulcers over 26 weeks of treatment in patients taking low-dose acetylsalicylic acid (ASA) and who are at risk for ulcer development. DESIGN: Multinational, randomised, blinded, parallel-group, placebo-controlled trial. SETTING: Cardiology, primary care and gastroenterology centres (n=240). PATIENTS: Helicobacter pylori-negative patients taking daily low-dose ASA (75-325 mg), who fulfilled one or more of the following criteria: age ≥18 years with history of uncomplicated peptic ulcer; age ≥60 years with either stable coronary artery disease, upper gastrointestinal symptoms and five or more gastric/duodenal erosions, or low-dose ASA treatment initiated within 1 month of randomisation; or age ≥65 years. All patients were ulcer-free at study entry. INTERVENTIONS: Once-daily, blinded treatment with esomeprazole 40 mg, 20 mg or placebo for 26 weeks. MAIN OUTCOME MEASURES: The primary end point was the occurrence of endoscopy-confirmed peptic ulcer over 26 weeks. RESULTS: A total of 2426 patients (52% men; mean age 68 years) were randomised. After 26 weeks, esomeprazole 40 mg and 20 mg significantly reduced the cumulative proportion of patients developing peptic ulcers; 1.5% of esomeprazole 40 mg and 1.1% of esomeprazole 20 mg recipients, compared with 7.4% of placebo recipients, developed peptic ulcers (both p<0.0001 vs placebo). Esomeprazole was generally well tolerated. Conclusions Acid-suppressive treatment with once-daily esomeprazole 40 mg or 20 mg reduces the occurrence of peptic ulcers in patients at risk for ulcer development who are taking low-dose ASA. Clinical trial registration number ClinicalTrials.gov identifier: NCT00441727.

Management of reflux symptoms with over-the-counter proton pump inhibitors: issues and proposed guidelines.

BACKGROUND: Symptoms of gastroesophageal reflux are widely prevalent. There is a continuum between subjects with mild reflux symptoms and those severely affected by gastroesophageal reflux disease (GERD). Both groups may at times access over-the-counter (OTC) therapies. For the purpose of this review, relevant papers, including national and international guidelines were reviewed and recommendations made for appropriate use of OTC proton pump inhibitor (PPI) therapy. RESULTS: PPIs are the gold standard for treatment of reflux symptoms. OTC therapy with histamine(2) receptor antagonists (H2RAs) also plays a role. For the majority affected by reflux symptoms, effective symptom control is the most important outcome, as only a subgroup requires investigations or interventions. However, patients with alarm features (i.e. troublesome dysphagia, weight loss, predominant upper abdominal pain) are not recommended for OTC therapy and need prompt medical referral. Frequent relapses or failure to adequately respond to OTC therapy are additional triggers for medical assessment. CONCLUSIONS: OTC treatment of typical reflux symptoms (acid regurgitation, heartburn) with antacids and H2RAs is now accepted as safe and results in short-term relief of symptoms. There is no evidence of additional risk with OTC PPIs compared to these existing OTC therapies and PPIs are significantly more efficacious.

A self administered reliable questionnaire to assess lower bowel symptoms.

BACKGROUND: Bowel symptoms are considered indicators of the presence of colorectal cancer and other bowel diseases. Self administered questionnaires that elicit information about lower bowel symptoms have not been assessed for reliability, although this has been done for upper bowel symptoms. Our aim was to develop a self administered questionnaire for eliciting the presence, nature and severity of lower bowel symptoms potentially related to colorectal cancer, and assess its reliability. METHODS: Immediately before consulting a gastroenterologist or colorectal surgeon, 263 patients likely to have a colonoscopy completed the questionnaire. Reliability was assessed in two ways: by assessing agreement between patient responses and (a) responses given by the doctor at the consultation; and (b) responses given by patients two weeks later. RESULTS: There was more than 75% agreement for 78% of the questions for the patient-doctor comparison and for 92% of the questions for the patient-patient comparison. Agreement for the length of time a symptom was present, its severity, duration, frequency of occurrence and whether or not medical consultation had been sought, all had agreement of greater than 70%. Over all questions, the chance corrected agreement for the patient-doctor comparison had a median kappa of 65% (which represents substantial agreement), interquartile range 57-72%. The patient-patient comparison also showed substantial agreement with a median kappa of 75%, interquartile range 68-81%. CONCLUSION: This self administered questionnaire about lower bowel symptoms is a useful way of eliciting details of bowel symptoms. It is a reliable instrument that is acceptable to patients and easily completed. Its use could guide the clinical consultation, allowing a more efficient, comprehensive and useful interaction, ensuring that all symptoms are assessed. It will also be a useful tool in research studies on bowel symptoms and their predictive value for colorectal cancer and other diseases. Studies assessing whether bowel symptoms predict the presence of colorectal cancer should provide estimates of the reliability of the symptom elicitation.

Defining the relationship between gastroesophageal reflux and cough: probabilities, possibilities and limitations.

The common co-existence of cough and gastroesophageal reflux disease (GORD) is well established. However, ascertaining cause and effect is more difficult for many reasons that include occurrence by chance of two common symptoms, the changing definition of GORD, equipment limitations and the lack of randomised controlled trials. Given these difficulties, it is not surprising that there is disparity of opinion between respiratory and gastroenterology society guidelines on the link between GORD and chronic cough. This commentary explores of these issues.

Small bowel adenocarcinoma with high levels of microsatellite instability in Crohn's disease.

Microsatellite instability (MSI) is a hallmark of carcinomas occurring in the setting of hereditary nonpolyposis colorectal cancer, but can also be found in sporadic and colitis-associated tumors. The incidence of MSI in Crohn's disease is unknown and has usually been reported in the colon. We report the case of a 26-year-old man, diagnosed 4 years earlier with Crohn's disease, who developed an associated small bowel adenocarcinoma. The tumor was found to have high levels of MSI by immunohistochemical staining and by MSI testing. No mutations were identified by genetic testing, and high levels of MSI are most probably due to hypermethylation.

Effect of Helicobacter pylori infection and low-dose aspirin use on iron stores in the elderly.

BACKGROUND AND AIMS: Helicobacter pylori infection has been associated with lower ferritin levels in some adult populations, but subsets of potentially higher risk subjects, such as the elderly have not been examined. The aim of the present study was to determine the impact of H. pylori infection and low-dose aspirin use on iron stores in a well elderly population. METHODS: Consecutive subjects aged 65 years or older attending day care facilities were studied. Each subject was assisted in completing a medical questionnaire. Serum ferritin, hemoglobin, mean corpuscular volumes (MCV) and IgG antibodies (ELISA) against H. pylori were measured. RESULTS: In 220 subjects (age 75 +/- 8 years), 42% were H. pylori seropositive (male 41%, female 44%). The median (IQR) ferritin level (ug/L) was higher in men 149 (89-280) than women 94 (54-161), p < 0.002. The ferritin levels were not different in H. pylori positive males 151 (105-283) compared with H. pylori negative males 145 (72-249), or H. pylori positive females 93 (60-142) compared with H. pylori negative females 97 (45-149). This relationship was not altered when controlled for non-steroidal anti-inflammatory agents (NSAID) use (9% of subjects), alcohol or dietary iron intake. Low-dose aspirin use was common (28%), but did not have an independent impact on iron stores: male users 181 (95-248), non-users 145 (86-284); female users 92 (43-162), non-users 95 (62-163). However, in female aspirin users, H. pylori infection was associated with significantly lower ferritin levels: 65 (43-112) compared with uninfected subjects 103 (41-180), p < 0.04. CONCLUSIONS: In this well elderly population, the combination of H. pylori infection and low-dose aspirin use was associated with significantly lower serum ferritin concentrations in females. This difference supports the observation that H. pylori, even in asymptomatic subjects, may be a stressor of iron stores.