Thiopurines and their optimization during infliximab induction and maintenance: A retrospective study in Crohn's disease.

BACKGROUND AND AIM: Combining therapy with a thiopurine is favored when commencing infliximab in Crohn's disease; however, the optimal 6-thioguanine nucleotide (TGN) level and how long to continue thiopurines after induction are uncertain. We aimed to compare outcomes after induction and during maintenance in combination therapy versus infliximab monotherapy in Crohn's and to examine whether TGN levels were associated with outcomes. METHODS: Crohn's patients induced with infliximab with or without concomitant thiopurines were retrospectively identified. Response to induction and clinical outcomes in subsequent 6-month maintenance semesters were analyzed. A TGN level ≥235 pmol/8 × 108 red blood cells was considered therapeutic. RESULTS: In 89 patients, response to induction was higher in combination therapy than monotherapy (74 vs 47%, P = 0.04). This benefit was only seen in patients with a therapeutic TGN (odds ratio 3.72, confidence interval 1.07-13.0, P = 0.04). Combination therapy during induction yielded a three times longer time to subsequent need for treatment escalation or treatment failure compared with monotherapy (29 vs 9 months, P = 0.01), with both therapeutic and subtherapeutic TGNs independent predictors on multivariate analysis. Among 370 semesters, there was no difference in outcomes between combination therapy and monotherapy (P = 0.42), nor when combination semesters were stratified by therapeutic versus subtherapeutic TGN (P = 0.56). In semester 1 only, a significantly higher remission rate was observed with therapeutic compared with subtherapeutic TGN (76% vs 33%, P = 0.02). CONCLUSIONS: Combination therapy dosed with an optimized thiopurine was superior to infliximab monotherapy for induction of response, durability of response, and clinical outcomes in the first 6 months following induction. Thereafter, combination therapy yielded no clinical advantage, supporting consideration of thiopurine withdrawal on a case-by-case basis.

Giant laterally spreading tumors of the duodenum: endoscopic resection outcomes, limitations, and caveats.

BACKGROUND: Giant hemicircumferential and greater nonampullary duodenal adenomas or laterally spreading tumors (LSTs) may be amenable to safe endoscopic resection, but little data exists on outcomes or risk stratification. DESIGN: We interrogated a prospectively maintained database of all patients who underwent endoscopic resection between January 2008 and November 2010. The resection technique was standardized. Major complications were defined as perforation, bleeding requiring readmission with hemoglobin drop of more than 20 g/L, or other substantial deviations from the usual clinical course. Outcomes were analyzed in 2 groups: giant lesions (>30 mm) and conventional duodenal polyps (<30 mm in diameter). Statistical evaluation was performed by using a χ(2) test. RESULTS: A total of 50 nonampullary duodenal polyps and LSTs were resected from 46 patients (23 men, mean age 59.4 years, range 35-83 years). Nineteen were giant hemicircumferential and greater LSTs (mean size 40.5 mm, range 30-80 mm), and 31 were less than 30 mm in diameter (mean size 14.5 mm, range 5-25 mm). Intraprocedural bleeding occurred more frequently in giant lesions (57.8% vs 19.3%, P = .005) and was treated with a combination of soft coagulation and endoscopic clips with hemostasis achieved in all cases. Major complications, mostly bleeding related, occurred in 5 patients (26.3%) with giant lesions and 1 patient (3.2%) with a smaller lesion (P = .014). There were no deaths. LIMITATION: Retrospective observational study in a tertiary center. CONCLUSIONS: Endoscopic resection of giant nonampullary duodenal LSTs is a successful treatment. However, it is hazardous and associated with significantly higher complication rates, primarily bleeding, when compared with conventional duodenal polypectomy. Safer and more effective hemostatic tools are required in this high-risk location.

Circumferential location predicts the risk of high-grade dysplasia and early adenocarcinoma in short-segment Barrett's esophagus.

BACKGROUND: Whether early Barrett's neoplasia has a predilection for particular spatial locations in shorter segment disease is currently unknown. Anatomic factors may play a role in lesion location because of differing levels of mucosal acid exposure. OBJECTIVE: To identify high-risk lesion locations, which has important implications for surveillance strategies. DESIGN: We interrogated a prospectively maintained database of patients who underwent endoscopic resection (ER) for Barrett's neoplasia at 2 Australian tertiary centers. Lesions targeted for ER were characterized and their location in the distal esophagus was noted as on a clock face. A Z test of proportions was used to test for deviation from uniformity in the distribution of lesions. SETTING: Two Australian tertiary centers. PATIENTS: Patients who underwent ER for Barrett's neoplasia. MAIN OUTCOME MEASUREMENTS: Lesion location in the distal oesophagus, resected specimen histology. RESULTS: A total of 146 consecutive patients had ER for biopsy-proven high-grade dysplasia or esophageal adenocarcinoma. A total of 75 patients had Barrett's segment length of 5 cm or less and a visible lesion. Five patients had 2 visible lesions giving a total of 80 lesions. ER of 66 lesions (82.5%) led to the identification of advanced pathology: 37 high-grade dysplasia (46%), 24 mucosal adenocarcinoma (30%), 5 submucosal adenocarcinoma (6%). Of a total of 80 lesions, 43 (53.8%) (95% CI, 42.9%-64.7%) were centered within the 2- to 5-o'clock arc, comprising 25% of the circumference. This area also accounted for 36 (54.5%) of the 66 lesions with advanced histology (95% CI, 42.5%-66.5%). All confidence intervals lie wholly above the 25% expected in a uniform circular distribution (P < .05). LIMITATIONS: Observational study in a tertiary center. CONCLUSIONS: In Barrett's maximal segments of 5 cm or less, the 2- to 5-o'clock arc, accounts for approximately 50% of macroscopically visible lesions and associated early neoplasia. This finding has important implications for surveillance strategies.

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.

Ulcerative Colitis and Cytomegalovirus Infection: From A to Z.

Despite multiple studies, the role of cytomegalovirus [CMV] infection in exacerbating the severity of inflammation in ulcerative colitis [UC], and its response to treatment, remain debatable. Additionally, the optimal diagnostic tests for CMV infection in the setting of UC relapse, and timing of antiviral treatment initiation, remain unclear. The challenge faced by gastroenterologists is to differentiate between an acute UC flare and true CMV colitis. It seems that the presence of CMV colitis, as defined by the presence of intranuclear or intracellular inclusion bodies on haematoxylin and eosin [H&E] staining and/or positive immunohistochemistry [IHC] assay on histology, is associated with more severe colitis. Patients with CMV infection and acute severe colitis are more resistant to treatment with corticosteroids than non-infected patients. This refractoriness to steroids is related to colonic tissue CMV viral load and number of inclusion bodies [high-grade CMV infection] which may have a pronounced effect on clinical outcomes and colectomy rates. Whereas many studies showed no effect for antiviral treatment on colectomy rates in CMV-infected UC patients, there was a significant difference in colectomy rates of patients with high-grade infection who received anti-viral therapy compared with those who did not receive treatment. It was therefore proposed that high-grade CMV disease indicates that the virus is acting as a pathogen, whereas in those with low-grade CMV disease, the severity of IBD itself is more likely to influence outcome. The different algorithms that have been put forward for the management of patients with UC and concomitant CMV infection are discussed.

Gastroenterologists' preference and risk perception on the use of immunomodulators and biological therapies in elderly patients with ulcerative colitis: an international survey.

BACKGROUND AND AIMS: Comorbidities, polypharmacy, malignancies, and infections complicate management of elderly patients with inflammatory bowel diseases (IBD). This study assessed gastroenterologists' preference in the prescription of medications or surgery to elderly patients with IBD, and the factors associated with their choices. METHODS: An international case-based survey was conducted that presented three cases of steroid-dependent ulcerative colitis assessing young-age versus elderly-age patients, with and without comorbidity. Physician characteristics and practice demographics were collected. Factors associated with selection of different choices of therapy were determined by logistic regression analysis. RESULTS: A total of 424 respondents from 41 countries were included. Vedolizumab (53.2%) and thiopurines (19.4%) were the top treatment preferences for moderate-to-severe ulcerative colitis (P < 0.0001). Comorbidity and older age were independently associated with more frequent use of vedolizumab (P < 0.0001), and less frequent use of immunomodulators and anti-tumour necrosis factor (TNF; P < 0.0001). Comorbidity was the only independent predictor for selecting colectomy (P < 0.0001). A history of lymphoma (94%) and opportunistic infection (78.3%) were the most frequent conditions precluding the use of thiopurine and anti-TNF in elderly patients with IBD. Only 6.1% of respondents considered patient age a limit for vedolizumab, while 37.9% considered age as a limiting factor in prescribing thiopurines (P < 0.001). Geographical heterogeneity was identified with significantly more physicians from Oceania and North America favouring the use of vedolizumab. CONCLUSION: Vedolizumab was the preferred first-line agent in the treatment of elderly patients with IBD with steroid-dependent moderate-to-severe ulcerative colitis. Older age and presence of comorbidity influenced the selection of medication. Comorbidity was the main predictor of colectomy. Geographical heterogeneity in prescribing habits may relate to medication reimbursement in individual countries.

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.

Thiopurines Dosed to a Therapeutic 6-Thioguanine Level in Combination with Adalimumab Are More Effective Than Subtherapeutic Thiopurine-based Combination Therapy or Adalimumab Monotherapy During Induction and Maintenance in Patients with Long-standing Crohn's Disease.

BACKGROUND: The benefit of concomitant immunomodulation with adalimumab (ADA) in Crohn's disease is poorly understood. We aimed to compare ADA monotherapy with combination therapy with thiopurines, stratified by thioguanine nucleotides (TGNs). METHODS: Retrospective observational study of ADA induction and maintenance. Thiopurines were classified according to TGNs (>235 pmol/8 × 10 red blood cell therapeutic). RESULTS: At induction, response was more frequent in combination than ADA monotherapy (83% versus 61%, P = 0.02) and with therapeutic compared with subtherapeutic TGNs (87% versus 70% P = 0.011). Among 280 maintenance semesters in 91 patients, remission was higher with combination than monotherapy (81% versus 60%, P < 0.0001) and therapeutic versus subtherapeutic TGNs (85% versus 58%, P = 0.004). Therapeutic TGN (odds ratio [OR] 4.32, 95% CI, 1.41-13.29, P = 0.01) and albumin (OR 1.09, 95% CI, 1.01-1.18, P = 0.03) were predictors of response to induction. Therapeutic TGN (OR 3.71, 95% CI, 1.87-7.34, P < 0.0001) and ileal disease (OR 0.21, 95% CI, 0.08-0.57, P = 0.002) were predictors of remission semesters. Concomitant immunomodulation at induction was associated with longer time to failure (69 versus 36 months, P = 0.009). Therapeutic TGN at induction (P = 0.03) and male sex (P = 0.026) were associated with time to failure. CONCLUSIONS: Combination therapy was superior to ADA monotherapy for induction and during maintenance. This benefit was increased further when thiopurines resulted in therapeutic TGNs. Early use of adequately dosed thiopurines (≥3 months before starting ADA) was associated with improved clinical outcomes.

Thioguanine in inflammatory bowel disease: Long-term efficacy and safety.

BACKGROUND: Thioguanine (TG) is efficacious in inflammatory bowel disease (IBD), but its toxicity, particularly nodular regenerative hyperplasia (NRH) of the liver, has limited its use. We assessed the long-term clinical outcomes and safety of TG in patients whom were intolerant or refractory to conventional immunomodulators. METHODS: This is a retrospective, single-centre study of IBD patients treated with TG from 2001-2013. Response was defined as clinical remission (Harvey-Bradshaw Index < 5 for Crohn's disease (CD), Simple Clinical Colitis Activity Index < 4 for ulcerative colitis (UC)) without corticosteroids or, if receiving anti-tumour-necrosis-factor (anti-TNF) therapy, absence of dose escalation. We recorded TG failure, withdrawal and adverse events. Patients were monitored with biochemistry, liver biopsy and/or magnetic resonance imaging (MRI). RESULTS: 54 patients (47 CD and 7 UC) whom received TG (mean dose: 27 mg/d (range: 20-40 mg/d)) as monotherapy (n = 36) or concomitantly with anti-TNF (n = 18) for a median inter-quartile range of 16 (5-37) months (126 patient-years of follow-up). 32 (59%) patients responded to TG at 6 months and 23 (43%) at 12 months. Pancreatitis did not recur amongst the 19 patients with prior thiopurine-induced pancreatitis. 16 (30%) patients ceased TG due to intolerance or toxicity (four serious); NRH was not observed. 6-thioguanine nucleotide concentrations did not correlate with efficacy nor with toxicity. CONCLUSIONS: TG was efficacious and well tolerated in one out of two patients who had previously failed conventional immunomodulators. NRH did not occur.

Prevalence and Risk Factors for Functional Vitamin B12 Deficiency in Patients with Crohn's Disease.

BACKGROUND: Crohn's disease (CD) is a risk factor for vitamin B12 deficiency due to frequent involvement of the terminal ileum. Conventional screening for B12 deficiency with serum B12 is relatively insensitive and measures total B12 concentration, of which a minority is present in a biologically active form. Holotranscobalamin (holoTC) combined with methylmalonic acid (MMA) is believed to be more accurate in identifying impaired B12 status. We evaluated the prevalence and risk factors for B12 deficiency using holoTC supported by MMA among patients with CD. METHODS: We performed a single-center service evaluation of 381 patients with CD who underwent B12 assessment (holoTC/MMA) and compared them with 141 patients with ulcerative colitis. Eighty-nine patients with CD underwent paired serum B12 and holoTC. Among patients with CD, risk factors including terminal ileal resection length, ileal inflammation on endoscopy, and disease characteristics on magnetic resonance imaging were recorded. RESULTS: Prevalence of B12 deficiency among patients with CD was 33% compared with 16% in ulcerative colitis (P < 0.0001). In 89 patients who underwent paired tests, conventional testing identified B12 deficiency in 5% of patients with CD, which increased to 32% using holoTC/MMA. Independent risk factors for B12 deficiency were ileal resection length ≤20 cm (odds ratio: 3.0, 95% confidence interval, 1.5-6.0, P = 0.002) and >20 cm (odds ratio: 6.7, 95% confidence interval, 3.0-14.7, P < 0.0001) and ileal inflammation (odds ratio: 3.9, 95% confidence interval, 2.2-6.9, P < 0.0001). On magnetic resonance imaging, active terminal ileal inflammation (P = 0.02) and an increased disease burden (≥1 skip lesion, P = 0.01 and prestenotic dilatation >3 cm, P = 0.01) were associated with B12 deficiency. CONCLUSIONS: Vitamin B12 deficiency is common in patients with CD. holoTC supported by MMA identifies patients with B12 deficiency considered replete on conventional testing.

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.

Australian tertiary care outcomes of entecavir monotherapy in treatment naive patients with chronic hepatitis B.

AIM: To evaluate the long-term treatment outcomes of entecavir monotherapy in treatment naive patients in an Australian tertiary care setting. METHODS: A retrospective analysis of treatment naive patients receiving entecavir monotherapy through Westmead Hospital was performed. Patients were excluded if they had received previous treatment with another nucleoside or nucleotide analogue, were pregnant or less than 18 years old. RESULTS: Out of 336 patients, 163 patients fulfilled the selection criteria. Range of follow up was 3-46 mo (mean 26 mo). 134 patients (82.2%) had pre-treatment biopsies, with 26 patients (16.0 %) demonstrating F3-4 fibrosis. In total, 153 patients (93.9%) achieved at least Partial Virological Suppression (PVS), with 134 patients (82.2%) achieving complete virological suppression. The cumulative CVS and PVS rates at 36 mo were 82.1% and 96.4%, respectively. 3 patients (1.8%) failed to achieve PVS, while 5 patients (3.0%) developed virological rebound. 128 patients (78.5%) maintained CVS throughout follow up. Predictors of CVS included lower baseline DNA level (P = 0.001), hepatitis B virus e antigen negative status (P = 0.001) and increasing age at treatment (log rank 0.001). No significant adverse effects were reported necessitating cessation of entecavir. CONCLUSION: Entecavir monotherapy is efficacious and safe in an Australian tertiary care setting. Resistance and rebound rates are very low. This is similar to data from controlled and uncontrolled trials around the world.