Dedicated Barrett's surveillance sessions managed by trained endoscopists improve dysplasia detection rate.

Background and study aim Barrett's esophagus (BE)-associated dysplasia is an important marker for risk of progression to esophageal adenocarcinoma (EAC) and an indication for endoscopic therapy. However, BE surveillance technique is variable. The aim of this study was to assess the effect of dedicated BE surveillance lists on dysplasia detection rate (DDR). Patients and methods This was a prospective study of patients undergoing BE surveillance at two hospitals - community (UHL) and upper gastrointestinal center (GSTT). Four endoscopists (Group A) were trained in Prague classification, Seattle protocol biopsy technique, and lesion detection prior to performing BE surveillance endoscopies at both sites, with dedicated time slots or lists. The DDR was then compared with historical data from 47 different endoscopists at GSTT and 24 at UHL (Group B) who had undertaken Barrett's surveillance over the preceding 5-year period. Results A total of 729 patients with BE underwent surveillance endoscopy between 2007 and 2012. There was no significant difference in patient age, sex, or length of BE between the two groups. There was a significant difference in detection rate of confirmed indefinite or low grade dysplasia and high grade dysplasia (HGD)/EAC between the two groups: 18 % (26 /142) Group A vs. 8 % (45/587) in Group B (P  < 0.001). Documentation of Prague criteria and adherence to the Seattle protocol was significantly higher in Group A. Conclusion This study demonstrated that a group of trained endoscopists undertaking Barrett's surveillance on dedicated lists had significantly higher DDR than a nonspecialist cohort. These findings support the introduction of dedicated Barrett's surveillance lists.

Abdominal hereditary angio-oedema caught on magnetic resonance imaging.

A 17-year-old woman presented with a 3-year history of recurrent, severe abdominal pain with spontaneous resolution within a few days. An ultrasound revealed nothing more than free fluid within the pelvis. An MRI of the small bowel was done within 24 hours of abdominal pain onset, which revealed extensive submucosal oedema associated with moderate volume ascites. A repeat MRI of the small bowel after 72 hours showed near-complete resolution of these changes. Checking C1 inhibitor levels confirmed a diagnosis of hereditary angio-oedema with an abdominal presentation. This is a rare cause of recurrent abdominal pain and, to our knowledge, the first case in which MR images have been obtained during and after an acute attack.

Tuberculosis complicating tertiary hyperparathyroidism in a patient with end-stage renal disease: a case report.

A 36-year-old Nigerian woman on thrice-weekly dialysis presented with symptoms and signs of hypercalcaemia. Laboratory findings were consistent with tertiary hyperparathyroidism. Parathyroid hormone levels remained elevated and she underwent elective parathyroidectomy. Intra-operatively all 4 parathyroid glands and local lymph nodes showed necrotising granulomas with occasional acid-fast bacilli, pathognomonic of tuberculosis (TB). Post-operatively she completed a full course of anti-TB therapy and at 9 months she experienced complete resolution in her plasma biochemistry and was essentially symptom-free. This is a rare yet fascinating cause of hypercalcaemia in a dialysis patient and is the first recorded case of tubercular involvement of parathyroid tissue in a case of tertiary hyperparathyroidism. This report demonstrates the coexistence of 2 diseases that simultaneously worsened hypercalcaemia and thus emphasises the importance of the differential diagnosis and of careful histological examination post-operation.

Is there a role for thioguanine therapy in IBD in 2017 and beyond?

INTRODUCTION: Conventional thiopurines are effective for the maintenance of remission of Crohn's disease and ulcerative colitis, however, up to half of patients are intolerant or unresponsive to these medications. Thioguanine is an alternative thiopurine that has shown efficacy in inflammatory bowel disease, and is particularly useful to circumvent certain side effects associated with conventional thiopurines, for example, pancreatitis. Its association with nodular regenerative hyperplasia of the liver has hindered its widespread use. Areas covered: We aim to outline the rational use of thioguanine, including safety monitoring, with particular regard to hepatotoxicity. A literature search was performed: PubMed was searched for full papers and abstracts published in English since January 2000 using the following terms, alone and in combination: 'azathioprine', 'thiopurine', 'Crohn's disease', 'inflammatory bowel disease', 'nodular regenerative hyperplasia', 'mercaptopurine', 'thioguanine', 'ulcerative colitis'. Further relevant papers were identified from the reference lists of selected papers. Expert commentary: Despite optimisation strategies such as metabolite measurements and the use of allopurinol, a significant proportion of patients will remain intolerant to thiopurines, especially those with allergic reactions, including pancreatitis. For this subgroup of patients we suggest that low dose thioguanine is an alternative to other therapies that are either parenteral or expensive.

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.

Management of acute severe ulcerative colitis (NICE CG 166).

Ulcerative colitis (UC) presents as an acute severe flare in 10-15% of new cases and it occurs in 15% of patients with established disease. Acute severe UC can lead to significant morbidity and mortality in predominantly younger patients without other comorbidities. Inpatient hospital admission and a multidisciplinary approach are vital in appropriate and timely management. Important but simple aspects in the initial work-up and treatment of such patients are frequently overlooked during the acute medical take. An overview of the general and more specialist management of this important presentation are discussed herein.

Getting the best out of thiopurine therapy: thiopurine S-methyltransferase and beyond.

Thiopurines are the cornerstone of treatment for a wide variety of medical disorders, ranging from pediatric leukemia to inflammatory bowel disease. Because of their complex metabolism and potential toxicities, the use of biomarkers to predict risk and response is paramount. Thiopurine S-methyltransferase and thiopurine metabolite levels have emerged as companion diagnostics with crucial roles in facilitating safe and effective treatment. This review serves to update the reader on how these tools are being developed and implemented in clinical practice. A useful paradigm in thiopurine therapeutic strategy is presented, along with fresh insights into the mechanisms underlying these approaches. We elaborate on potential future developments in the optimization of thiopurine therapy.

Optimizing the use of thiopurines in inflammatory bowel disease.

Immunomodulator drugs, of which thiopurines can be considered the backbone, are widely used in the treatment of inflammatory bowel disease. They have been shown to be highly effective and safe; however, a significant proportion of patients are deemed to have a poor response or suffer adverse reactions. Knowing how to monitor and optimize thiopurine therapy in these scenarios is crucial to effective management. We discuss the metabolism of thiopurines, the use of enzyme/metabolite testing to guide treatment, as well as strategies to circumvent toxicity and side effects, such as allopurinol coprescription. The indications, use in pregnancy, safety profile and duration of thiopurine therapy are also discussed.

Steroids in villous atrophy: opening a can of worms?

A 60 year old man presented to the emergency department with septic shock and respiratory distress. He noted significant weight loss over the last 6 months with associated postprandial bloating. Endoscopy demonstrated partial villous atrophy. He had been on a gluten free diet, received empirical treatment for giardiasis and was receiving treatment with high dose systemic steroids for retroperitoneal fibrosis. This case discusses histology findings, differentials and reason for this acute presentation.

Let's get personal: predicting thiopurine and fluoropyrimidine toxicity.

The US FDA now recognizes the need to individualize treatment paradigms using biomarkers that predict response to therapy. In clinical practice the best example of this is TPMT testing, which is used to rationalize the starting dose of azathioprine and mercaptopurine. The more recent addition of drug metabolite monitoring means that thiopurine therapy can now be personalized to unprecedented levels. Of interest, parallels exist between TPMT deficiency as an explanation for thiopurine toxicity and DPD deficiency in fluoropyrimidine toxicity. For these drugs, variations in a single locus predict severe toxicity. However, while TPMT testing has translated into routine clinical practice, DPD testing has not. This article summarizes the recent research investigating interindividual differences in the metabolism of thiopurine and fluoropyrimidine drugs, and explores the attitudes which influence the uptake of pharmacogenetic testing.

The pharmacogenetic basis of individual variation in thiopurine metabolism.

Thiopurines are an important class of immunosuppressive therapy, which have been used in clinical practice for over 50 years. Despite this extensive experience many of the pharmacodynamic and pharmacokinetic properties of these drugs remain unknown. As a consequence there is often no clear explanation for the individual variation in response to treatment, both in terms of efficacy or adverse drug reactions. This review, which emphasizes practice in gastroenterology, summarizes the current understanding of thiopurine drug metabolism and highlights the role of nongenetic and genetic factors other than TPMT, which should be a focus for future research. Correlation of polymorphic variations in these genes with clinical outcomes is expected to clarify the basis for interindividual differences in thiopurine metabolism and enable a more personalized approach to therapy.

Optimising outcome on thiopurines in inflammatory bowel disease by co-prescription of allopurinol.

BACKGROUND AND AIMS: Azathioprine and mercaptopurine remain first line immunomodulatory treatments for inflammatory bowel disease. Toxicity and non-response are significant issues. Co-prescription of allopurinol with reduced-dose (25-33%) azathioprine or mercaptopurine may overcome these problems. We present the outcome of co-prescription in a large single-centre cohort. METHOD: Patients on thiopurine/allopurinol co-prescription were identified. Indication for and outcome on combination treatment were established. Blood parameters and metabolite results were compared on single agent and combination treatment. Toxicity associated with combination treatment was sought. RESULTS: 110 patients on combination treatment were identified. Clinical remission was achieved in 60/79 (76%) of patients in whom the effect of thiopurine could be studied in isolation. 20/25 patients with hepatotoxicity tolerated combination treatment and normalised their liver function tests. 24/28 patients with atypical side effects tolerated co-therapy. 13/20 non-responders responded to combination treatment. In patients started on combination treatment as first line therapy, 15/23 achieved clinical remission. Thioguanine nucleotides were significantly higher and methylated metabolites significantly lower on combination therapy. Mean cell volume was higher and total white cell and neutrophil counts lower on combination treatment. 13 adverse events occurred, including 6 specific to co-therapy (3 rash, 2 abnormal liver function tests, 1 dosing error). All were minor and self-limiting. CONCLUSION: This is the largest published experience of the use of allopurinol to optimise outcomes on thiopurine treatment. Combination therapy permitted successful treatment of a significant number of patients who would otherwise have been labelled as thiopurine failures. A few self-limiting side effects were encountered.

Blockers of sodium and calcium entry protect axons from nitric oxide-mediated degeneration.

Axonal degeneration can be an important cause of permanent disability in neurological disorders in which inflammation is prominent, including multiple sclerosis and Guillain-Barré syndrome. The mechanisms responsible for the degeneration remain unclear, but it is likely that axons succumb to factors produced at the site of inflammation, such as nitric oxide (NO). We previously have shown that axons exposed to NO in vivo can undergo degeneration, especially if the axons are electrically active during NO exposure. The axons may degenerate because NO can inhibit mitochondrial respiration, leading to intraaxonal accumulation of Na(+) and Ca(2+) ions. Here, we show that axons can be protected from NO-mediated damage using low concentrations of Na(+) channel blockers, or an inhibitor of Na(+)/Ca(2+) exchange. Our findings suggest a new strategy for axonal protection in an inflammatory environment, which may be effective in preventing the accumulation of permanent disability in patients with neuroinflammatory disorders.