Antony Friedman

The failure of gastroenterologists to apply intestinal ultrasound in inflammatory bowel disease in the Asia-Pacific: A need for action

Intestinal ultrasound (IUS) is a cheap, noninvasive, risk‐free procedure that is significantly underutilized in the diagnosis and management of patients with inflammatory bowel disease (IBD) in the Asia‐Pacific region. More cost‐effective methods of monitoring disease activity are required in light of the increasing global burden of IBD (especially in Asia), the advent of personalized medicine, and the rising cost of healthcare. IUS is a prime example of a technique that meets these needs. Its common clinical applications include assessing the activity and complications of IBD. In continental Europe, countries such as Germany and Italy use this imaging tool as the standard of care and have integrated it into management protocols. There are formal training programs in these countries to train gastroenterologists in IUS, and it is used in an outpatient setting during patient consultations. Barriers to its use in the Asia‐Pacific region include lack of experience and research data, and there are few established centers with active training programs. These concerns can be addressed by investing more in IUS service provision and by increasing allocation of resources toward local research and training. Increased uptake of IUS will ultimately benefit patients with IBD.

Gastrointestinal ultrasound in inflammatory bowel disease: an underused resource with potential paradigm-changing application

Evolution of treatment targets in IBD has increased the need for objective monitoring of disease activity to guide therapeutic strategy. Although mucosal healing is the current target of therapy in IBD, endoscopy is invasive, expensive and unappealing to patients. GI ultrasound (GIUS) represents a non-invasive modality to assess disease activity in IBD. It is accurate, cost-effective and reproducible. GIUS can be performed at the point of care without specific patient preparation so as to facilitate clinical decision-making. As compared with ileocolonoscopy and other imaging modalities (CT and MRI), GIUS is accurate in diagnosing IBD, detecting complications of disease including fistulae, strictures and abscesses, monitoring disease activity and detecting postoperative disease recurrence. International groups increasingly recognise GIUS as a valuable tool with paradigm-changing application in the management of IBD; however, uptake outside parts of continental Europe has been slow and GIUS is underused in many countries. The aim of this review is to present a pragmatic guide to the positioning of GIUS in IBD clinical practice, providing evidence for use, algorithms for integration into practice, training pathways and a strategic implementation framework.

The role of thiopurine metabolites in inflammatory bowel disease and rheumatological disorders

Thiopurines have been a cornerstone of medical management of patients with inflammatory bowel disease (IBD) and many rheumatological disorders. The thiopurines are metabolized to their end products, 6‐methymercaptopurine (6MMP) and the 6‐thioguanine nucleotides (6TGN), with 6TGN being responsible for thiopurine efficacy by causing apoptosis and preventing activation and proliferation of T‐lymphocytes. In IBD, conventional weight‐based dosing with thiopurines leads to an inadequate response in many patients. Utilizing measurement of these metabolites and then employing dose optimization strategies has led to markedly improved outcomes in IBD. Switching between thiopurines as well as the addition of low‐dose allopurinol can overcome adverse events and elevate 6TGN levels into the therapeutic window. There is a paucity of data on thiopurine metabolites in rheumatological diseases and further research is required.

The role of thiopurine metabolite monitoring in inflammatory bowel disease

Thiopurines are the mainstay of medical management in inflammatory bowel disease (IBD), especially in the maintenance of disease remission. Given the limited IBD armamentarium it is important to optimize each therapy before switching to an alternative drug. Conventional weight based dosing of thiopurines in IBD leads to intolerance or inefficacy in many patients. More recently increased knowledge of their metabolism has allowed for dose optimization using thiopurine metabolite levels, namely 6-thioguanine nucleotides and 6-methylmercaptopurine, with the potential for improved outcomes in patients with IBD. This review will outline the current understanding of thiopurine metabolism and pharmacogenomics and will describe the clinical application of this knowledge in the optimization of thiopurines in individual patients.

Randomised clinical trial: Efficacy, safety and dosage of adjunctive allopurinol in azathioprine/mercaptopurine nonresponders (AAA Study)

Thiopurine hypermethylation towards 6‐methylmercaptopurine (6MMP) instead of 6‐thioguanine nucleotides (6TGN) is associated with inefficacy in patients with IBD. Allopurinol reverses such hypermethylation.

Why thiopurine metabolites are relevant

SIRS, We read with interest the research published by Gonzalez-Lama et al. who concluded that determination of thiopurine metabolites is not useful in predicting response to or safety of thiopurines, and that ‘‘...further research is needed before recommending dose adjustments of thiopurines based on the RBC levels of metabolites.’’ We do not believe that the results support such conclusions. The methodology used for the power calculations is incompletely explained, in that previous literature upon which it is based is not referenced. It remains unclear as to how the figure of 20% was reached as the clinically relevant difference of 6-thioguianine (6TGN) levels between patients with and without disease activity. While the data were collected prospectively, the investigators were blinded to the results and unable to act on the metabolite results and dose-adjust to optimise 6TGN levels. As such, it was a purely observational cohort study with retrospective analysis to look for differences between the two groups. Most importantly, this study does not answer the question of how many more patients could have achieved remission with dose optimisation and escalation. The therapeutic range of 6TGN concentrations used in practice has been derived, at least in part, from the incremental effect of increasing the dose on disease response ⁄ remission. The two patient cohorts that were not addressed in this study are those not in remission with low 6TGN levels (recently, dose escalation in such patients prevented implementation of an alternative treatment in 63% of this cohort) and thiopurine ‘shunters’ (addition of low-dose allopurinol in combination with low-dose thiopurine achieves remission in approximately 75% of these patients by increasing 6TGN levels.) We agree that routine measurement of metabolites is not indicated for patients in remission. However, for patients who are not in remission, metabolites are an invaluable tool that may prevent unnecessary and costly escalation of treatment.

Low-dose thiopurine with allopurinol co-therapy overcomes thiopurine intolerance and allows thiopurine continuation in inflammatory bowel disease

AIMS To assess the utility and tolerability of thiopurine-allopurinol co-therapy in inflammatory bowel disease (IBD) patients with intolerance to thiopurine monotherapy. METHODS A retrospective observational study assessed cases of thiopurine intolerance then switched to thiopurine allopurinol co-therapy between 2011 and 2015 at two centres. Indications for switch, dosing and subsequent clinical outcomes (including thiopurine persistence) were recorded. RESULTS Of 767 patients on thiopurines for IBD, 89 (12%) were switched to co-therapy for intolerance. 64/89 (72%) had Crohns disease, 38 (43%) were males, median age at switch was 40y (range 17-78), median IBD duration 6y (0-29). Median follow-up was 1.9y (0-5). Reasons for switching to co-therapy included fatigue (37%), hepatotoxicity (23%), nausea (23%), arthralgia (10%), headache (12%) and hypersensitivity reaction (4%). Overall, 66 (74%) patients remained on co-therapy until most recent review and achieved a clinical response. High rates of overcoming intolerance (62-100%) occurred with co-therapy for all reasons above, although fatigue was less amenable to switching than non-fatigue indications (62% vs 91%, p = <0.001). Of 34 patients not escalated to biologics with endoscopic data, 15 were in remission (44%) at most recent review. CONCLUSION Low-dose thiopurine combined with allopurinol appears safe and effective in overcoming intolerances to thiopurine monotherapy in many cases.

Thiopurines best practice

For over 30 years, the thiopurine immunomodulators, azathioprine (AZA), and 6-mercaptopurine (6MP) have been well established in inflammatory bowel disease treatment algorithms. Traditional use of thiopurines has focused on weight-based dosing, using 1 to 1.5mg/kg for 6MP and 2 to 2.5mg/kg for AZA. However, up to 60% of patients do not respond to a conventional dose and duration of thiopurine therapy, and up to 40% will experience some sort of adverse event leading to drug cessation. Combination therapy with a TNF antagonist and a thiopurine leads to the greatest proportion of patients with Crohn’s disease or ulcerative colitis, achieving steroid free clinical remission and mucosal/endoscopic healing. Despite this, 45–60% of patients still fail to achieve these outcomes with standard weight-based dosing of thiopurines. Thiopurines are pro-drugs metabolized to produce the active metabolites 6-thioguanine nucleotides (6TGN) and 6-methylmercaptopurine (6MMP), but weight-based dosing of thiopurines does not correlate with 6TGN and 6MMP levels. 6TGN is the active metabolite responsible for therapeutic efficacy, and 6TGN levels above a threshold of 230–260pmol/8×108 red blood cells improve remission rates (odds ratio of 3.15). For combination therapy with a TNF antagonist, optimizing thiopurine metabolites also improves remission rates. Mean corpuscular volume has also been shown to be a surrogate marker for 6TGN levels. So if a clinician is unable to measure 6TGN and 6MMP levels, a rise in mean corpuscular volume by at least 7 fL confers similar improvements in outcomes with combination therapy. Higher 6TGN levels also improve outcomes of TNF antagonist therapy by increasing TNF antagonist trough levels and decreasing the risk of anti-drug antibody formation. To achieve a therapeutic 6TGN level, when both 6TGN and 6MMP levels are low, the dose of thiopurine can be increased. Also, adding mesalazine can favorably affect thiopurine metabolites. For patients with high levels of 6MMP, low levels of 6TGN, adding 100mg of allopurinol and reducing thiopurine dose by two-thirds, improves outcomes without any increased toxicity. Overcoming thiopurine-related adverse events to allow patients to remain on thiopurines is vital. Approximately 50% of patients who are intolerant to AZA will tolerate 6MP without recurrence of their adverse event. Furthermore, 75% to 80% of patients who are intolerant to conventional thiopurines can tolerate either allopurinol (with dose-reduced thiopurine) or 6-thioguanine (6TG). Combining these options can allow up to 85% of patients to remain on thiopurine therapy without complication. Clinicians also have concerns regarding risks associated with long-term use of combination therapy, and patients are usually interested in reducing their medication to the lowest levels possible. However, this has to be balanced against the risk of relapse and subsequent complications of uncontrolled inflammation. Data suggest that in patients who achieve clinical remission, de-escalating to monotherapy with either a thiopurine or a TNF antagonist leads to relapse rates of 20–50% after 1 year. However, the risk of relapse can be reduced to less than 10% if a number of key endpoints are achieved prior reducing therapy. From a disease activity perspective, these include normalization of the bowel at colonoscopy, normalization of C-reactive protein and hemoglobin levels and reduction in fecal calprotectin levels to less than 300μg/g. It is feasible to continue with either agent as monotherapy; however, both drugs need to be maintained within their respective therapeutic ranges in order to prevent relapse. It has also been shown that length of time on therapy is important, as rates of relapse increase if a patient is on combination therapy for less than 2.5 years. For the newest available biologic agent vedolizumab, optimal treatment strategies are yet to be determined. In the landmark phase 3 studies, the combination of vedolizumab and a thiopurine led to higher vedolizumab trough levels and decreased antivedolizumab antibody formation; however, this did not translate to improved clinical outcomes. Studies are currently exploring these issues at the moment. In summary, in order for patients to have the best chance of both achieving and remaining in clinical and endoscopic remission, it is vital to optimize thiopurine metabolites and overcome any drug specific adverse event preventing a patient from tolerating a thiopurine. Similarly, when de-escalating therapy, it is important to ensure that drug levels remain within the therapeutic range and a patient is both in endoscopic and biochemical remission prior to drug cessation. This highlights that weight-based dosing of thiopurines is no longer standard of care and pro-active monitoring of both disease activity and drug levels are required to achieve these outcomes.

Sa1269 Adjunctive Allopurinol in Azathioprine/6-Mercaptopurine Non-Responders Optimises 6-Thioguanine Nucleotide Production and Improves Clinical Outcomes in Inflammatory Bowel Disease: The Prospective, Multicentre, Double Blind, Dose-Ranging AAA Study

Background: Infliximab (IFX) treatment failure in patients with Crohns disease is generally handled by intensifying the IFX regimen. However, an alternative strategy defined by an algorithm based on serum IFX and anti-IFX antibody measurements to identify reasons for failure and corresponding interventions has been proposed. In a randomized controlled trial, we observed substantial cost reductions after 12 weeks when using this algorithm as compared to IFX intensification, and without negative influence on symptom control.(1) The current study primarily investigated long-term cost outcomes at time of the week 20 follow-up study visit and after 1 year. In addition, clinical outcomes were assessed at week 20. Methods: Predefined follow-up from a 12-week, single-blind, clinical trial where Crohns disease patients with IFX treatment failure (CDAI ≥220 or ≥1 draining perianal fistula) were randomized to IFX intensification (5 mg/kg every 4 weeks) (n=36), or algorithm-defined interventions in form of IFX intensification, change to adalimumab, or use of pharmaceuticals other than TNF-inhibitors (n=33). Patients were treated at the discretion of the physician from week 12 onwards. Blinding was maintained until week 20. Accumulated costs, expressed as mean costs per patient, were based on the Danish National Patient Registry. Data were analyzed in the following populations: intention-to-treat (ITT) (n=69), per protocol (PP) (n=55), per protocol completion at end of trial week 12 (PPCw12) (n=45) or end of followup week 20 (PPCw20) (n=29). NCT00851565. Results: At the scheduled follow-up study visit at week 20, response (CDAI reduction ≥70 point or ≥50% reduction of active fistulas) and remission rates (CDAI ≤150 or closure of all fistulas) were similar in all study populations between patients treated by the algorithm or by IFX intensification (p>0.05). However, the sum of health care costs related to Crohns disease was substantially lower (31%) for patients randomized to algorithm-based interventions than IFX intensification in the ITT population:

Response to Clarke K, Regueiro M. Stopping immunomodulators and biologics in inflammatory bowel disease patients in remission. Inflamm Bowel Dis 2011 [Epub ahead of print].

10,815 vs.