Thiopurine Metabolite Testing Research Articles

Inflammatory Bowel Disease and Pregnancy

Inflammatory Bowel Disease and Pregnancy

THU488 - Examining the role of thiopurine metabolite testing in the management of patients with autoimmune hepatitis

THU488 - Examining the role of thiopurine metabolite testing in the management of patients with autoimmune hepatitis

Intensive drug therapy versus standard drug therapy for symptomatic intestinal Crohn's disease strictures (STRIDENT): an open-label, single-centre, randomised controlled trial

Strictures are the most common structural complication of Crohn's disease. Surgery and endoscopic balloon dilation are the main treatments; drug therapy has been considered contraindicated. Given that most strictures have an inflammatory component, we aimed to find out whether strictures are responsive to drug treatment and whether intensive drug therapy is more effective than standard drug therapy. This open-label, single-centre, randomised controlled trial was performed in one specialist inflammatory bowel disease centre in Australia. Patients aged 18 years or older with Crohn's disease were included. Eligible patients had a de novo or postoperative anastomotic intestinal stricture on MRI or ileocolonoscopy, symptoms consistent with chronic or subacute intestinal obstruction (postprandial abdominal pain in the presence of a confirmed stricture), and evidence of active intestinal inflammation. Patients were randomly assigned (2:1) to receive intensive high-dose adalimumab (160 mg adalimumab once per week for 4 weeks followed by 40 mg every 2 weeks, with escalation of dose at 4 months and 8 months if assessment of disease activity indicated active inflammation) plus thiopurine (initial dose of azathioprine 2·5 mg/kg or mercaptopurine 1·5 mg/kg, with dose adjustment based on thiopurine metabolite testing) or standard adalimumab monotherapy (160 mg at week 0, 80 mg at week 2, then 40 mg every 2 weeks) using stratified fixed block randomisation. Stratification factors were stricture dilation at study baseline colonoscopy and current biologic drug use. The primary endpoint was improvement (decrease) in the 14-day obstructive symptom score at 12 months by one or more points compared with baseline. This trial is registered with ClinicalTrials.gov, NCT03220841, and is completed. Between Sept 10, 2017, and Sept 6, 2019, 123 patients were screened and 77 randomly assigned to intensive adalimumab plus thiopurine treatment (n=52) or standard adalimumab treatment (n=25). At 12 months, improvement in obstructive symptom score was noted in 41 (79%) of 52 patients in the intensive treatment group and 16 (64%) of 25 in the standard treatment group (odds ratio [OR] 2·10 [95% CI 0·73-6·01]; p=0·17). Treatment failure occurred in five (10%) patients in the intensive treatment group versus seven (28%) in the standard treatment group (OR 0·27 [95% CI 0·08-0·97]; p=0·045); four patients in each group required stricture surgery (0·44 [0·10-1·92]; p=0·27). Crohn's Disease Activity Index was less than 150 in 36 (69%) patients in the intensive treatment group versus 15 (60%) in the standard treatment group (1·50 [0·56-4·05]; p=0·42). MRI at 12 months showed improvement using the stricture MaRIA score (≥25%) in 31 (61%) of 51 versus seven (28%) of 25 patients (3·99 [1·41-11·26]; p=0·0091). MRI complete stricture resolution was seen in ten (20%) versus four (16%) patients (1·28 [0·36 to 4·57]; p=0·70). Intestinal ultrasound at 12 months showed improvement (>25%) in bowel wall thickness in 22 (51%) of 43 versus seven (33%) of 21 patients (2·10 [0·71 to 6·21]; p=0·18). Faecal calprotectin normalised in 32 (62%) versus 11 (44%) patients (2·04 [0·77-5·36]; p=0·15). Normalisation of CRP was seen in 32 (62%) versus 11 (44%) patients (2·04 [0·77-5·36]; p=0·15). Eight (15%) patients in the intensive treatment group and four (16%) in the standard treatment group reported serious adverse events. No deaths occurred during the study. Crohn's disease strictures are responsive to drug treatment. Most patients had improved symptoms and stricture morphology. Treat-to-target therapy intensification resulted in less treatment failure, a reduction in stricture-associated inflammation, and greater improvement in stricture morphology, although these differences were not significantly different from standard therapy. Australian National Health and Medical Research Council, Gastroenterological Society of Australia Ferring IBD Clinician Establishment Award, Australasian Gastro Intestinal Research Foundation, AbbVie, and the Spotlight Foundation.

Utility of thiopurine metabolite testing in autoimmune hepatitis: defining an optimal therapeutic range for disease management and measurement may avert relapse and adverse drug reactions

Utility of thiopurine metabolite testing in autoimmune hepatitis: defining an optimal therapeutic range for disease management and measurement may avert relapse and adverse drug reactions

Systematic Review: Cost-effective Strategies of Optimizing Anti-tumor Necrosis and Immunomodulators in Inflammatory Bowel Disease

Medication costs in inflammatory bowel disease (IBD) are now the principal driver of health care costs. Cost-effective strategies to optimize and rationalize treatment are therefore necessary. A systematic review until April 30, 2018, was performed to identify economic evaluations of strategies to optimize infliximab, adalimumab, and immunomodulators for the treatment of IBD in adults. A qualitative synthesis of the identified studies was performed. Seventy articles were identified that met the inclusion criteria. Adalimumab seems cost-effective compared with infliximab as maintenance therapy for moderate to severe Crohn's disease (CD). Infusion costs are a significant additional treatment cost with infliximab. However, other studies found biosimilar infliximab more cost-effective than alternative biologics in fistulizing and moderate-severe luminal CD-although the latter did not reach a willingness-to-pay threshold of <$50,000. In moderate-severe ulcerative colitis, infliximab seems more cost-effective than adalimumab. Multiple tailored approaches to treatment based on objective markers of disease activity or efficacy have been shown to be cost-effective in CD, including following secondary loss of response to anti-TNF therapy for postoperative recurrence and in escalating treatment. For immunomodulator treatment, both thiopurine methyltransferase (TPMT) testing before commencing thiopurines and thiopurine metabolite testing for dose optimization seem cost-effective. In a win-win for patients and payers, several potential avenues to achieve cost-effectiveness-but also therapeutic optimization of anti-TNF therapies-were elucidated in this review with comparatively sparse data for immunomodulators. Optimizing immunomodulator and anti-tumor necrosis factor alpha therapy to achieve objective disease control seems to be cost-effective at conventional willingness-to-pay thresholds in a number of clinical settings.

Editorial: can we get more clinical benefit from thiopurine metabolite testing? Authors’ reply

Linked ContentThis article is linked to Wong and Coenen et al and Fraser papers. To view these articles visit https://doi.org/10.1111/apt.13879 and https://doi.org/10.1111/apt.13942.

Thiopurine metabolite testing in inflammatory bowel disease.

Thiopurine use in inflammatory bowel disease (IBD) is limited by drug toxicity and lack of therapeutic efficacy. We assessed the utility of thiopurine metabolite testing and the relationship between disease activity, dose, and metabolite levels in a real world setting. Patients identified from pathology databases (2007-2012) at two tertiary IBD centers were included if they had thiopurines for at least four weeks. Demographics, dose, test indication, clinical status, action taken, and outcome were obtained by retrospective medical record review. A total of 169 patients were included. 6-Thioguanine (TGN) levels were sub-therapeutic in 52%, therapeutic in 34%, and supratherapeutic in 14%. Test indication was active disease (79%), adverse effect (11%), or adherence assessment (7%). TGN trended lower in the active disease group compared to those with adverse effects (273 (+/- 23.2) versus 447 (+/- 117.7) pmol/8 × 10(8) RBC, P = 0.05). Weight-based dosing did not improve rates of therapeutic TGN levels (under-dosed 31.5% vs standard dose 35.4%), but was significantly associated with shunting toward 6-MMP (23.1% vs 6.8%, P = 0.008, OR = 4.1). Testing resulted in a change in patient treatment in 86% of patients with active disease and subtherapeutic levels and in 68% of tested patients overall. Metabolite testing resulted in a change in management in most patients not responding to thiopurines or experiencing adverse events. Weight-based dosing did not increase rates of therapeutic levels but was associated with increased 6MMP shunting.

PWE-070 Initial experience of thiopurine metabolite measurements in the management of ibd in edinburgh

Introduction Thiopurine metabolites 6-thioguanine nucleotides (6TGN) and 6-methylmercaptopurine (6MMPN) are end products of thiopurine metabolism which are linked to thiopurine efficacy and increased risk of hepatotoxicity respectively. Variation in metabolism amongst individuals leads to differences in metabolite levels among patients. Thiopurine metabolite testing is used as a tool to guide thiopurine dosing based on metabolite concentrations with the aim of improving disease control and reducing drug related toxicity. 1 Method Patients within NHS Lothian who had thiopurine metabolite tests for IBD between January 2011 and February 2013 were identified. Electronic patient records and case notes were reviewed retrospectively to determine metabolite test indication, changes to therapy post-metabolite testing and subsequent clinical outcomes. An improvement in outcome encompassed improved disease control, improved adherence, reduced adverse drug effects and a decision to escalate to other therapies where this was motivated by knowledge of adequate 6TGN concentration. Results 159 patients who had thiopurine metabolite testing were studied after 44 exclusions. Test indication was lack of efficacy in 117 patients (73.6%), adverse effects in 6 (3.8%), combination of inefficacy and adverse effects in 3 (1.9%) and routine monitoring in 33 (22.8%). Fifty-eight (49.6%) of those tested for inefficacy, 3 (50.0%) in the adverse reaction group and 3 (10.7%) who were routinely monitored showed improved clinical outcomes related to their testing. Addition of allopurinol in 13 patients who were deemed thiopurine shunters led to marked increased in 6TGN concentrations and reduction in those of 6MMPN. Conclusion Thiopurine metabolite testing is of significant clinical benefit in patients showing inefficacious response to thiopurines and those with low 6TGN concentrations. It is also useful in detecting non-adherence to therapy. Thiopurine and allopurinol co-therapy results in marked increase in 6TGN concentrations and improved patient outcomes. This study does not show clear benefits for routine testing of metabolites. Disclosure of interest None Declared. References Gearry RB, Barclay ML. Azathioprine and 6-mercaptopurine pharmacogenetics and metabolite monitoring in inflammatory bowel disease. J Gastroenterol Hepatol . 2005;20(8):1149–57 Sparrow MP, Hande SA, Friedman S, Cao D, Hanauer SB. Effect of allopurinol on clinical outcomes in inflammatory bowel disease nonresponders to azathioprine or 6-mercaptopurine. Clin Gastroenterol Hepatol . 2007;5(2):209–14 Kennedy NA, Asser TL, Mountifield RE, Doogue MP, Andrews JM, Bampton PA. Thiopurine metabolite measurement leads to changes in management of inflammatory bowel disease. Intern Med J . 2013;43(3):278–86

P420. Thiopurine metabolite testing to guide management in inflammatory bowel disease (IBD) yields clinical benefit at 12 months: A retrospective observational study.

P420. Thiopurine metabolite testing to guide management in inflammatory bowel disease (IBD) yields clinical benefit at 12 months: A retrospective observational study.

Thiopurine monitoring in children with inflammatory bowel disease: a systematic review

The aim was to systematically review the evidence on the clinical usefulness of thiopurine metabolite and white blood count (WBC) monitoring in the assessment of clinical outcomes in children with inflammatory bowel disease (IBD). Medline, Embase, Cochrane Central Register of controlled trials and http://www.clinicaltrials.gov were screened in adherence to the PRISMA statement by two independent reviewers for identification of eligible studies. Eligible studies were randomized controlled trials (RCTs), cohort studies and large case series of children with inflammatory bowel disease (IBD) (<18 years) who underwent monitoring of thiopurine metabolites and/or WBC. Fifteen papers were identified (n = 1026). None of the eligible studies were RCTs. High 6-thioguanine nucleotide (6TGN) concentrations were not consistently associated with leucopenia. Leucopenia was not associated with achievement of clinical remission. A positive but not consistent correlation between 6TGN and clinical remission was reported. Haematological toxicity could not be reliably assessed with 6TGN measurements only. A number of studies supported the use of high 6-methylmercaptopurine ribonucleotides (6MMPR) as an indicator of hepatotoxicity. Low thiopurine metabolite concentration may be indicative of non-compliance. Thiopurine metabolite testing does not safely predict clinical outcome, but may facilitate toxicity surveillance and treatment optimization in poor responders. Current evidence favours the combination of thiopurine metabolite/WBC monitoring and clinic follow-up for prompt identification of haematologic/hepatic toxicity safe dose adjustment, and treatment modification in cases of suboptimal clinical outcome or non-compliance. Well designed RCTs for the identification of robust surrogate markers of thiopurine efficacy and toxicity are required.

P312 Thiopurine metabolite testing in inflammatory bowel disease

P312 Thiopurine metabolite testing in inflammatory bowel disease

Role of Thiopurine Metabolite Testing and Thiopurine Methyltransferase Determination in Pediatric IBD

Role of Thiopurine Metabolite Testing and Thiopurine Methyltransferase Determination in Pediatric IBD

Role of Thiopurine Metabolite Testing and Thiopurine Methyltransferase Determination in Pediatric IBD

Thiopurines have been used in inflammatory bowel disease (IBD) for >30 years, and measurements of both thiopurine methyltransferase (TPMT) and thiopurine (TP) metabolites, 6-thioguanine nucleotides (6-TGN) and 6-methylmercaptopurine (6-MMP), have been readily available. The North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition (NASPGHAN) Committee on Inflammatory Bowel Disease thought it appropriate to review the present indications for use of TPMT and TP metabolite testing. Substantial evidence demonstrates that TP therapy is useful for both Crohn disease and ulcerative colitis. Review of the existing data yielded the following recommendations. TPMT testing is recommended before initiation of TPs to identify individuals who are homozygote recessive or have extremely low TPMT activity, with the latter having more reliability than the former. Individuals who are homozygous recessive or have extremely low TPMT activity should avoid the use of TPs because of concerns for significant leukopenia. TMPT testing does not predict all cases of leukopenia and has no value to predict hypersensitivity adverse effects such as pancreatitis. Any potential value to reduce the risk of malignancy has not been studied. All individuals taking TPs should have routine monitoring with complete blood cell count and white blood cell count differential to evaluate for leukopenia regardless of TPMT testing results. Metabolite testing can be used to determine adherence with TP therapy. Metabolite testing can be used to guide dose increases or modifications in patients with active disease. Consideration would include either increasing the dose, changing therapy or for those with elevated transaminases or an elevated 6-MMP, using adjunctive allopurinol to help raise 6-thioguanine metabolites and suppress formation of 6-MMP. Routine and repetitive metabolite testing has little or no role in patients who are doing well and taking an acceptable dose of a TP.

Thiopurine metabolite measurement leads to changes in management of inflammatory bowel disease

The thiopurines azathioprine and 6-mercaptopurine are recommended for maintenance of remission in inflammatory bowel disease (IBD). Measurement of concentrations of the metabolites 6-thioguanine nucleotide and 6-methylmercaptopurine helps delineate interindividual variation in metabolism that may underlie variability in efficacy and toxicity. We aimed to perform a retrospective observational study to determine the utility of thiopurine metabolite testing following its introduction into South Australia. All patients having thiopurine metabolite tests done at Flinders Medical Centre between November 2008 and January 2010 were identified. Case notes of patients with testing done in the context of treatment for IBD were interrogated to determine the reason for testing, clinical context and outcome. One hundred and fifty-one patients were identified with thiopurine metabolite testing for IBD with 157 testing episodes. Eighty (51.0%) had testing done for flare or inefficacy, 18 (11.5%) for adverse effects, 5 (3.2%) for a combination of inefficacy and adverse effects, and 54 (34.4%) for routine or other reasons. Testing was followed by improved outcomes of increased efficacy, reduced toxicity or change to alternative therapy in 55.0% of the inefficacy/flare group, 27.8% of the suspected adverse reaction group, 60.0% of the combination group, and 13.0% of the routine/other group. Allopurinol was used as cotherapy in 16 patients and led to marked improvements in metabolite concentrations. Thiopurine metabolite testing has quickly become established in South Australia. When used for inefficacy or adverse effects, it often leads to improved outcomes. Prospective studies are needed to determine whether routine testing to guide dosing is of benefit.

Clinical usefulness of therapeutic drug monitoring of thiopurines in patients with inadequately controlled inflammatory bowel disease

Circulating concentrations of 6-thioguanine nucleotide (6-TGN) and 6-methyl mercaptopurine (6-MMP) are associated with thiopurine efficacy and may predict toxicity. This study aimed to examine retrospectively the utility of measuring metabolite concentrations in patients with inflammatory bowel disease (IBD) who had continuing symptoms despite stable thiopurine treatment. Concentrations of 6-TGN and 6-MMP were measured in lysates of washed red cells by high-performance liquid chromatography in peripheral blood drawn from 63 symptomatic patients with IBD (63% men, mean age 37, range 14-74 years, 67% Crohn's disease, 33% ulcerative colitis) treated with azathioprine or 6-mercaptopurine. Short-term clinical outcomes were examined. 6-TGN concentrations weakly correlated with the thiopurine dose (r = 0.28, P = 0.08). On weight-based criteria, 50% of patients were underdosed. However, metabolite patterns suggested 7 (11%) patients were noncompliant, 18 (29%) were being underdosed, 33 (52%) were refractory to treatment with either appropriate (41%) or elevated (11%) metabolite concentrations, and 6 (10%) had a raised 6-MMP:6-TGN ratio consistent with aberrant thiopurine metabolism. The clinical outcome improved in 40 of 46 (87%) of patients in whom the course of action taken was as recommended by a metabolite-directed algorithm, while 3 of 17 patients (18%) improved where discordant actions were taken (P = 0.0001; Fisher's exact test). Fifteen patients (24%) avoided inappropriate escalation of therapy. Dose-optimization or toxicity-avoidance strategies frequently result from metabolite testing in patients with inadequate efficacy from thiopurines, with evidence of better outcomes. Thiopurine metabolite testing is a potentially powerful tool for optimizing thiopurine usage in IBD.

Thiopurine Methyltransferase and Thiopurine Metabolite Testing in Patients with Inflammatory Bowel Disease who are Taking Thiopurine Drugs

Thiopurine methyltransferase genotyping and thiopurine metabolite testing has been established as an adjunct to monitoring patients taking thiopurine drugs. This special report describes the clinical implications for this type of testing for patients with inflammatory bowel disease who are taking thiopurine drugs. A total of 10% of patients were found to be intermediate metabolizers and the mean dosage (in mg/kg equivalent) was lower in intermediate metabolizers than extensive metabolizers. The metabolite levels did not correlate with scores measuring clinical severity but levels of 6-methylmercaptopurine were related to the dosage of the drugs. Despite considerable study of thiopurine methyltransferase testing in the literature, it is still not widely used in many geographical areas. This study adds to the evidence about using such testing as well as expanding the role of simultaneously measuring thiopurine metabolites. Further work is planned to evaluate the uptake when such testing becomes available locally as a clinical service.

Improved HPLC methodology for monitoring thiopurine metabolites in patients on thiopurine therapy

Objective: Standardization of thiopurine metabolite testing is currently lacking. This paper presents in-depth methodological analysis and optimization of two currently available HPLC procedures (Lennard–Singleton [J. Chromatogr. 583 (1992) 83] and Dervieux–Boulieu [Clin. Chem. 44 (1998) 551]) to improve precision, turn-around time, ruggedness, and cost effectiveness. Design and methods: Reversed-phase chromatography with UV detection was performed on a Waters HPLC system. The two protocols were improved with regards to internal standardization (IS), chromatographic conditions, as well as reagent preparation, storage, and use. 6-Thioguanine nucleotides (6-TGNs) were analyzed by our optimized techniques in samples from patients on thiopurine therapy ( n = 24) and the results were compared. Results: 6-Mercaptopurine (6-MP) was an ideal internal standard in either procedure. Isocratic elution with 5% acetonitrile (ACN) in 20 mmol/l phosphate buffer pH 2.5 allowed for minimal background interference in both protocols. 6-Thioguanine, 6-mercaptopurine, and 6-methylmercaptopurine (6-MMP) eluted at around 4, 5, and 6 min, respectively. Dithiothreitol (DTT) was critical only during the acid hydrolysis step. Less mercury-containing waste was generated in the Lennard–Singleton procedure. With our optimized protocols recovery of 6-TGNs was on average 1.38-fold higher in the Dervieux–Boulieu method over a range of 10–678 pmol/8 × 10 8 RBC and no interfering peaks hindered analysis. Specific extraction of thiopurines before their analysis as per Lennard–Singleton procedure may be redundant. Conclusions: We improved the quality and cost effectiveness of two known procedures for thiopurine metabolite assay. Through common chromatographic conditions and internal standardization, future comparison studies are now facilitated a great deal. The less tedious Dervieux–Boulieu procedure for routine thiopurine metabolite testing is warranted.