Melissa A. Smith

Review article: malignancy on thiopurine treatment with special reference to inflammatory bowel disease

Aliment Pharmacol Ther 2010; 32: 119–130

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.

Process mapping the patient journey: an introduction

Process mapping enables the reconfiguring of the patient journey from the patient’s perspective in order to improve quality of care and release resources. This paper provides a practical framework for using this versatile and simple technique in hospital.

Pharmacogenomics in the treatment of inflammatory bowel disease

In recent years, the benefits of early aggressive treatment paradigms for inflammatory bowel disease have emerged. Symptomatic improvement is no longer considered adequate; instead, the aim of treatment has become mucosal healing and altered natural history. Nonetheless, we still fail to achieve these end points in a large number of our patients. There are many reasons why patients fail to respond or develop toxicity when exposed to drugs used for inflammatory bowel disease, but genetic variation is likely to account for a significant proportion of this. Some examples, notably thiopurine methyltransferase polymorphism in thiopurine treatment, are already established in clinical practice. We present a review of the expanding literature in this field, highlighting many interesting developments in pharmacogenomics applied to inflammatory bowel disease and, where possible, providing guidance on the translation of these developments into clinical practice.

Nutritional management of adults with inflammatory bowel disease: practical lessons from the available evidence

Inflammatory bowel disease (IBD) is associated with impairment of nutritional status both anthropometrically and biochemically, which results from both qualitative and quantitative changes in dietary intake alongside disease activity. Dietary intervention to replace deficiency is essential and may also be used to treat active disease and to reduce symptoms. The evidence for dietary interventions in this area is reviewed and the following recommendations made: ■ Assessment of nutritional status is an essential part of the investigation of all patients with IBD and deficiency should be actively sought. ■ Any patient with macro- or micronutrient deficiency should be referred for dietetic assessment. ■ Micronutrient deficiency (most frequently iron, vitamin B12, folate and magnesium) should be replaced aggressively, parenterally if necessary. ■ Significant improvement in gastrointestinal symptoms can be achieved by low-residue diets (for stricturing disease) and (always under dietetic supervision) management of lactose and other intolerances. ■ Irritable bowel syndrome symptoms in patients with IBD can respond to low fermentable oligo-, di-, monosaccharide and polyol (FODMAP) diets, again this must be done under dietetic supervision. ■ Active Crohns disease can be treated by exclusive enteral nutrition (elemental/polymeric/altered fat formulations all have equivalent efficacy). ■ Enteral nutrition can maintain remission in Crohns disease and in this context can be given alongside normal oral intake. ■ Nutritional support does not have an established role in the treatment of active ulcerative colitis, other than in the management of malnutrition. ■ Total parenteral nutrition should not be used unless intestinal failure occurs. ■ There is insufficient evidence to support the routine use of Ω3 fish oil, prebiotics and glutamine in the treatment of active IBD.

567 Optimizing the Response to Thiopurine Therapy: A Search for Novel Explanations for Thiopurine Hypermethylation

Introduction Thiopurines are not effective in up to 1/3 of patients with inflammatory bowel disease (IBD) and 1/5 have to discontinue therapy due to side effects. An important cause of these problems is thiopurine hypermethylation. This is a catabolic process leading to an unfavourable thiopurine metabolite profile (high methyl-mercaptopurine (MeMP) to low thioguanine nucleotide (TGN) ratio; >11:1), which cannot be predicted by measurement of thiopurine- S -methyltransferase (TPMT) activity. Importantly thiopurine hypermethylation can be circumvented with the use allopurinol in combination with a low dose thiopurine. The aim of this study is to establish the mechanism of thiopurine hypermethylation and identify predictive genetic markers to allow early combination therapy. We hypothesised that thiopurine hypermethylation occurs as a result of genetic factors that affect methylation flux and the cellular transport of methylated metabolites. Methods 168 age and dose-matched patients prescribed AZA/6-MP were identified. Genomic DNA was extracted from EDTA blood samples of 76 patients demonstrating thiopurine hypermethylation and 92 patients with normal methylation profiles. Polymorphic sequence variants in genes predicted to affect thiopurine methylation flux and cellular metabolite transport were identified from single nucleotide polymorphism (SNP) databases and genotyped by Taqman assay. Associations were tested using Fisher9s Exact test. Results We found a significant association between the haplotype of rs9332377 T and rs4646316 C, which encodes a low-activity synonymous Catechol-O-methyltransferase (COMT) variant, and protection from thiopurine hypermethylation (rs9332377 T, p=0.0178, rs4646316 C, p=0.03). A polymorphism in the nucleo-base transporter, ABCB5, was significantly associated with thiopurine hypermethylation (rs2031641 G/G, p=0.0098). The association was strengthened when patients with MeMP levels >5000 pmol/l vs MeMP Conclusion Changes in methylation flux due to the activity of methyltransferases other than TPMT affect the formation of thiopurine methylated metabolites, likely through direct competition for the essential co-factor S-adenosylmethionine. Furthermore, polymorphism in the ABCB5 gene, which affects the nucleotide-binding domain of this transporter, is associated with thiopurine hypermethylation, suggesting reduced cellular efflux of methylated metabolites. Further studies are now indicated to establish the role of these genetic markers in clinical practice. Competing interests None declared.

655 Genetic Polymorphism in the Multi-Drug Resistance-5 Gene is Associated With Non-Response to Azathioprine Treatment in Inflammatory Bowel Disease

Introduction Multidrug resistance (MDR) genes encode transmembrane ATP-dependent pumps, otherwise known as the ATP-binding cassette subfamily-b (ABCB) transporters responsible for removing xenobiotics, particularly drugs, from cells. Thiopurine metabolites are exported from cells by MDR-4 and MDR-5. Altered ABCB pump activity has been linked to treatment resistance in other contexts. Methods Using Taqman® real-time PCR genotyping assays, a prospective cohort of 192 patients receiving azathioprine for IBD was genotyped for three coding region SNPs in MDR4 and three in MDR5, (all of which occur commonly in the Caucasian population). The SNPs tested were in MDR4: 175C→T, 711A→T and 1954A→G and in MDR5: 2T→C, 343A→G and 1573G→A. Association between genotype and clinical outcome on azathioprine treatment (complete response, non-response or withdrawal due to side-effects) was sought. Association tests were performed under a dominant model, using Fisher9s Exact test. No correction for multiple testing has been applied. Results The SNP MDR-5 c.343A→G was associated with a lack of clinical response to thiopurine treatment p=0.02, OR 2.43, 95%CI 1.14 to 5.17. Moreover, when analysed alongside other known markers of non-response to thiopurine treatment, (TPMT activity >35 pmol/h/mgHb and AOX 3404A→G) increasing numbers of markers increased their chance of non-response, p=0.0001 (χ2 for trend). No other SNP had a significant effect on clinical response and no SNP was associated with ADRs. Conclusion This study raises the possibility that MDR polymorphism could be important in thiopurine pharmacogenetics and warrants further study in other cohorts. Reliable markers of non-response to thiopurines could be incorporated into a panel of pharmacogenetic markers to inform the selection and dosing of immunomodulatory drugs, offering each individual the best chance of achieving early effective disease control Abstract 043.

Sa1911 Calculating the “Missed Opportunity” of Thiopurine Monotherapy Overcome With Thiopurine and Allopurinol Combination Therapy

Introduction A proportion of patients preferentially methylate thiopurines, resulting in high levels of methylated metabolites and low levels of thioguanine nucleotides. This can result in hepatotoxicity and treatment non-response. Co-prescription of thiopurines (at 25%–50% of standard dose) with allopurinol, (which blocks xanthine oxidase) circumvents this problem, optimising metabolite profile and clinical outcome and additionally overcomes atypical side effects experienced on thiopurine monotherapy. Using data from a large cohort of patients receiving combination therapy, we aimed to establish what proportion of all patients starting thiopurines could benefit from combination treatment. Methods Using data from a cohort of 109 patients recruited retrospectively, all receiving combination therapy in our clinic, 1yr clinical response rates were calculated by indication. Using data from a published prospective cohort and side effect rates from meta-analysis, we calculated the proportion of all patients starting thiopurines that could be salvaged from treatment failure to 1yr remission by combination therapy. Results 10/17 (59%) of hyper-methylating non-responders to thiopurine monotherapy, 8/17 (47%) of those treated for atypical side effects and 11/15 (73%) switched for hepatotoxicity achieved remission at 1 year. Using these response rates, potential gain was calculated from a prospective cohort (n=207) from our centre. 60 patients discontinued thiopurine monotherapy due to non-specific side effects, eight due to hepatitis and 32 were hyper-methylating non-responders, a total of 100 patients with clear indications for combination treatment. Our results predict that 53/100 could have achieved 1-year remission, representing 26% of the original cohort. Using a more conservative published side effect rate of 10% (Prefontaine et al 2010, Cochrane Database of Systematic Reviews, CD000545) and excluding 2.8% due to side effects unsuitable for combination therapy (pancreatitis and myelotoxicity), 12% of all patients started on azathioprine could have their outcome on thiopurine therapy converted from treatment failure to 1-year remission by combination therapy. Conclusion 12%–26% represents the “missed opportunity” of patients starting thiopurine monotherapy which can be realistically overcome by combination treatment with allopurinol, converting treatment failure to successful 1-year remission. Given that thiopurines remain a key part of most IBD treatment paradigms, this is an important opportunity for improved treatment outcomes in IBD. Competing interests None declared.

W1915 Further Experience of Optimising Treatment Outcome on Azathioprine by Co-Prescription of Allopurinol in Patients With Inflammatory Bowel Disease

Introduction Many patients, particularly those with high thiopurine methyltransferase (TPMT) activity, preferentially methylate thiopurine drugs, resulting in high levels of methylated metabolites and low thioguanine nucleotides (TGNs). This metabolite pattern is associated with hepatotoxicity and non-response to treatment. Co-prescription of thiopurines (at 25–50% of standard dose) with allopurinol, (which blocks xanthine oxidase) appears to circumvent this problem, optimising both metabolite profile and clinical outcome. Data on the use of allopurinol and thiopurines remain limited. We previously reported our experience of using this combination in thiopurine-related hepatotoxicity. In this study we report further experience for a broader indication, including toxicity (mainly hepatic) non-response with adverse metabolite profile, and very high TPMT activity. Methods Patients prescribed combination treatment were identified from notes in the IBD clinic, TGN monitoring results and hospital pharmacy records. Data were collected retrospectively. We were particularly interested in whether combination treatment overcame the specific problem that precluded thiopurine monotherapy. We also analysed changes in metabolite profiles and subsequent clinical outcome. Results 35 patients have been co-prescribed allopurinol and thiopurines since our previous report. 20 had Crohn9s disease and 15 ulcerative colitis, age range 20–65 years. Their average TPMT activity was 40 pmol/h/mgHb, (vs 32.5 in our population overall). In those receiving co-prescription for adverse effects (14 hepatotoxicity and three other: rash, nausea, fatigue) 94% were able to tolerate combination treatment with complete resolution of liver function tests abnormalities where relevant, of these 88% achieved clinical remission. In 10 patients failing thiopurine monotherapy 50% achieved clinical response on combination treatment. In eight started on combination treatment as primary therapy six (75%) achieved remission, comparing favourably with historical controls. The only adverse event was a transient lymphopaenia in a patient that had mistakenly continued full dose thiopurine. TGN levels increased from an average of 192 to 449 pmol/8×108 RBC on co-treatment, while methylmercaptopurine levels decreased from an average of 503 pmol/8×108 RBC on single agent treatment to just 16 on combination therapy. Conclusion Combination treatment with reduced-dose thiopurine and allopurinol circumvents predominant methylation, optimising metabolite profiles, avoiding hepatotoxicity and improving clinical response. Using combination treatment as first line should lead to a faster remission in those with high TPMT activity. Allopurinol co-prescription may also overcome other side effects. Whether combination therapy should be used first-line in those with high TPMT activity, or more extensively, warrants further investigation in a prospective trial.