炎症性肠病患者硫嘌呤甲基转移酶与嘌呤类药物毒副反应的关系

背景：嘌呤类药物广泛用于炎症性肠病（IBD）患者的诱导缓解和维持治疗,然而毒副反应的频繁发生使其临床应用受到限制。有研究显示检测硫嘌呤甲基转移酶（TPMT）活性和基因型能预测硫唑嘌呤（AZA）相关的毒副反应。目的：评价TPMT活性和基因型与AZA治疗IBD的毒副反应的关系。方法：收集2008年10月～2010年12月于上海仁济医院确诊并接受AZA治疗（每日1（？）kg）的78例IBD患者。采用高效液相色谱法（HPLC）检测TPMT活性,以直接测序和PCR法检测TPMT基因型。分析TPMT活性和基因型与AZA毒副反应的关系。结果：共19例患者发生毒副反应,包括4例血液学毒副反应。78例IBD患者的平均TPMT活性为（36.10±10.11）nmol 6-MTG·gHb~（-1）·h~（-1）。低TPMT活性组与高TPMT活性组发生总毒副反应和血液学毒副反应的OR值分别为6.82（95%CI：0.58～79.91）和12.00（95%CI：0.84～172.22）,但差异均无统计学意义。仅1例患者发生TPMT＊3C杂合子突变,突变率为1.3%,且该例患者发生了血液学毒副反应。结论：IBD患者的TPMT活性降低和基因突变与嘌呤类药物的总毒副反应和血液学毒副反应可能相关,但其临床实际应用价值有待进一步研究。     

How I treat my inflammatory bowel disease-patients with thiopurines?

Thiopurines are essential drugs to maintain remission in patients with inflammatory bowel disease(IBD).Thiopurines used in IBD are azathioprine(2.0-2.5 mg/kg),mercaptopurine(1.0-1.5 mg/kg) and thioguanine(0.2-0.3 mg/kg).However,mainly due to numerous adverse events associated with thiopurine use,almost 50% of the patients have to discontinue conventional thiopurine treatment.Extensive monitoring and the application of several treatment strategies,such as split-dose administration,co-administration with allopurinol or dose reduction/increase,may increase the chance of successful therapy.With this review,we provide practical information on how thiopurines are initiated and maintained in two thiopurine research centers in The Netherlands.We provide clinical information concerning safety issues,indications and management of therapy that may serve as a guide for the administration of thiopurines in IBD patients in daily practice.     

Low dose methotrexate in inflammatory bowel disease: current status and future directions

Despite many recent advances, some notable limitations exist in the medical management of patients with inflammatory bowel disease. Glucocorticoids suppress active inflammation very effectively, but their long term use is associated with high rates of relapse and unacceptable toxicity. 6-Mercaptopurine and its prodrug azathioprine are effective in inducing and maintaining remission; however, a significant number of patients are resistant or intolerant to thiopurines. Low dose methotrexate, an anti-inflammatory drug, is a well established medication for rheumatoid arthritis and psoriasis. After an initial report in 1989, several clinical trials and analyses of clinical notes have examined the role of methotrexate in patients with ulcerative colitis and Crohn's disease. This review was conducted to summarize the current knowledge about the underlying basic anti-inflammatory mechanisms of methotrexate as well as the pharmacology and toxicology of this drug with particular emphasis on inflammatory bowel disease. It also critically evaluates all existing trials not only in the induction of remission but also in maintenance therapy. We conclude that low dose methotrexate is an effective and safe treatment in glucocorticoid-dependent and thiopurine intolerant patients with Crohn's disease but not ulcerative colitis. It remains to be seen whether low dose methotrexate may also be useful in long term maintenance therapy in patients with inflammatory bowel disease.     

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.     

Compliance to drug therapy in inflammatory bowel diseases outpatients from a university hospital

BACKGROUND: Compliance to drug therapy is important for a successful treatment. Although many studies have assessed compliance to treatment in patients with chronic diseases, few investigations have been carried out in inflammatory bowel diseases. AIM: To assess compliance to drug therapy in patients with inflammatory bowel diseases, Crohn's disease and ulcerative colitis, followed at a university hospital, who had prescribed medication supplied by the Brazilian National Health System. METHODS: In a cross sectional study, a structured interview was applied to assess the compliance of 26 Crohn's disease patients, 26 ulcerative colitis patients and 4 cases with undetermined colitis. Patients were characterized as presenting higher or lower degree of compliance, based on the comparison of the information provided by the patient in the interview and data in the medical records. The Morisky test was also used to assess the behavioral pattern of the patient regarding the daily use of the medication. RESULTS: The interview showed that 15.4% of patients with Crohn's disease and 13.3% of those with ulcerative colitis could be regarded as less compliant. However, the Morisky test revealed lower compliance in 50% of patients with Crohn's disease and 63.3% of those with ulcerative colitis. Univariate analysis showed an association between low compliance and long disease duration, married status and colon involvement in Crohn's disease, and between low compliance and increased disease activity and greater number of medications in ulcerative colitis. However, multivariate analysis did not confirm any association between low compliance and any demographic or clinical factor. CONCLUSIONS: A high degree of noncompliance to treatment, linked to habitual behavior and hard to predict from demographic or clinical factor, was detected in inflammatory bowel disease patients, which suggests the need for investment in patient education regarding medication use.     

Safety of thiopurines in the treatment of inflammatory bowel disease

BACKGROUND: Thiopurines have proven efficacy in inflammatory bowel disease. However, concerns regarding toxicity have limited the use of these agents as first line of medical therapy. METHODS: Review of the literature regarding metabolism, efficacy and side effects. RESULTS: In clinical trials, up to 15% of patients discontinued 6-mercaptopurine or its pro-drug azathioprine prematurely due to adverse events. These events may be divided into dose-independent idiosyncratic reactions and dose-related, pharmacologically explainable toxicity. Dose-independent reactions include skin rash, fever, diarrhoea and pancreatitis. Most frequently observed dose-dependent adverse events are nausea, malaise and myelotoxicity. Furthermore, dose-dependent and dose-independent hepatotoxicity may occur. Recent insights obtained by therapeutic drug monitoring in patients on azathioprine or 6-mercaptopurine have led to strategies to reduce toxicity. One strategy is to detect poor metabolisers of thiopurines by establishing the activity of the key enzyme thiopurine methyltransferase. However, the clinical relevance of this strategy is still a point of debate. Another strategy is to administer 6-thioguanine, which is an agent close to the effective 6-thioguanine nucleotides. CONCLUSION: Therapeutic drug monitoring of thiopurines resulted in strategies to reduce toxicity. The value of these strategies has yet to be proven in prospective randomized trials.     

Thiopurines in inflammatory bowel disease: pharmacogenetics, therapeutic drug monitoring and clinical recommendations

There is a growing interest in the use of thiopurines (azathioprine, 6-mercaptopurine and 6-thioguanine) for the management of inflammatory bowel disease. The genetically controlled thiopurine (S)-methyltransferase enzyme is involved in the metabolism of these agents and is hypothesised to determine the clinical response to thiopurines. Diminished activity of this enzyme decreases the methylation of thiopurines, theoretically resulting in potential overdosing, while high thiopurine (S)-methyltransferase status leads to overproduction of toxic metabolites and ineffectiveness of azathioprine and 6-mercaptopurine. In practice, controversies exist regarding the utility of standard thiopurine (S)-methyltransferase pheno- and genotyping. Current pharmacogenetic insights suggest that another enzyme system may participate in the efficacy and toxicity of thiopurines; inosine triphosphate pyrophosphatase. Other topics discussed in this review are the utilisation of therapeutic drug monitoring and the experimental use of 6-thioguanine in the treatment of inflammatory bowel disease. 6-Thioguanine has a less genetically controlled metabolism and skips genetically determined metabolic steps. On theoretical basis, 6-thioguanine might therefore have a more predictable profile than azathioprine and 6-mercaptopurine. However, the use of 6-thioguanine has been associated with an increased risk of nodular regenerative hyperplasia of the liver and veno-occlusive disease. Further research is warranted before 6-thioguanine can be considered as a treatment option for inflammatory bowel disease.     

Biomarkers for gastrointestinal adverse events related to thiopurine therapy

Thiopurines are immunomodulators used in the treatment of acute lymphoblastic leukemia and inflammatory bowel diseases. Adverse reactions to these agents are one of the main causes of treatment discontinuation or interruption. Myelosuppression is the most frequent adverse effect; however, approximately 5%-20% of patients develop gastrointestinal toxicity. The identification of biomarkers able to prevent and/or monitor these adverse reactions would be useful for clinicians for the proactive management of long-term thiopurine therapy. In this editorial, we discuss evidence supporting the use of PACSIN2, RAC1, and ITPA genes, in addition to TPMT and NUDT15, as possible biomarkers for thiopurine-related gastrointestinal toxicity.     

Thiopurines in inflammatory bowel disease revisited

Although a great variety of new drugs have been introduced for the therapy of inflammatory bowel diseases so far,a definite cure of the disease is still out of scope.An anti-inflammatory approach to induce remission followed by maintenance therapy with immunosupressants is still the mainstay of therapy.Thiopurines comprising azathioprine and its active metabolite mercaptopurine as well as tioguanine,are widely used in the therapy of chronic active inflammatory bowel disease(IBD).Their steroid sparing potential and efficacy in remission maintenance are out of doubt.Unfortunately,untoward adverse events are frequently observed and may preclude further administration or be life threatening.This review will focus on new aspects of thiopurine therapy in IBD,its efficacy and safety.     

Azathioprine and 6-mercaptopurine pharmacogenetics and metabolite monitoring in inflammatory bowel disease

The thiopurine drugs azathioprine and 6-mercaptopurine (6-MP) are well-established in the treatment of inflammatory bowel disease (IBD). However, there is a wide inter- and intra-patient variation in the concentrations of active and toxic metabolites due to their complex metabolism and genetic polymorphisms in metabolizing enzymes. Serious drug toxicity leads to cessation of therapy in 9-25% of patients, and there is failure to achieve efficacy in approximately 15% of cases. Advances in the understanding of thiopurine drug metabolism have led to new genetic and metabolite tests to help clinicians optimize thiopurine use. Thiopurine methyltransferase (TPMT) enzyme activity can predict life-threatening myelotoxicity in the one in 300 patients who are TPMT-deficient. However, myelotoxicity can also occur in the presence of normal TPMT activity so blood count monitoring should remain standard practice. TPMT testing may also aid in dose individualization. 6-Thioguanine nucleotides (6-TGN) are thought to be the predominant active metabolites of the thiopurines. 6-thioguanine nucleotide concentration is correlated with bone marrow toxicity and may also correlate with efficacy in IBD. Measurement of 6-TGN and 6-methylmercaptopurine (6-MMP) concentration is most useful in determining why a patient is not responding to a standard dose of a thiopurine drug and may help in avoiding myelosuppression. The ratio of these metabolites can help distinguish non-compliance, under-dosing, thiopurine-resistant and thiopurine-refractory disease. Some of these investigations are entering routine clinical practice but more research is required to determine their optimal use in patients with IBD.     

Efficacy and safety of 6-thioguanine in the management of inflammatory bowel disease

OBJECTIVE: 6-Thioguanine has been used as an alternative immunomodulator in the treatment of inflammatory bowel disease but data on its efficacy and safety are limited. The aim of this study was to analyse our experience of the efficacy and safety of 6-thioguanine in inflammatory bowel disease. MATERIAL AND METHODS: Patients attending the inflammatory bowel disease clinic who were started on 6-thioguanine therapy were included in this prospective observational study. Indications for initiating 6-thioguanine therapy and other related clinical, pharmacological and laboratory parameters prior to and during therapy were recorded to determine the efficacy and safety of 6-thioguanine. RESULTS: A total of 40 patients were treated with 6-thioguanine, 28 with Crohn's disease, 10 with ulcerative colitis and 2 with indeterminate colitis, at a fixed daily dose of 40 mg and continued for a median duration of 34 weeks (range 2-90 weeks). The indications for 6-thioguanine therapy included previous clinical resistance to thiopurine analogues (n=21), intolerance to thiopurine analogues (n=8) and de novo 6-thioguanine use in steroid refractory disease (n=11). Disease remission was reached in 44%, 73% and 89% of these patient groups at 3, 6 and 12 months, respectively. Inflammatory markers and steroid use were significantly lower during 6-thioguanine therapy compared with in the period before therapy. Therapy was discontinued in 13 patients (33%), mainly because of thrombocytopenia and associated hepatotoxicity. CONCLUSIONS: 6-Thioguanine is a useful addition to treatment in inflammatory bowel disease but the frequent occurrence of hepatotoxicity limits its routine use.     

Some cases demonstrating the clinical usefulness of therapeutic drug monitoring in thiopurine-treated inflammatory bowel disease patients

The thiopurines azathioprine and 6-mercaptopurine (6-MP) are effective drugs in steroid-dependent and refractory inflammatory bowel disease patients. Therapeutic drug monitoring (TDM) is a new concept to improve drug efficacy and prevent toxic adverse events. As thiopurine metabolism is influenced by genetic polymorphisms of methylating enzymes, metabolite levels may vary considerably, enabling significant adverse effects. In the present paper five patients are described to demonstrate the clinical usefulness of TDM when applying thiopurines for inflammatory bowel disease. Emphasized are patients with liver function test abnormalities and myelosuppression due to inappropriate 6-MP metabolite levels, and subsequently the treatment of these events. In addition, sophisticated 6-MP metabolite level-guided therapy, including non-compliance, is demonstrated. These cases demonstrate that TDM may improve effectivity and safety of thiopurine treatment.     

The use of thiopurines for the treatment of inflammatory bowel diseases in clinical practice

BACKGROUND: Thiopurines are the most commonly used immunomodulatory drugs in inflammatory bowel diseases. AIM: To evaluate the use, the therapeutic and safety profiles of thiopurines in a large sample of IBD patients. METHODS: We reviewed 3641 case histories of IBD patients. Thiopurines were prescribed in 582 patients (16.0%); the analysis was performed on the 553 (267 ulcerative colitis, 286 Crohn's disease) with exhaustive clinical data. RESULTS: The main indications for treatment were steroid-dependence (328/553, 59.3%) and steroid-resistance (113/553, 20.7%). Thiopurines were started when CD were younger than UC patients (p<0.001) but earlier from diagnosis in UC than in CD patients (p=0.003). Efficacy was defined as optimal (258/553, 46.6%), partial (108/553, 19.5%), absent (85/553, 15.4%) and not assessable (102/553, 18.4%). Efficacy was independent of disease type, location/extension or duration and age at starting. Side effects were observed in 151/553 (27.3%) patients, leading to drug discontinuation in 101 (18.3%). 15 out of the 130 (11.5%) patients who took thiopurines for more than 4 years relapsed, more frequently in CD than in UC (OR=3.67 95% C.I. 0.98-13.69; p=0.053). CONCLUSIONS: Thiopurines confirm their clinical usefulness and acceptable safety profile in managing complicated IBD patients. The majority of patients treated for longer than 4 years maintain response. No clinical and demographic predictive factors for efficacy and side effects were identified.     

Usefulness of thiopurine methyltransferase and thiopurine metabolite analysis in clinical practice in patients with inflammatory bowel diseases

Thiopurines (TP) are widely used in the management of inflammatory bowel diseases. Side-effects and inefficacy are a major concern as they lead to withdrawal of the drug. Tools investigating TP metabolism are useful to avoid inadequate cessation of TP therapy. TP metabolism is complex and many enzymes are involved. Among them, Thiopurine methyltransferase (TPMT) is the only one routinely measured by pheno- or genotyping. In this review, the rationale for TPMT and thiopurine metabolites, 6-thioguanine nucleotides and 6-methylmercaptopurine, determination in clinical practice is discussed, specifically in case of thiopurine failure and recommendations are given about their interpretation and potential dose optimization of TP drugs.     

Recomendaciones del Grupo Español de Trabajo en Enfermedad de Crohn y Colitis Ulcerosa (GETECCU) sobre el uso de tiopurinas en la enfermedad inflamatoria intestinal

Thiopurines (azathioprine and mercaptopurine) are widely used in patients with inflammatory bowel disease. In this paper, we review the main indications for their use, as well as practical aspects on efficacy, safety and method of administration. They are mainly used to maintain remission in steroid-dependent disease or with ciclosporin to control a severe ulcerative colitis flare-up, as well as to prevent postoperative Crohn's disease recurrence, and also in combination therapy with biologics. About 30-40% of patients will not respond to treatment and 10-20% will not tolerate it due to adverse effects. Before they are prescribed, immunisation status against certain infections should be checked. Determination of thiopurine methyltransferase activity (TPMT) is not mandatory but it increases initial safety. The appropriate dose is 2.5 mg/kg/day for azathioprine and 1.5 mg/kg/day for mercaptopurine. Some adverse effects are idiosyncratic (digestive intolerance, pancreatitis, fever, arthromyalgia, rash and some forms of hepatotoxicity). Others are dose-dependent (myelotoxicity and other types of hepatotoxicity), and their surveillance should never be interrupted during treatment. If therapy fails or adverse effects develop, management can include switching from one thiopurine to the other, reducing the dose, combining low doses of azathioprine with allopurinol and assessing metabolites, before their use is ruled out. Non-melanoma skin cancer, lymphomas and urinary tract tumours have been linked to thiopurine therapy. Thiopurine use is safe during conception, pregnancy and breastfeeding.     

TPMT genotype and the use of thiopurines in paediatric inflammatory bowel disease

BACKGROUND: Thiopurines are used in the treatment of inflammatory bowel disease. They are metabolised via methylation by thiopurine-S-methyltransferase (TPMT), which displays a genetically determined polymorphic activity. Subjects with reduced TPMT activity have a higher concentration of active thiopurine metabolites and may be at increased risk of bone-marrow suppression. AIMS: To evaluate the relevance of TPMT genotyping in the management of thiopurines therapy in inflammatory bowel disease patients. PATIENTS AND METHODS: Adverse effects and clinical response were determined retrospectively and correlated with TPMT genotype in 70 paediatric inflammatory bowel disease patients. RESULTS: Nineteen patients (27.1%) developed adverse effects; of the 51 who did not, 34 (66.7%) responded to treatment. Five patients (7.1%) were heterozygous for a variant TPMT allele; two of these (40%) were intolerant to thiopurines, compared to 17 of the 65 patients (26.2%) with a wild type gene (O.R. 1.88, 95% CI 0.29-12.2, p=0.61); among the 34 responders, the median dosage of the drug required to obtain remission was lower for mutated than for wild type patients (1.6mgkg(-1)day(-1) versus 2.0mgkg(-1)day(-1), p=0.043). CONCLUSIONS: There was no significant association between adverse effects of thiopurines and TPMT heterozygous genotype, but TPMT genotyping could be useful in establishing the most appropriate dose of thiopurines to start treatment.     

How are thiopurines used and monitored by Swedish gastroenterologists when treating patients with inflammatory bowel disease?

Abstract

Objective. To perform a survey of thiopurine treatment in inflammatory bowel disease (IBD) among Swedish gastroenterologists. Material and methods. A web-based questionnaire consisting of 25 multiple-choice questions was sent to 322 gastroenterologists in adult practice. Results. A total of 132 questionnaires were received giving a response rate of 41%. Thiopurines were used by all 122 gastroenterologists in IBD practice and azathioprine was the first-choice thiopurine among 118 (97%) of them. Almost all gastroenterologists (97%) used weight-based dosing that was gradually escalated. The vast majority (89%) considered that efficacy should be evaluated within 6 months of therapy, while opinions regarding the optimal duration of therapy varied considerably. It was seen that 74% switched thiopurine in case of intolerance to the first-line substance. Thiopurine S-methyltransferase (TPMT) determinations were performed by 74% of the gastroenterologists and 67% used metabolite measurements. TPMT analyzers were more likely to measure metabolites (74 vs. 43%, p = 0.002). A quarter of the respondents were familiar with unconventional immunomodulation (co-administration of allopurinol, 6-thioguanine, mycophenolate mofetil or tacrolimus) and these respondents were also more likely to measure metabolites (79 vs. 52%; p = 0.002). Conclusions. Thiopurines are well established in the treatment of IBD among Swedish gastroenterologists. New and evolving knowledge about thiopurine therapy in IBD has been adapted to a large extent. Whether this change in clinical practice will have an impact on treatment outcomes has yet to be proven.     

TPMT in the treatment of Crohn's disease with azathioprine

Azathioprine induced profound myelosuppression linked to TPMT deficiency has now been documented in many patient groups, including those with Crohn's disease. At the start of azathioprine or mercaptopurine therapy, measurement of TPMT activity has a role in identifying the 1 in 300 patients who are at risk of severe myelosuppression when treated with standard thiopurine dosages. During the initial months of azathioprine therapy a knowledge of TPMT status warns of early bone marrow toxicity. In patients established on azathioprine these is no clear evidence to suggest that TPMT is predictive of clinical response or drug toxicity, indicating a role for TPMT in the prediction of early events rather than long term control. In patients with Crohn's disease on long term azathioprine therapy, it is clear that myelosuppression, particularly leucopenia, is caused by other factors in addition to variable TPMT activity and therefore monitoring of blood cell counts throughout treatment is essential.     

Optimizing thiopurine therapy in inflammatory bowel disease

Despite recent advances, the therapeutic armamentarium for inflammatory bowel disease (IBD) is still limited. In addition, a step-up approach is recommended for most IBD patients. Thus, optimizing each medical therapy before switching to another drug class is the rule in clinical practice. Conventional therapies for IBD have not received the same amount of attention as biologic therapies over the last decade. However, due to their efficacy, safety, and low cost the thiopurine drugs azathioprine and 6-mercaptopurine remain the backbone of therapy for IBD. Pharmacogenomic advances and increased knowledge of their metabolism are allowing dosage optimization. Herein, after describing the pharmacogenetics and pharmacokinetics of thiopurines, we will discuss how to optimize thiopurine therapy. We will then underscore the need to take into account safety issues when optimizing thiopurine treatment.     

Optimization of the treatment with immunosuppressants and biologics in inflammatory bowel disease

Many placebo controlled trials and meta-analyses evaluated the efficacy of different drugs for the treatment of inflammatory bowel disease(IBD),including immunosuppressants and biologics.Their use is indicated in moderate to severe disease in non responders to corticosteroids and in steroid-dependent patients,as induction and maintainance treatment.Infliximab,as well as cyclosporine,is considered a second line therapy in the case of severe ulcerative colitis,or non-responders to intravenous corticosteroids.An adequate dosage and duration of therapy with thiopurines should be reached before evaluating their efficacy.Methotrexate is a valid option in patients with Crohn’s disease but its use is confined to patients who are intolerant or non-responders to thiopurines.Evidence for the use of methotrexate in ulcerative colitis is insufficient.The use of thalidomide and mycophenolate mofetil is not recommended in patients with inflammatory bowel disease,these treatments could be considered in case of failure of all other therapeutic options.In patients with moderately active ulcerative colitis,refractory to thiopurines,the use of tacrolimus is considered an alternative to biologics.An increase of the dose or a decrease in the interval of administration of biologic treatment could be useful in the presence of an incomplete clinical response.In the case of primary failure of an anti-tumor necrosis factor alpha a switch to another one should be considered.Data on the efficacy of combination therapy are up to now insufficient to consider this strategy in all IBD patients.The final outcome of the treatment should be considered the clinical remission,with mucosa healing,and not the clinical response.The evaluation of serum concentration of thiopurine methyl transferase activity,thiopurine metabolites,biologic serum levels and antibiologic antibodies could be useful for the management of the treatment but it has not been routinely applied in clinical practice.The evidence of high risk development of lymphoma and cutaneous malignancies should be considered in patients treated with immunosuppressants and biologics for a long period.