Safety Of Thiopurines Research Articles

Role of Pharmacogenomics in the Efficacy and Safety of Thiopurines in Inflammatory Bowel Disease: A Systematic Review and Meta-analysis.

Thiopurines' toxicity often leads to dose reduction or discontinuation. This systematic review aims to synthesize the evidence on the effect of genotype-based dosing of thiopurines on treatment efficacy and safety in inflammatory bowel disease (objective #1), and the association between genotype status and the efficacy and safety profile (objective #2). The Cochrane Library, MEDLINE, and EMBASE were searched in August 2021. A total of 80 studies (19,859 individuals) were included. Meta-analyses for mortality, different types of adverse events (AEs), withdrawal due to AE, change in disease activity and clinical remission were performed following mainly a fixed-effects model. PROSPERO registration: CRD42020148130. Genotype-based dosing was associated to a significantly lower incidence of hematologic AEs (risk ratio=0.71; 95% CI: 0.56-0.90; I2: 47%; 4 randomized controlled trials; moderate quality), which may be attributable to nudix hydrolase 15 (NUDT15) testing more than to thiopurine methyltransferase (TPMT) genotyping. No differences were found in other outcomes. Mutations in TPMT and NUDT15 genes were associated to a higher probability of serious AEs [odds ratio (OR) TPMT=4.98; OR NUDT15=11.44], hematologic AEs (OR TPMT=3.18), and serious hematologic AEs (OR TPMT=7.88; OR NUDT15=12.83). TPMT was also associated with a higher risk of withdrawals due to AEs (OR=3.38), and NUDT15 with gastrointestinal AEs (OR=2.04). Mutations in the ITPA gene did not lead to significant differences. Evidence of an association between other genes and clinical outcomes is still scarce. Mutations in TPMT and NUDT15 genes predispose patients to suffer thiopurine-induced toxicity, and genotype-guided treatment has been shown to contribute to the prevention of thiopurine-induced toxicity, especially in the case of NUDT15 in Asians.

Optimizing thiopurine therapy in children with acute lymphoblastic leukemia: A promising "MINT" sequencing strategy and therapeutic "DNA-TG" monitoring.

Thiopurines, including thioguanine (TG), 6-mercaptopurine (6-MP), and azathioprine (AZA), are extensively used in clinical practice in children with acute lymphoblastic leukemia (ALL) and inflammatory bowel diseases. However, the common adverse effects caused by myelosuppression and hepatotoxicity limit their application. Metabolizing enzymes such as thiopurine S-methyltransferase (TPMT), nudix hydrolase 15 (NUDT15), inosine triphosphate pyrophosphohydrolase (ITPA), and drug transporters like multidrug resistance-associated protein 4 (MRP4) have been reported to mediate the metabolism and transportation of thiopurine drugs. Hence, the single nucleotide polymorphisms (SNPs) in those genes could theoretically affect the pharmacokinetics and pharmacological effects of these drugs, and might also become one of the determinants of clinical efficacy and adverse effects. Moreover, long-term clinical practices have confirmed that thiopurine-related adverse reactions are associated with the systemic concentrations of their active metabolites. In this review, we mainly summarized the pharmacogenetic studies of thiopurine drugs. We also evaluated the therapeutic drug monitoring (TDM) research studies and focused on those active metabolites, hoping to continuously improve monitoring strategies for thiopurine therapy to maximize therapeutic efficacy and minimize the adverse effects or toxicity. We proposed that tailoring thiopurine dosing based on MRP4, ITPA, NUDT15, and TMPT genotypes, defined as “MINT” panel sequencing strategy, might contribute toward improving the efficacy and safety of thiopurines. Moreover, the DNA-incorporated thioguanine nucleotide (DNA-TG) metabolite level was more suitable for red cell 6-thioguanine nucleotide (6-TGNs) monitoring, which can better predict the efficacy and safety of thiopurines. Integrating the panel “MINT” sequencing strategy with therapeutic “DNA-TG” monitoring would offer a new insight into the precision thiopurine therapy for pediatric acute lymphoblastic leukemia patients.

Editorial: safety of thiopurines in pregnancy—considering the mother, foetus and newborn

LINKED CONTENTThis article is linked to Flanagan et al paper. To view this article, visit https://doi.org/10.1111/apt.16294

Steering a Course through the COVID-19 Pandemic: Should the SECURE-IBD Registry Influence Prescribing for Patients with Inflammatory Bowel Disease?

Summary The global pandemic caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2, also referred to as COVID-19) rapidly became an unprecedented healthcare challenge. It represents a particular concern for patients with inflammatory bowel disease (IBD), many of whom require treatment with immunosuppressive medication which may be associated with an increased risk of both viral and bacterial infections (Gastroenterology 2018;155(2):337-346.e10). Moreover, as IBD is a lifelong condition, patients are frequently older with comorbidities, further increasing the potential risks of a more severe COVID-19 disease course. This has led to considerable uncertainty over appropriate treatment of IBD in the COVID-19 era, and has brought safety considerations into the focus of the patients and physicians.

Review article: opportunities to improve and expand thiopurine therapy for autoimmune hepatitis.

Thiopurines in combination with glucocorticoids are used as first-line, second-line and maintenance therapies in autoimmune hepatitis and opportunities exist to improve and expand their use. To describe the metabolic pathways and key factors implicated in the efficacy and toxicity of the thiopurine drugs and to indicate the opportunities to improve outcomes by monitoring and manipulating metabolic pathways, individualising dosage and strengthening the response. English abstracts were identified in PubMed by multiple search terms. Full-length articles were selected for review, and secondary and tertiary bibliographies were developed. Thiopurine methyltransferase activity and 6-tioguanine (6-thioguanine) nucleotide levels influence drug efficacy and safety, and they can be manipulated to improve treatment response and prevent myelosuppression. Methylated thiopurine metabolites are associated with hepatotoxicity, drug intolerance and nonresponse and their production can be reduced or bypassed. Universal pre-treatment assessment of thiopurine methyltransferase activity and individualisation of dosage to manipulate metabolite thresholds could improve outcomes. Early detection of thiopurine resistance by metabolite testing, accurate estimations of drug onset and strength by surrogate markers and adjunctive use of allopurinol could improve the management of refractory disease. Dose-restricted tioguanine (thioguanine) could expand treatment options by reducing methylated metabolites, increasing the bioavailability of 6-tioguanine nucleotides and ameliorating thiopurine intolerance or resistance. The efficacy and safety of thiopurines in autoimmune hepatitis can be improved by investigational efforts that establish monitoring strategies that allow individualisation of dosage and prediction of outcome, increase bioavailability of the active metabolites and demonstrate superiority to alternative agents.

P677 Azathioprine dosing and metabolite measurement in paediatric inflammatory bowel disease—does one size fit all?

Azathioprine (AZA) is an effective immunomodulatory maintenance therapy in children with inflammatory bowel disease (IBD). Current recommended dosing is 2–2.5 mg/kg/dose in the presence of normal thiopurine methyltransferase (TPMT) level. Elevated levels of the AZA metabolites 6-TGN and 6-MMP have been associated with increased risk of myelotoxicity and hepatotoxicity, however evidence suggests that monitoring metabolites can help optimise effectiveness and safety of thiopurines. We aim to assess association between AZA weight-based dosing, thiopurine metabolites and disease activity index in a cohort of paediatric IBD patients. Retrospective data review (2015–2017) from the paediatric gastroenterology department at Evelina London Children’s Hospital. Children with IBD who were taking AZA and had regular thiopurine metabolites measurement were included. PCDAI and PUCAI were used to assess disease activity. A total of 41 patients, 38% female, 62% male with mean (±SD) age of diagnosis 12.2 (±3.4) years, were included. Twelve patients had ulcerative colitis (UC), 27 Crohn’s disease (CD) and 2 very early onset IBD (VEOIBD). Mean AZA dose, in mg/kg (±SD), 1.3 (±0.08). Mean 6TGN value (±SEM) 260 (±25.2), and mean MMT value (±SEM) 1023 (±168). Thiopurine metabolites were measured at (mean ± SEM) after (75 ± 13.5) days after starting AZA, 5 patients had elevated 6TGN levels >450. Mean lymphocyte count at time of metabolite measurement (±SD) 1.7 (±0.8). Activity index at the start of thiopurine were (±SD) 22.5 (±16.3) and when metabolites were measured 8.1 (±12). We have identified that the majority of our patients maintain clinical remission (defined by an activity index—PUCAI/PCDAI—of less than 10) on lower AZA doses than currently recommended. We have also identified a number of patients with elevated 6TGN levels without signs of myelosuppression. Higher doses of AZA are associated with higher metabolite levels, and we propose that regular routine measurement of AZA metabolites will help optimise therapy, minimise side effects and identify children at risk of hepato- and myelotoxicity.

Mo1912 Long Term Efficacy and Safety of Thiopurines in Patients With Steroid Dependent Ulcerative Colitis: A Retrospective Investigation

Mo1912 Long Term Efficacy and Safety of Thiopurines in Patients With Steroid Dependent Ulcerative Colitis: A Retrospective Investigation

Mo1901 Long-Term Efficacy and Safety of Thiopurines in Patients With Biologic-Naïve Ulcerative Colitis: A Multicenter Cohort Study

Mo1901 Long-Term Efficacy and Safety of Thiopurines in Patients With Biologic-Naïve Ulcerative Colitis: A Multicenter Cohort Study

P333. Long-term efficacy and safety of thiopurines in patients with steroid-dependent ulcerative colitis: a retrospective investigation

P333. Long-term efficacy and safety of thiopurines in patients with steroid-dependent ulcerative colitis: a retrospective investigation

Use of Thiopurines in Inflammatory Bowel Disease: A Consensus Statement by the Korean Association for the Study of Intestinal Diseases (KASID).

Background/AimsFor decades, thiopurines have been the mainstay of inflammatory bowel disease (IBD) treatment and will play an important role in the future. However, complex metabolism and various side effects limit the use of these potent drugs in clinical practice. The Korean Association for the Study of Intestinal Diseases developed a set of consensus statements with the aim of guiding clinicians on the appropriate use of thiopurines in the management of IBD.MethodsSixteen statements were initially drafted by five committee members. The quality of evidence and classification of recommendation were assessed according to the Grading of Recommendations Assessment, Development and Evaluation system. The statements were then circulated to IBD experts in Korea for review, feedback, and then finalized and accepted by voting at the consensus meeting.ResultsThe consensus statements comprised four parts: (1) pre-treatment evaluation and management strategy, including value of thiopurine S-methyltransferase screening, dosing schedule, and novel biomarkers for predicting thiopurine-induced leukopenia; (2) treatment with thiopurines with regards to optimal duration of thiopurine treatment and long-term outcomes of combination therapy with anti-tumor necrosis factors; (3) safety of thiopurines, especially during pregnancy and lactation; and (4) monitoring side effects or efficacy of therapy using biomarkers.ConclusionsThiopurines are an effective treatment option for patients with IBD. Management decisions should be individualized according to the risk of relapse and adverse events.

How should immunomodulators be optimized when used as combination therapy with anti-tumor necrosis factor agents in the management of inflammatory bowel disease?

In the last 15 years the management of inflammatory bowel disease has evolved greatly, largely through the increased use of immunomodulators and, especially, anti-tumor necrosis factor (anti-TNF) biologic agents. Within this time period, confidence in the use of anti-TNFs has increased, whilst, especially in recent years, the efficacy and safety of thiopurines has been questioned. Yet despite recent concerns regarding the risk: benefit profile of thiopurines, combination therapy with an immunomodulator and an anti-TNF has emerged as the recommended treatment strategy for the majority of patients with moderate-severe disease, especially those who are recently diagnosed. Concurrently, therapeutic drug monitoring has emerged as a means of optimizing the dosage of both immunomodulators and anti-TNFs. However the recommended therapeutic target levels for both drug classes were largely derived from studies of monotherapy with either agent, or studies underpowered to analyze outcomes in combination therapy patients. It has been assumed that these target levels are applicable to patients on combination therapy also, however there are few data to support this. Similarly, the timing and duration of treatment with immunomodulators when used in combination therapy remains unknown. Recent attention, including post hoc analyses of the pivotal registration trials, has focused on the optimization of anti-TNF agents, when used as either monotherapy or combination therapy. This review will instead focus on how best to optimize immunomodulators when used in combination therapy, including an evaluation of recent data addressing unanswered questions regarding the optimal timing, dosage and duration of immunomodulator therapy in combination therapy patients.

Safety of Thiopurines and Anti-TNF-α Drugs During Pregnancy in Patients With Inflammatory Bowel Disease

The safety of thiopurines and anti-tumor necrosis factor-α (TNF-α) drugs during pregnancy remains controversial, as the experience with these drugs in this situation is limited. Our aim is to assess the safety of thiopurines and anti-TNF-α drugs for the treatment of inflammatory bowel disease (IBD) during pregnancy. Retrospective, multicenter study in IBD patients. Pregnancies were classified according to the therapeutic regimens during pregnancy or during the 3 months before the conception: non-exposed group, pregnancies exposed to thiopurines alone (group A), and pregnancies exposed to anti-TNF-α drugs (group B). An unfavorable Global Pregnancy Outcome (GPO) was considered if pregnancy developed with obstetric complications in the mother and in the newborn. A total of 187 pregnancies in the group A, 66 pregnancies in the group B, and 318 pregnancies in the non-exposed group were included. The rate of unfavorable GPO was different among the three groups (31.8% in non-exposed group, 21.9% in group A, and 34.8% in group B), being lower in pregnancies under thiopurines than among non-exposed (P = 0.01). The rate of pregnancy complications was similar among the three groups (27.7% in non-exposed, 20.9% in group A, and 30.3% in group B). The rate of neonatal complications was different among the three groups (23.3% in non-exposed group, 13.9% in group A, and 21.2% in group B), being lower in pregnancies under thiopurines than among non-exposed (P = 0.01). In the multivariate analysis, the treatment with thiopurines (odds ratio = 0.6; 95% confidence interval = 0.4-0.9, P = 0.02) was the only predictor of favorable GPO, whereas maternal age >35 years at conception was the only predictor of unfavorable GPO. The treatment with anti-TNF-α drugs was not associated with an unfavorable GPO. The treatment with thiopurines and anti-TNF-α drugs does not seem to increase the risk of complications during pregnancy and does seem to be safe for the newborn.

Response Evaluation and Safety of Thiopurines in the Treatment of Inflammatory Bowel Diseases (IBD)

Response Evaluation and Safety of Thiopurines in the Treatment of Inflammatory Bowel Diseases (IBD)

The Safety of Thiopurines: New Data, New Decisions

The Safety of Thiopurines: New Data, New Decisions

W1195 Safety of Thiopurines in a Population-Based Cohort of Inflammatory Bowel Disease

W1195 Safety of Thiopurines in a Population-Based Cohort of Inflammatory Bowel Disease

141 Pregnancy Outcome in Inflammatory Bowel Disease for Women Treated with Thiopurine: Cohort from the CESAME Study

Introduction Few datas on safety of thiopurines for IBD treatment during pregnancy are available. The aim of this study was to evaluate the pregnancy outcome of women exposed to thiopurines. Patients and methods 215 pregnancies in 204 women were registered and documented in the CESAME cohort between may 2004 and october 2007. Treatment informations included : last menstrual date, delivery term, pregnancy outcome details as spontaneous abortion, therapeutic abortion, prematurity (gestational age of under 37 weeks of gestation), birth weight and height, congenital abnormality, medication history during each trimester, smoking history and ethanol ingestion. Datas were compared between women exposed to thiopurines (thiopurines only or associated with another treatment aminosalicylates, corticosteroids ou anti-TNFa-), womens receiving another drug than thiopurines and patients without any medication. Results The median age of the women was 28.4 years old, 75.7% had a Crohn's disease (CD), 21.8% a ulcerative colitis (UC) and 2.5% an unclassified bowel disease (UIBD), with a mean disease duration of 6.8 years at inclusion. Of 215 pregnancies, there were 138 births (142 newborns because of 4 gemellary pregnancies). 86 of the 215 pregnancies (39.6%) occured with exposure to thiopurines during all or part of the pregnancy, 84 (38.7%) with exposure to other drugs and 45 (20.7%) without any IBD treatment. No significant differences were found among the 3 groups with respect to interrupted pregnancies (36%, 33% et 40% respectively) as seen on table. 29 women with CD were still smoking (18.6%), 2 with UC (2.2%). The mean birth weight was 3135g. Conclusion The results of this large cohort indicate that thiopurine use during pregnancy is not associated with increased congenital abnormalities risk. The increased incidence of hypotrophy and prematurity under thiopurine was not significant and may correlate to the underlying disease.

P239 - Pregnancy outcomes in women exposed to adalimumab: the OTIS autoimmune diseases in pregnancy project

Introduction Few datas on safety of thiopurines for IBD treatment during pregnancy are available. The aim of this study was to evaluate the pregnancy outcome of women exposed to thiopurines. Patients and methods 215 pregnancies in 204 women were registered and documented in the CESAME cohort between may 2004 and october 2007. Treatment informations included : last menstrual date, delivery term, pregnancy outcome details as spontaneous abortion, therapeutic abortion, prematurity (gestational age of under 37 weeks of gestation), birth weight and height, congenital abnormality, medication history during each trimester, smoking history and ethanol ingestion. Datas were compared between women exposed to thiopurines (thiopurines only or associated with another treatment aminosalicylates, corticosteroids ou anti-TNFa-), womens receiving another drug than thiopurines and patients without any medication. Results The median age of the women was 28.4 years old, 75.7% had a Crohn's disease (CD), 21.8% a ulcerative colitis (UC) and 2.5% an unclassified bowel disease (UIBD), with a mean disease duration of 6.8 years at inclusion. Of 215 pregnancies, there were 138 births (142 newborns because of 4 gemellary pregnancies). 86 of the 215 pregnancies (39.6%) occured with exposure to thiopurines during all or part of the pregnancy, 84 (38.7%) with exposure to other drugs and 45 (20.7%) without any IBD treatment. No significant differences were found among the 3 groups with respect to interrupted pregnancies (36%, 33% et 40% respectively) as seen on table. 29 women with CD were still smoking (18.6%), 2 with UC (2.2%). The mean birth weight was 3135g. Conclusion The results of this large cohort indicate that thiopurine use during pregnancy is not associated with increased congenital abnormalities risk. The increased incidence of hypotrophy and prematurity under thiopurine was not significant and may correlate to the underlying disease.

Safety of thiopurines in the treatment of inflammatory bowel disease.

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. Review of the literature regarding metabolism, efficacy and side effects. 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. 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.