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.

Use of thiopurines in inflammatory bowel disease

The use of thiopurines as immunosuppression for the treatment of refractory or chronic active inflammatory bowel disease is established for both Crohn's disease and ulcerative colitis.Nevertheless,many questions remain concerning the optimal treatment regimens of azathioprine,6-mercaptopurine and thioguanine.We will briefly summarize dose recommendations,indications for thiopurine therapy and side effects which are relevant in clinical practice.We discuss some currently debated topics,including the combination of azathioprine and allopurinol,switching of thiopurine therapy in case of side effects,the use of azathioprine in pregnancy,the infection risk using thiopurines and the evidence when to stop thiopurines.Excellent reviews have been published on the thiopurine metabolic pathway which will not be discussed here in detail.

Thiopurines and inflammatory bowel disease: Current evidence and a historical perspective

The use of thiopurines in inflammatory bowel disease(IBD) has been examined in numerous prospective, controlled trials, with a majority demonstrating a clinical benefit. We conducted this review to describe the historical and current evidence in the use of thiopurines in IBD. A systematic search was performed on MEDLINE between 1965 and 2016 to identify studies on thiopurines in IBD. The most robust evidence for thiopurines in IBD includes induction of remission in combination with anti-tumor necrosis factor(antiTNF) agents, and maintenance of remission and postoperative maintenance in Crohn's disease. Less evidence exists for thiopurine monotherapy in induction of remission, maintenance of ulcerative colitis, chemoprevention of colorectal cancer, and in preventing immunogenicity to anti-TNF. Evidence was often limited by trial design. Overall, thiopurines have demonstrated efficacy in a broad range of presentations of IBD. With more efficacious novel therapeutic agents, the positioning of thiopurines in the management of IBD will change and future studies will analyze the benefit of thiopurines alone and in conjunction with these new medications.

Use of thiopurines in inflammatory bowel disease: Safety issues

Thiopurines are widely used for maintenance treatment of inflammatory bowel disease. Interindividual variability in clinical response to thiopurines may be attributed to several factors including genetic polymorphisms, severity and chronicity of disease, comorbidities, duration of administration, compliance issues and use of concomitant medication, environmental factors and clinician and patient preferences. The purpose of this review is to summarise the current evidence on thiopurine safety and toxicity, to describe adverse drug events and emphasise the significance of drug interactions, and to discuss the relative safety of thiopurine use in adults, elderly patients, children and pregnant women. Thiopurines are safe to use and well tolerated, however dose adjustment or discontinuation of treatment must be considered in cases of non-response, poor compliance or toxicity. Drug safety, clinical response to treatment and short to long term risks and benefits must be balanced throughout treatment duration for different categories of patients. Treatment should be individualised and stratified according to patient requirements. Enzymatic testing prior to treatment commencement is advised. Surveillance with regular clinic follow-up and monitoring of laboratory markers is important. Data on long term efficacy, safety of thiopurine use and interaction with other disease modifying drugs are lacking, especially in paediatric inflammatory bowel disease. High quality, collaborative clinical research is required so as to inform clinical practice in the future.

Thiopurines related malignancies in inflammatory bowel disease:Local experience in Granada,Spain

AIM:To investigate the incidence of neoplasms in inflammatory bowel disease(IBD)patients and the potential causative role of thiopurines.METHODS:We performed an observational descriptive study comparing the incidence of malignancies in IBD patients treated with thiopurines and patients not treated with these drugs.We included 812 patients which were divided in two groups depending on whether they have received thiopurines or not.We have studied basal characteristics of both groups(age when the disease was diagnosed,sex,type of IBD,etc.)and treatments received(Azathioprine,mercaptopurine,infliximab,adalimumab or other immunomodulators),as well as neoplasms incidence.Univariate analysis was performed with the student t test,χ 2 test or Wilcoxon exact test as appropriate.A logistic regression analysis was performed as multivariate analysis.Statistical significance was establish at P values of less than 0.05,and 95%CI were used for the odds ratios.RESULTS:Among 812 patients included,429(52.83%)have received thiopurines:79.5% azathioprine,14% mercaptopurine and 6.5% both drugs.44.76% of patients treated with thiopurines and 46,48% of patients who did not receive this treatment were women(P > 0.05).The proportion of ulcerative colitis patients treated with thiopurines was 30.3% compare to 66.67% of patients not treated(P < 0.001).Mean azathioprine dose was 123.79 ± 36.5 mg/d(range:50-250 mg/d),mean usage time was 72.16 ± 55.7 mo(range:1-300 mo)and the accumulated dose along this time was 274.32 ± 233.5 g(1.5-1350 g).With respect to mercaptopurine,mean dose was 74.7 ± 23.9 mg/d(range:25-150 mg/d),mean usage time of 23.37 ± 27.6 mo(range:1-118 mo),and the accumulated dose along this time was 52.2 ± 63.5 g(range:1.5-243 g).Thiopurine S-methyltransferase activity was tested in 66% of patients treated with thiopurines,among which 98.2% had an intermediate or high activity.Among the patients treated with thiopurines,27.27%(112 patients)and 11.66%(50 patients)received treatment with Infliximab and Adalimumab respectively,but only 1.83%(7 patients)and 0.78%(3 patients)received these drugs in the group of patients who did not received thiopurines(P < 0.001 and P < 0.001 respectively).Finally,6.8%(29 patients)among those treated with thiopurines have received other immunesupresants(Methotrexate,Tacrolimus,Cyclosporin),compare to 1%(4 patients)of patients not treated with thiopurines(P < 0.001).Among patients treated with thiopurines,3.97% developed a malignancy,and among those not treated neoplasms presented in 8.1%(P = 0.013).The most frequent neoplasms were colorectal ones(12 cases in patients not treated with thiopurines but none in treated,P < 0.001)followed by non-melanoma skin cancer(8 patients in treated with thiopurines and 6 in not treated,P > 0.05).CONCLUSION:In our experience,thiopurine therapy did not increase malignancies development in IBD patients,and was an efective and safe treatment for these diseases.

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.

Individually administered or co-prescribed thiopurines and mesalamines for inflammatory bowel disease

Data from both basic research and clinical experience continue to suggest that mesalamines and thioputines are effective and efficient for the maintenance of remission of inflammatory bowel diseases. Several decades following the formalization of their indications, attention on these two drugs has been fostered by recent achievements. Demonstration of the ability of mesalamine to activate a colonocyte differentiation factor has shed light on its chemopreventive effects on colorectal cancer; in addition to their anti-proliferative efficacy, thiopurines have been shown to be specific regulators of apoptosis. The two drugs are often coadministered in clinical practice. Recent advancements have shown that mesalamines exert a positive synergism in this context, insofar as they can inhibit sidemethylation of thiopurines and hasten the function of the main immunosuppressive pathways. Considering that up to 40% of patients cannot tolerate thiopurines, such renovated targets have stimulated efforts to improve compliance by research on the toxicity mechanisms. The definition of genetic polymorphisms in the enzymes of thiopurine metabolism, and the uncovering of synergistic drug interactions, such as that with allopurinol, are just two of the results of such efforts. Interaction between basic research and clinical practice has continued to inform indications and refine the prescriptions of mesalamines and thiopurines; these have not been restrained （they have been implemented in some cases） by the advent of the novel biological molecules with anti-cytokine activity.

Routine use of thiopurines in maintaining remission in pediatric Crohn's disease

AIM: To evaluate the effectiveness of thiopurines in maintaining steroid-free remission in routine clinical practice.

Thiopurines are an independent risk factor for active tuberculosis in inflammatory bowel disease patients

The use of thiopurines is an independent risk factor for active tuberculosis in patients with inflammatory bowel disease.

Impact of thiopurines and anti-tumour necrosis factor therapy on hospitalisation and long-term surgical outcomes in ulcerative colitis

Ulcerative colitis(UC) is a chronic inflammatory condition affecting the large bowel and is associated with a significant risk of both requirement for surgeryand the need for hospitalisation. Thiopurines, and more recently, anti-tumour necrosis factor(a TNF) therapy have been used successfully to induce clinical remission. However, there is less data available on whether these agents prevent long-term colectomy rates or the need for hospitalisation. The focus of this article is to review the recent and pertinent literature on the long-term impact of thiopurines and a TNF on long-term surgical and hospitalisation rates in UC. Data from population based longitudinal research indicates that thiopurine therapy probably has a protective role against colectomy, if used in appropriate patients for a sufficient duration. a TNF agents appear to have a short term protective effect against colectomy, but data is limited for longer periods. Whereas there is insufficient evidence that thiopurines affect hospitalisation, evidence favours that a TNF therapy probably reduces the risk of hospitalisation within the first year of use, but it is less clear on whether this effect continues beyond this period. More structured research needs to be conducted to answer these clinically important questions.

Pharmacogenetics of thiopurines

Polychemotherapeutic protocols for the treatment of pediatric acute lymphoblastic leukemia(ALL)always include thiopurines.Specific approaches vary in terms of drugs,dosages and combinations.Such therapeutic schemes,including risk-adapted intensity,have been extremely successful for children with ALL who have reached an outstanding 5-year survival of greater than 90%in developed countries.Innovative drugs such as the proteasome inhibitor bortezomib and the bi-specific T cell engager blinatumomab are available to further improve therapeutic outcomes.Nevertheless,daily oral thiopurines remain the backbone maintenance or continuation therapy.Pharmacogenetics allows the personalization of thiopurine therapy in pediatric ALL and clinical guidelines to tailor therapy on the basis of genetic variants in TPMT and NUDT15 genes are already available.Other genes of interest,such as ITPA and PACSIN2,have been implicated in interindividual variability in thiopurines efficacy and adverse effects and need additional research to be implemented in clinical protocols.In this review we will discuss current literature and clinical guidelines available to implement pharmacogenetics for tailoring therapy with thiopurines in pediatric ALL.

Thiopurine metabolites variations during co-treatment with aminosalicylates for inflammatory bowel disease:Effect of N-acetyl transferase polymorphisms

AIM: To evaluate variation of the concentration of thiopurine metabolites after 5-aminosalicylate(5-ASA) interruption and the role of genetic polymorphisms of N-acetyl transferase(NAT) 1 and 2. METHODS: Concentrations of thioguanine nucleotides(TGN) and methymercaptopurine nucleotides(MMPN), metabolites of thiopurines, were measured by high performance liquid chromatography in 12 young patients(3 females and 9 males, median age 16 years) with inflammatory bowel disease(6 Crohn's disease and 6 ulcerative colitis) treated with thiopurines(7 mercaptopurine and 5 azathioprine) and 5-ASA. Blood samples were collected one month before and one month after the interruption of 5-ASA. DNA was extracted and genotyping of NAT1, NAT2, inosine triphosphate pyrophosphatase(ITPA) and thiopurine methyl transferase(TPMT) genes was performed using PCR assays. RESULTS: Median TGN concentration before 5-ASA interruption was 270 pmol/8 x 108 erythrocytes(range: 145-750); after the interruption of the aminosalicylate, a 35% reduction in TGN mean concentrations(absolutemean reduction 109 pmol/8 × 108 erythrocytes) was observed(median 221 pmol/8 × 108 erythrocytes, range: 96-427, P value linear mixed effects model 0.0011). Demographic and clinical covariates were not related to thiopurine metabolites concentrations. All patients were wild-type for the most relevant ITPA and TPMT variants. For NAT1 genotyping, 7 subjects presented an allele combination corresponding to fast enzymatic activity and 5 to slow activity. NAT1 genotypes corresponding to fast enzymatic activity were associated with reduced TGN concentration(P value linear mixed effects model 0.033), putatively because of increased 5-ASA inactivation and consequent reduced inhibition of thiopurine metabolism. The effect of NAT1 status on TGN seems to be persistent even after one month since the interruption of the aminosalicylate. No effect of NAT1 genotypes was shown on MMPN concentrations. NAT2 genotyping revealed that 6 patients presented a genotype corresponding to fast enzymatic activity and 6 to slow activity; NAT2 genotypes were not related to thiopurine metabolites concentration in this study. CONCLUSION: NAT1 genotype affects TGN levels in patients treated with thiopurines and aminosalicylates and could therefore influence the toxicity and efficacy of these drugs; however the number of patients evaluated is limited and this has to be considered a pilot study.

Time to clinical response and remission for therapeutics in inflammatory bowel diseases: what should the clinician expect, what should patients be told?

An awareness of the expected time for therapies to induce symptomatic improvement and remission is necessary for determining the timing of follow-up, disease(re)assessment, and the duration to persist with therapies, yet this is seldom reported as an outcome in clinical trials. In this review, we explore the time to clinical response and remission of current therapies for inflammatory bowel disease(IBD) as well as medication, patient and disease related factors that may influence the time to clinical response. It appears that the time to therapeutic response varies depending on the indication for therapy(Crohn's disease or ulcerative colitis). Agents with the most rapid time to clinical response included corticosteroids, calcineurin inhibitors, exclusive enteral nutrition, aminosalicylates and anti-tumor necrosis factor therapy which will work in most patients within the first 2 mo. Vedolizumab,methotrexate and thiopurines had a longer time to clinical response and can take several months to achieve maximal efficacy. Factors affecting the time to clinical response of therapies included use of concomitant therapy, disease duration, smoking status, disease phenotype and advanced age. There appears to be marked variation in time to clinical response for therapies used in IBD which is further influenced by disease and patient related factors. Understanding the expected time to therapeutic response is integral to inform further decision making, maintain a patientcentered approach and ensure treatment is given an appropriate timeframe to achieve maximal benefit prior to cessation.

Efficacy of thioguanine treatment in inflammatory bowel disease: A systematic review

AIM To critically assess the available literature regarding the efficacy of thioguanine treatment in inflammatory bowel disease(IBD) patients, irrespective of the(hepato-) toxicity profile.METHODS A systematic literature search of the MEDLINE database using Pub Med was performed using the keywords "thioguanine", "6-TG", "thioguanine", "inflammatory bowel disease", "IBD", "Crohn's disease", "Ulcerative colitis" and "effectiveness" in order to identify relevant articles published in English starting from 2000. Reference lists of the included articles were crosschecked for missing articles. Reviewed manuscripts concerning the effectiveness of thioguanine treatment in IBD were reviewed by the authors and the data were extracted. Data were subsequently analyzed with descriptive statistics. Due to the lack of standardized outcomes, a formal meta-analysis was not performed.RESULTS A total of 11 applicable studies were found that involved the effectiveness of thioguanine therapy in IBD. Eight studies were conducted in a prospectivemanner, in the remaining three studies, data was collected retrospectively. In total, 353 IBD-patients(225 patients with Crohn's disease, 119 with ulcerative colitis and nine with unclassified IBD) with prior azathioprine/mercaptopurine resistance and/or intolerance(n = 321) or de novo thioguanine administration(n = 32) were included for analysis, of which 228(65%) had clinical improvement on thioguanine therapy, based on standard IBD questionnaires, biochemical parameters or global physician assessments. Short-term results were based on 268 treatment years(median follow-up 9 mo, range 3-22 mo) with a median daily dose of 20 mg(range 10-80 mg). Discontinuation, mostly due to adverse events, was reported in 72 patients(20%). CONCLUSION The efficacy of thioguanine therapy in IBD patients intolerant to conventional thiopurine therapy is observed in 65%, with short term adverse events in 20% of patients.

Small intestinal bacterial overgrowth in inactive Crohn's disease:Influence of thiopurine and biological treatment

AIM: To investigate the influence of thiopurines and biological drugs on the presence of small intestinal bacterial overgrowth (SIBO) in patients with inactive Crohn&#x02019;s disease (CD).

Impact of inflammatory bowel disease activity and thiopurine therapy on birth weight: A meta-analysis

AIM To investigate the effect of disease activity or thiopurine use on low birth weight and small for gestational age in women with inflammatory bowel disease(IBD).METHODS Selection criteria included all relevant articles on the effect of disease activity or thiopurine use on the risk of low birth weight(LBW) or small for gestational age(SGA) among pregnant women with IBD. Sixtynine abstracts were identified,35 papers were full text reviewed and,only 14 of them met inclusion criteria. Raw data were extracted to generate the relative risk of LBW or SGA. Quality was assessed using the Newcastle Ottawa Scale.RESULTS This meta-analysis is reported according to PRISMA guidelines. Fourteen studies met inclusion criteria,and nine reported raw data suitable for meta-analysis. We found an increased risk ratio of both SGA and LBW in women with active IBD,when compared with women in remission: 1.3 for SGA(4 studies,95%CI: 1.0-1.6,P = 0.04) and 2.0 for LBW(4 studies,95%CI: 1.5-2.7,P < 0.0001). Women on thiopurines during pregnancy had a higher risk of LBW(RR 1.4,95%CI: 1.1-1.9,P = 0.007) compared with non-treated women,but when adjusted for disease activity there was no significant effect on LBW(RR 1.2,95%CI: 0.6-2.2,P = 0.6). No differences were observed regarding SGA(2 studies; RR 0.9,95%CI: 0.7-1.2,P = 0.5). CONCLUSION Women with active IBD during pregnancy have a higher risk of LBW and SGA in their neonates. This should be considered in treatment decisions during pregnancy.

Hemophagocytic lymphohistiocytosis caused by primary Epstein-Barr virus in patient with Crohn's disease

We present a case of a 19-year-old man with a 6-year history of Crohn's disease(CD), previously treated with 6-mercaptopurine, who was admitted to our department for Epstein-Barr virus(EBV) infection and subsequently developed a hemophagocytic lymphohistiocytosis(HLH). HLH is a rare disease which causes phagocytosis of all bone marrow derived cells. It can be a primary form as a autosomic recessive disease, or a secondary form associated with a variety of infections; EBV is the most common, the one with poorer prognosis. The incidence of lymphoproliferative disorders was increased in patients with inflammatory bowel disease(IBD) treated with thiopurines. Specific EBV-related clinical and virological management should be considered when treating a patient with IBD with immunosuppressive therapy. Moreover EBV infection in immunosuppressed patient can occur with more aggressive forms such as encephalitis and diffuse large B cell lymphoma. Our case confirms what is described in the literature; patients with IBD, particularly patients with CD receiving thiopurine therapy, who present 5 d of fever and cervical lymphadenopathy or previous evidence of lymphopenia should be screened for HLH.

Therapeutic drug monitoring in patients with inflammatory bowel disease

Thiopurine analogs and anti-tumor necrosis factor (TNF) agents have dramatically changed the therapeutics of inflammatory bowel diseases (IBD), improving short and long-term outcomes. Unfortunately some patients do not respond to therapy and others lose response over time. The pharmacokinetic properties of these drugs are complex, with high inter-patient variability. Thiopurine analogs are metabolized through a series of pathways, which vary according to the patients&#x02019; pharmacogenetic profile. This profile largely determines the ratios of metabolites, which are in turn associated with likelihoods of clinical efficacy and/or toxicity. Understanding these mechanisms allows for manipulation of drug dose, aiming to reduce the development of toxicity while improving the efficacy of treatment. The efficacy of anti-TNF drugs is influenced by many pharmacodynamic variables. Several factors may alter drug clearance, including the concomitant use of immunomodulators (thiopurine analogs and methotrexate), systemic inflammation, the presence of anti-drug antibodies, and body mass. The treatment of IBD has evolved with the understanding of the pharmacologic profiles of immunomodulating and TNF-inhibiting medications, with good evidence for improvement in patient outcomes observed when measuring metabolic pathway indices. The role of routine measurement of metabolite/drug levels and antibodies warrants further prospective studies as we enter the era of personalized IBD care.

Clinical predictors of thiopurine-related adverse events in Crohn's disease

AIM: To determine the incidence and predictors of thiopurine-related adverse events. METHODS: Subjects with Crohn's disease who were followed in the Alberta Inflammatory Bowel Disease Consortium patient database registry were identified. Retrospective chart review was conducted between August 5th, 2010 and June 1st, 2012. We collected data on: age at diagnosis; sex; disease location and behaviour at time of prescribing thiopurine; perianal fistulising disease at or prior to thiopurine prescription; smoking status at time of thiopurine prescription, use of corticosteroid within 6 mo of diagnosis; dosage, age at onset, and cessation of 5-aminosalicyclic acid(5-ASA); anti-tumour necrosis factor medication exposure and intestinal resection before thiopurine prescription. The primary outcome of interest was the first adverse event that led to discontinuation of the first thiopurine medication used. Logistic regression models were used to associate clinical characteristics with outcomes after adjusting for potential confounders. Risk estimates were presented as odds ratios(OR) with 95% CI. Effect modification by age and sex were explored.RESULTS: Our cohort had a median follow-up duration of 5.8 years [interquartile range(IQR 25th-75th) 2.7-9.1]. Thiopurine therapy was discontinued in 31.3% of patients because of: hypersensitivity reactions(7.1%), acute pancreatitis(6.2%), gastrointestinal intolerance(5.4%), leucopenia(3.7%), hepatotoxicity(3.4%), infection(1.1%) and other reasons(4.3%). A higher incidence of thiopurine withdrawal was observed in patients over the age of 40(39.4%, P = 0.007). A sexby-age interaction(P = 0.04) was observed. Females older than 40 years of age had an increased risk of thiopurine discontinuation due to an adverse event(age above 40 vs age below 40, adjusted OR = 2.8; 95%CI: 1.4-5.6). In contrast, age did not influence thiopurine withdrawal in males(age above 40 vs below 40, adjusted OR = 0.9; 95%CI: 0.4-2.1). Other clinical variables(disease location and phenotype, perianal disease, smoking history, history of intestinal resection and prior 5-ASA or corticosteroid use) were not associated with an increased risk an adverse event leading to therapy cessation. CONCLUSION: Thiopurine withdrawal due to adverse events is commoner in women over the age of 40 at prescription. These findings need to be replicated in other cohorts.

Solid extraintestinal malignancies in patients with inflammatory bowel disease

Malignancies constitute the second cause of death in patients with inflammatory bowel diseases(IBD),after cardiovascular diseases.Although it has been postulated that IBD patients are at greater risk of colorectal cancer compared to the general population,lately there has been evidence supporting that this risk is diminishing over time as a result of better surveillance,while the incidence of extraintestinal cancers(EICs)is increasing.This could be attributed either to systemic inflammation caused by IBD or to long-lasting immunosuppression due to IBD treatments.It seems that the overall risk of EICs is higher for Crohn’s disease patients and it is mainly driven by skin cancers,and liver-biliary cancers in patients with IBD and primary sclerosing cholangitis.The aims of this review were first to evaluate the prevalence,characteristics,and risk factors of EICs in patients with IBD and second to raise awareness regarding a proper surveillance program resulting in early diagnosis,better prognosis and survival,especially in the era of new IBD treatments that are on the way.