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...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.展开更多
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 r...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.展开更多
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 f...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.展开更多
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 histor...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.展开更多
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 arti...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.展开更多
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 r...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.展开更多
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...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.展开更多
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 rec...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.展开更多
AIM To identify which blood and mucosal lymphocyte populations are specifically depleted by thiopurine use in vivo.METHODS The thiopurines azathioprine and 6-mercaptopurine have been a mainstay of inflammatory bowel d...AIM To identify which blood and mucosal lymphocyte populations are specifically depleted by thiopurine use in vivo.METHODS The thiopurines azathioprine and 6-mercaptopurine have been a mainstay of inflammatory bowel disease(IBD) therapy for decades, but their mechanism of action in vivo remains obscure. Although thiopurines are lymphotoxic at high doses, and have been reported to cause T cell apoptosis in vitro, their ability to control IBD at lower doses suggests that they may selectively deplete particular lymphocyte populations. Blood cells from 19 IBD patients on a thiopurine, 19 IBD patients not on a thiopurine, and 38 matched healthy control subjects were analyzed by multiple multi-color flow cytometry panels to quantify the immune cell subsets contained therein, both as a percent of cells, and as an absolute cell count. Similar analyses were performed on colon biopsies from 17 IBD patients on a thiopurine, 17 IBD patients not on a thiopurine, and 49 healthy screening colonoscopy recipients.RESULTS Complete blood counts revealed lower lymphocyte, but not monocyte or granulocyte, counts in IBD patients who were taking thiopurines at the timeof sampling. This reduction was restricted to CD3-negative lymphocytes, wherein both natural killer(NK) and B cells were significantly reduced among thiopurine recipients. Among CD19+ B cells, the transitional B cells were particularly depleted, being nearly absent in both blood and colon biopsies of thiopurine recipients. No differences were associated with thiopurine use in CD8+ T cells, mucosa-associated invariant T(MAIT) cells, invariant natural killer T(i NKT) cells, gamma/delta T cells, Th1, Th17, regulatory T cells(Tregs) or na?ve CD4+ T cells. However, patients with IBD had significantly more circulating FOXP3+, Helios+ Tregs and fewer iN KT and MAIT cells than healthy controls. CONCLUSION Thiopurine use is associated with reduced B and NK cell, but not T cell, subpopulations in the blood of IBD patients.展开更多
AIM:To analyze the prevalence of thiopurine-methyltransferase(TPMT)genotypes and their associationwith drug toxicity in inflammatory bowel disease(IBD)patients from southeastern Brazil.METHODS:A total of 219 consecuti...AIM:To analyze the prevalence of thiopurine-methyltransferase(TPMT)genotypes and their associationwith drug toxicity in inflammatory bowel disease(IBD)patients from southeastern Brazil.METHODS:A total of 219 consecutive patients with IBD,of which 146 had Crohn’s disease and 73 had ulcerative colitis,regularly seen at the outpatient unit of the Division of Gastroenterology at the University Hospital Pedro Ernesto of the State University of Rio de Janeiro,a tertiary referral center,were enrolled in this study from February 2009 to January 2011.We analyzed the presence of major TPMT genetic variants(TPMT*2,*3A,*3C)in IBD patients by means of a specific allele and RFLP-PCR.Genomic DNA was isolated from peripheral blood leukocytes by proteinase-K/Sodium Dodecyl Sulfate digestion and phenol-chloroform extraction.TPMT*2(C238G),TPMT*3A(G460A/A719G),and TPMT*3C(A719G)genotypes were detected by real-time polymerase chain reaction followed by direct sequencing with specific primers.Clinical data were systematically recorded,and correlated with the genotype results.RESULTS:The distribution of the selected TPMT gene polymorphism TPMT*2(C238G),TPMT*3A(G460A/A719G),and TPMT*3C(A719G)genotypes was 3.6%,5.4%,and 7.7%of the patients,respectively.Among the side effects recorded from patients taking azathioprine,14 patients presented with pancreatitis and/or an elevation of pancreatic enzymes,while 6 patients had liver toxicity,and 2 patients exhibited myelosuppression/neutropenia.TPMT polymorphisms were detected in 37/219 patients(8 heterozygous for*2,11 heterozygous for*3A,and 18 heterozygous for*3C).No homozygotic polymorphisms were found.Despite the prevalence of the TPMT*3C genotype,no differences among the genotype frequencies were significant.Although no association was detected regarding myelotoxicity or hepatotoxicity,a trend towards the elevation of pancreatic enzymes was observed for TPMT*2 and TPMT*3C genotypes.CONCLUSION:The prevalence of TPMT genotypes was high among Brazilian patients.Variants genes*2and*3C may be associated with azathioprine pancreatic toxicity in a IBD southeastern Brazilian population.展开更多
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 ...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.展开更多
AIM: To evaluate the effectiveness of thiopurines in maintaining steroid-free remission in routine clinical practice.METHODS: The multi-center Pediatric Inflammatory Bowel Disease Network(PIBDNet) cohort study prospec...AIM: To evaluate the effectiveness of thiopurines in maintaining steroid-free remission in routine clinical practice.METHODS: The multi-center Pediatric Inflammatory Bowel Disease Network(PIBDNet) cohort study prospectively collected data on thiopurine naive patients initiating mercaptopurine(6MP) or azathioprine. Patients with a diagnosis of Crohn's disease(CD) were included in our study upon entering remission as determined by physician global assessment(PGA) within 365 d of initiation of thiopurines. The primary outcome of the study was maintenance of steroid-free remission(SFR) at each follow up visit. Patients were considered treatment failures if there had been a change in PGA from remission to mild, moderate or severe disease;disease relapse between visits; need for rescue therapy(biologic therapy, methotrexate, steroids); thiopurine discontinuation, hospitalization or surgical intervention. A secondary outcome defined treatment failure as a change from remission to moderate or severe(not mild) in addition to the previously defined criteria.RESULTS: Sixty-five of 182 patients in the PIBDNet registry met criteria for inclusion in this study. Fortyfive of 65(69%) of included patients achieved remission within 180 d of thiopurine initiation. For the primary outcome, 47% and 23% of patients remained in SFR at 6 and 12 mo. The mean thiopurine dose at initiation for the 65 included patients was 0.89 ± 0.31 mg/kg per day. Metabolite levels were obtained in 48%(31/65) of the included patients with a mean 6TG level of 258 pmole/8 × 108 RBC ± 147. For the secondary outcome, 65% and 42% of patients remained in SFR at 6 and 12 mo.CONCLUSION: Thiopurines were less effective in maintaining remission for pediatric CD in this "real world" cohort than has been previously described. Variation in thiopurine dosing and metabolite measurement was found among practitioners.展开更多
Hepatosplenic T-cell lymphoma(HSTCL) is a rare nonHodgkin lymphoma with a high mortality rate. Higher incidence is reported in patients with inflammatory bowel disease, specifically in male patients that are younger t...Hepatosplenic T-cell lymphoma(HSTCL) is a rare nonHodgkin lymphoma with a high mortality rate. Higher incidence is reported in patients with inflammatory bowel disease, specifically in male patients that are younger than 35 years, and have been treated with thiopurine and tumor necrosis factor(TNF)-α inhibitor combination therapy for over 2 years. In this case report we describe a 47-year-old patient with Crohn's disease(CD) who developed HSTCL after having been treated with thiopurine monotherapy for 14 years. To our best knowledge, only eleven cases exist of patients with CD who developed HSTCL while on thiopurine monotherapy. We report the first patient with CD, older than 35 years, who developed HSTCL while on thiopurine monotherapy. This emphasizes that HSTCL risk is not limited to young men receiving both thiopurines and TNF-α inhibitors.展开更多
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 inter...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.展开更多
BACKGROUND Azathioprine(AZA)and its close analog 6-mercaptopurine are thiopurines widely used in the treatment of patients with cancer,organ transplantation,and autoimmune or inflammatory diseases,including systemic l...BACKGROUND Azathioprine(AZA)and its close analog 6-mercaptopurine are thiopurines widely used in the treatment of patients with cancer,organ transplantation,and autoimmune or inflammatory diseases,including systemic lupus erythematosus.Bone marrow inhibition is a common side effect of AZA,and severe bone marrow inhibition is related to decreased thiopurine S-methyltransferase(TPMT)activity.CASE SUMMARY We herein report a patient with proliferative lupus nephritis who was using AZA for maintenance therapy,had no common TPMT pathogenic site mutations,and exhibited severe bone marrow inhibition on the 15th day after oral administration.CONCLUSION This report alerts physicians to the fact that even though the TPMT gene has no common pathogenic site mutation,severe myelosuppression may also occur.展开更多
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/k...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.展开更多
BACKGROUND Thiopurine-induced leukopenia(TIL)is a life-threatening toxicity and occurs with a high frequency in the Asian population.Although nucleoside diphosphate-linked moiety X-type motif 15(NUDT15)variants signif...BACKGROUND Thiopurine-induced leukopenia(TIL)is a life-threatening toxicity and occurs with a high frequency in the Asian population.Although nucleoside diphosphate-linked moiety X-type motif 15(NUDT15)variants significantly improve the predictive sensitivity of TIL,more than 50%of cases of this toxicity cannot be predicted by this mutation.The potential use of the 6-thioguanine nucleotide(6TGN)level to predict TIL has been explored,but no decisive conclusion has been reached.Can we increase the predictive sensitivity based on 6TGN by subgrouping patients according to their NUDT15 R139C genotypes?AIM To determine the 6TGN cut-off levels after dividing patients into subgroups according to their NUDT15 R139C genotypes.METHODS Patients’clinical and epidemiological characteristics were collected from medical records from July 2014 to February 2017.NUDT15 R139C,thiopurine S methyltransferase,and 6TGN concentrations were measured.RESULTS A total of 411 Crohn’s disease patients were included.TIL was observed in 72 individuals with a median 6TGN level of 323.4 pmol/8×10^8 red blood cells(RBC),which was not different from that of patients without TIL(P=0.071).Then,we compared the 6TGN levels based on NUDT15 R139C.For CC(n=342)and CT(n=65)genotypes,the median 6TGN level in patients with TIL was significantly higher than that in patients without(474.8 vs 306.0 pmol/8×10^8 RBC,P=9.4×10-^5;291.7 vs 217.6 pmol/8×10^8 RBC,P=0.039,respectively).The four TT carriers developed TIL,with a median 6TGN concentration of 135.8 pmol/8×10^8 RBC.The 6TGN cut-off levels were 411.5 and 319.2 pmol/8×108 RBC for the CC and CT groups,respectively.CONCLUSION The predictive sensitivity of TIL based on 6TGN is dramatically increased after subgrouping according to NUDT15 R139C genotypes.Applying 6TGN cut-off levels to adjust thiopurine therapies based on NUDT15 is strongly recommended.展开更多
AIM:To investigate the influence of thiopurines and biological drugs on the presence of small intestinal bacterial overgrowth(SIBO) in patients with inactive Crohn's disease(CD).METHODS:This was a prospective stud...AIM:To investigate the influence of thiopurines and biological drugs on the presence of small intestinal bacterial overgrowth(SIBO) in patients with inactive Crohn's disease(CD).METHODS:This was a prospective study in patients with CD in remission and without corticosteroid treatment,included consecutively from 2004 to 2010.SIBO was investigated using the hydrogen glucose breath test.RESULTS:One hundred and seven patients with CD in remission were included.Almost 58%of patients used maintenance immunosuppressant therapy and 19.6%used biological therapy.The prevalence of SIBO was16.8%.No association was observed between SIBO and the use of thiopurine Immunosuppressant(12/62patients),administration of biological drugs(2/21 patients),or with double treatment with an anti-tumor necrosis factor drugs plus thiopurine(1/13 patients).Half of the patients had symptoms that were suggestive of SIBO,though meteorism was the only symptom that was significantly associated with the presence of SIBO on univariate analysis(P<0.05).Multivariate analysis revealed that the presence of meteorism and a fistulizing pattern were associated with the presence of SIBO(P<0.05).CONCLUSION:Immunosuppressants and/or biological drugs do not induce SIBO in inactive CD.Fistulizing disease pattern and meteorism are associated with SIBO.展开更多
In the last decades,with the development of biological therapy,the treatment paradigms in patients with Crohn's disease have continuously evolved.Several studies focusing on the optimal use of both traditional imm...In the last decades,with the development of biological therapy,the treatment paradigms in patients with Crohn's disease have continuously evolved.Several studies focusing on the optimal use of both traditional immunosupressants and biological therapy have been published,investigating conventional,accelerated step-up and topdown approaches.In addition,much emphasis has been placed in recent years on the determination of important predictive factors that could enable early patient stratification,which would lead to a tailored management strategy.In this review,the authors try to highlight new evidence on the optimal timing,benefits,and risks of immunosupressants alone,or in combination,in patients with Crohn's disease.展开更多
基金Supported by Italian Ministry of Health,and Fondazione Benefica Alberto e Kathleen Casali
文摘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.
文摘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.
文摘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.
文摘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.
文摘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.
基金the Alberta Inflammatory Bowel Disease Consortium and the Alberta Innovates Health Solutions for funding support for this project
文摘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.
文摘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.
文摘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.
基金Supported by Virginia Mason Medical Center,Digestive Disease Institute Research Grant Award,No.0506812-2011
文摘AIM To identify which blood and mucosal lymphocyte populations are specifically depleted by thiopurine use in vivo.METHODS The thiopurines azathioprine and 6-mercaptopurine have been a mainstay of inflammatory bowel disease(IBD) therapy for decades, but their mechanism of action in vivo remains obscure. Although thiopurines are lymphotoxic at high doses, and have been reported to cause T cell apoptosis in vitro, their ability to control IBD at lower doses suggests that they may selectively deplete particular lymphocyte populations. Blood cells from 19 IBD patients on a thiopurine, 19 IBD patients not on a thiopurine, and 38 matched healthy control subjects were analyzed by multiple multi-color flow cytometry panels to quantify the immune cell subsets contained therein, both as a percent of cells, and as an absolute cell count. Similar analyses were performed on colon biopsies from 17 IBD patients on a thiopurine, 17 IBD patients not on a thiopurine, and 49 healthy screening colonoscopy recipients.RESULTS Complete blood counts revealed lower lymphocyte, but not monocyte or granulocyte, counts in IBD patients who were taking thiopurines at the timeof sampling. This reduction was restricted to CD3-negative lymphocytes, wherein both natural killer(NK) and B cells were significantly reduced among thiopurine recipients. Among CD19+ B cells, the transitional B cells were particularly depleted, being nearly absent in both blood and colon biopsies of thiopurine recipients. No differences were associated with thiopurine use in CD8+ T cells, mucosa-associated invariant T(MAIT) cells, invariant natural killer T(i NKT) cells, gamma/delta T cells, Th1, Th17, regulatory T cells(Tregs) or na?ve CD4+ T cells. However, patients with IBD had significantly more circulating FOXP3+, Helios+ Tregs and fewer iN KT and MAIT cells than healthy controls. CONCLUSION Thiopurine use is associated with reduced B and NK cell, but not T cell, subpopulations in the blood of IBD patients.
基金Supported by Brazilian research agencies CNPq and FAPERJ for financial support
文摘AIM:To analyze the prevalence of thiopurine-methyltransferase(TPMT)genotypes and their associationwith drug toxicity in inflammatory bowel disease(IBD)patients from southeastern Brazil.METHODS:A total of 219 consecutive patients with IBD,of which 146 had Crohn’s disease and 73 had ulcerative colitis,regularly seen at the outpatient unit of the Division of Gastroenterology at the University Hospital Pedro Ernesto of the State University of Rio de Janeiro,a tertiary referral center,were enrolled in this study from February 2009 to January 2011.We analyzed the presence of major TPMT genetic variants(TPMT*2,*3A,*3C)in IBD patients by means of a specific allele and RFLP-PCR.Genomic DNA was isolated from peripheral blood leukocytes by proteinase-K/Sodium Dodecyl Sulfate digestion and phenol-chloroform extraction.TPMT*2(C238G),TPMT*3A(G460A/A719G),and TPMT*3C(A719G)genotypes were detected by real-time polymerase chain reaction followed by direct sequencing with specific primers.Clinical data were systematically recorded,and correlated with the genotype results.RESULTS:The distribution of the selected TPMT gene polymorphism TPMT*2(C238G),TPMT*3A(G460A/A719G),and TPMT*3C(A719G)genotypes was 3.6%,5.4%,and 7.7%of the patients,respectively.Among the side effects recorded from patients taking azathioprine,14 patients presented with pancreatitis and/or an elevation of pancreatic enzymes,while 6 patients had liver toxicity,and 2 patients exhibited myelosuppression/neutropenia.TPMT polymorphisms were detected in 37/219 patients(8 heterozygous for*2,11 heterozygous for*3A,and 18 heterozygous for*3C).No homozygotic polymorphisms were found.Despite the prevalence of the TPMT*3C genotype,no differences among the genotype frequencies were significant.Although no association was detected regarding myelotoxicity or hepatotoxicity,a trend towards the elevation of pancreatic enzymes was observed for TPMT*2 and TPMT*3C genotypes.CONCLUSION:The prevalence of TPMT genotypes was high among Brazilian patients.Variants genes*2and*3C may be associated with azathioprine pancreatic toxicity in a IBD southeastern Brazilian population.
文摘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.
文摘AIM: To evaluate the effectiveness of thiopurines in maintaining steroid-free remission in routine clinical practice.METHODS: The multi-center Pediatric Inflammatory Bowel Disease Network(PIBDNet) cohort study prospectively collected data on thiopurine naive patients initiating mercaptopurine(6MP) or azathioprine. Patients with a diagnosis of Crohn's disease(CD) were included in our study upon entering remission as determined by physician global assessment(PGA) within 365 d of initiation of thiopurines. The primary outcome of the study was maintenance of steroid-free remission(SFR) at each follow up visit. Patients were considered treatment failures if there had been a change in PGA from remission to mild, moderate or severe disease;disease relapse between visits; need for rescue therapy(biologic therapy, methotrexate, steroids); thiopurine discontinuation, hospitalization or surgical intervention. A secondary outcome defined treatment failure as a change from remission to moderate or severe(not mild) in addition to the previously defined criteria.RESULTS: Sixty-five of 182 patients in the PIBDNet registry met criteria for inclusion in this study. Fortyfive of 65(69%) of included patients achieved remission within 180 d of thiopurine initiation. For the primary outcome, 47% and 23% of patients remained in SFR at 6 and 12 mo. The mean thiopurine dose at initiation for the 65 included patients was 0.89 ± 0.31 mg/kg per day. Metabolite levels were obtained in 48%(31/65) of the included patients with a mean 6TG level of 258 pmole/8 × 108 RBC ± 147. For the secondary outcome, 65% and 42% of patients remained in SFR at 6 and 12 mo.CONCLUSION: Thiopurines were less effective in maintaining remission for pediatric CD in this "real world" cohort than has been previously described. Variation in thiopurine dosing and metabolite measurement was found among practitioners.
文摘Hepatosplenic T-cell lymphoma(HSTCL) is a rare nonHodgkin lymphoma with a high mortality rate. Higher incidence is reported in patients with inflammatory bowel disease, specifically in male patients that are younger than 35 years, and have been treated with thiopurine and tumor necrosis factor(TNF)-α inhibitor combination therapy for over 2 years. In this case report we describe a 47-year-old patient with Crohn's disease(CD) who developed HSTCL after having been treated with thiopurine monotherapy for 14 years. To our best knowledge, only eleven cases exist of patients with CD who developed HSTCL while on thiopurine monotherapy. We report the first patient with CD, older than 35 years, who developed HSTCL while on thiopurine monotherapy. This emphasizes that HSTCL risk is not limited to young men receiving both thiopurines and TNF-α inhibitors.
文摘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.
文摘BACKGROUND Azathioprine(AZA)and its close analog 6-mercaptopurine are thiopurines widely used in the treatment of patients with cancer,organ transplantation,and autoimmune or inflammatory diseases,including systemic lupus erythematosus.Bone marrow inhibition is a common side effect of AZA,and severe bone marrow inhibition is related to decreased thiopurine S-methyltransferase(TPMT)activity.CASE SUMMARY We herein report a patient with proliferative lupus nephritis who was using AZA for maintenance therapy,had no common TPMT pathogenic site mutations,and exhibited severe bone marrow inhibition on the 15th day after oral administration.CONCLUSION This report alerts physicians to the fact that even though the TPMT gene has no common pathogenic site mutation,severe myelosuppression may also occur.
文摘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.
基金Supported by the National Natural Science Foundation of China,No.81573507,No.81473283,No.81173131,and No.81320108027Guangdong Provincial Key Laboratory Construction Foundation,No.2017B030314030+1 种基金The National Key Research and Development Program,No.2016YFC0905003the 111 Project,No.B16047
文摘BACKGROUND Thiopurine-induced leukopenia(TIL)is a life-threatening toxicity and occurs with a high frequency in the Asian population.Although nucleoside diphosphate-linked moiety X-type motif 15(NUDT15)variants significantly improve the predictive sensitivity of TIL,more than 50%of cases of this toxicity cannot be predicted by this mutation.The potential use of the 6-thioguanine nucleotide(6TGN)level to predict TIL has been explored,but no decisive conclusion has been reached.Can we increase the predictive sensitivity based on 6TGN by subgrouping patients according to their NUDT15 R139C genotypes?AIM To determine the 6TGN cut-off levels after dividing patients into subgroups according to their NUDT15 R139C genotypes.METHODS Patients’clinical and epidemiological characteristics were collected from medical records from July 2014 to February 2017.NUDT15 R139C,thiopurine S methyltransferase,and 6TGN concentrations were measured.RESULTS A total of 411 Crohn’s disease patients were included.TIL was observed in 72 individuals with a median 6TGN level of 323.4 pmol/8×10^8 red blood cells(RBC),which was not different from that of patients without TIL(P=0.071).Then,we compared the 6TGN levels based on NUDT15 R139C.For CC(n=342)and CT(n=65)genotypes,the median 6TGN level in patients with TIL was significantly higher than that in patients without(474.8 vs 306.0 pmol/8×10^8 RBC,P=9.4×10-^5;291.7 vs 217.6 pmol/8×10^8 RBC,P=0.039,respectively).The four TT carriers developed TIL,with a median 6TGN concentration of 135.8 pmol/8×10^8 RBC.The 6TGN cut-off levels were 411.5 and 319.2 pmol/8×108 RBC for the CC and CT groups,respectively.CONCLUSION The predictive sensitivity of TIL based on 6TGN is dramatically increased after subgrouping according to NUDT15 R139C genotypes.Applying 6TGN cut-off levels to adjust thiopurine therapies based on NUDT15 is strongly recommended.
文摘AIM:To investigate the influence of thiopurines and biological drugs on the presence of small intestinal bacterial overgrowth(SIBO) in patients with inactive Crohn's disease(CD).METHODS:This was a prospective study in patients with CD in remission and without corticosteroid treatment,included consecutively from 2004 to 2010.SIBO was investigated using the hydrogen glucose breath test.RESULTS:One hundred and seven patients with CD in remission were included.Almost 58%of patients used maintenance immunosuppressant therapy and 19.6%used biological therapy.The prevalence of SIBO was16.8%.No association was observed between SIBO and the use of thiopurine Immunosuppressant(12/62patients),administration of biological drugs(2/21 patients),or with double treatment with an anti-tumor necrosis factor drugs plus thiopurine(1/13 patients).Half of the patients had symptoms that were suggestive of SIBO,though meteorism was the only symptom that was significantly associated with the presence of SIBO on univariate analysis(P<0.05).Multivariate analysis revealed that the presence of meteorism and a fistulizing pattern were associated with the presence of SIBO(P<0.05).CONCLUSION:Immunosuppressants and/or biological drugs do not induce SIBO in inactive CD.Fistulizing disease pattern and meteorism are associated with SIBO.
文摘In the last decades,with the development of biological therapy,the treatment paradigms in patients with Crohn's disease have continuously evolved.Several studies focusing on the optimal use of both traditional immunosupressants and biological therapy have been published,investigating conventional,accelerated step-up and topdown approaches.In addition,much emphasis has been placed in recent years on the determination of important predictive factors that could enable early patient stratification,which would lead to a tailored management strategy.In this review,the authors try to highlight new evidence on the optimal timing,benefits,and risks of immunosupressants alone,or in combination,in patients with Crohn's disease.
