Use Of Thiopurines Research Articles

Thiopurines in IBD Linked with Myeloid Disorders

Recent study findings have strengthened the evidence of a positive association between thiopurine use in patients with inflammatory bowel disease (IBD)

Management of inflammatory bowel disease patients with a cancer history.

In inflammatory bowel disease (IBD) patients, thiopurines promote carcinogenesis of Epstein-Barr Virus (EBV)-related lymphomas, non-melanoma skin cancers and urinary tract cancers, while anti-TNF agents could promote carcinogenesis of melanomas. Patients with IBD and previous cancer are at a higher risk of developing new or recurrent cancer than IBD patients without a history of cancer, irrespective of the use of immunosuppressants. In transplant recipients, the use of thiopurines is associated with a high rate of cancer recurrence, particularly within the first two years following transplantation. In patients with chronic inflammatory disease, limited data suggest that no dramatic incidence of cancer recurrence is associated with the use of thiopurines or anti-TNF agents. However, there is a rationale for a two-year drug holiday from immunosuppressants after the diagnosis and treatment of the majority of incident cancers, as often as possible. Extending the duration of the immunosuppressant drug holiday to 5 years in patients with previous cancers associated with a high risk of recurrence in the post-transplant state should be considered. The immunosuppressants that can be initiated or resumed after cancer treatment should be chosen according to the type of the previous cancer. All individual decisions should be made on a case-by-case basis, together with the oncologist, according to characteristics and expected evolution of the index cancer, expected impact of the immunosuppressants on cancer evolution, and intrinsic severity of IBD, with its associated risks.

Early use of thiopurines or methotrexate reduces major abdominal and perianal surgery in Crohn's disease.

Earlier introduction of immunomodulators (IM) thiopurine or methotrexate is advocated to improve Crohn's disease (CD) outcomes, but whether abdominal surgery can be prevented remains controversial. A specialist-referred cohort of CD was recruited from 1970 to 2009. Early IM use was defined as commencement of azathioprine or methotrexate within 3 years of CD diagnosis and adherence of at least 6 months. Propensity score matching was conducted to correct for confounders influencing early IM introduction. Outcomes of interest were rates of initial and recurrent major abdominal surgery for CD and their predictive factors. A total of 1035 consecutive patients with CD (13,061 patient-years) were recruited. The risk of first and recurrent major abdominal surgery at 1, 5, and 10 years were 17.5%, 28.4%, and 39.5% and 5.9%, 19.0%, and 33.3%, respectively. Early IM use increased over time from 1.3% to 55.3% (P < 0.0001) and was a significant independent predictor of lower rates of initial abdominal surgery (hazard ratio [HR], 0.45; 95% confidence interval [CI], 0.35-0.69), recurrent abdominal surgery (HR, 0.44; 95% CI, 0.25-0.79) and perianal surgery (HR, 0.30; 95% CI, 0.16-0.56). Using propensity score matching, early IM significantly reduced surgical rates (HR, 0.54; 95% CI, 0.37-0.79). Number needed to treat to prevent a surgical event at 5 years from diagnosis and after initial surgery was 6.99 (95% CI, 5.34-11.95) and 8.59 (95% CI, 6.26-23.93), respectively. Early IM use with thiopurines or methotrexate was significantly associated with the reduced need for abdominal and perianal surgery in CD.

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

To evaluate the effectiveness of thiopurines in maintaining steroid-free remission in routine clinical practice. The multi-center Pediatric Inflammatory Bowel Disease Network (PIBDNet) cohort study prospectively collected data on thiopurine naïve 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. Sixty-five of 182 patients in the PIBDNet registry met criteria for inclusion in this study. Forty-five 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 × 10(8) RBC ± 147. For the secondary outcome, 65% and 42% of patients remained in SFR at 6 and 12 mo. 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.

Anti–Tumor Necrosis Factor Agents: Continued Evidence of Low Cancer Risk

Recent study findings suggest that thiopurine use increases the risk for lymphoma and nonmelanoma skin cancers in patients with inflammatory bowel

PTU-106 Successful Pregnancies With Thiopurine-allopurinol Co-therapy For Inflammatory Bowel Disease

IntroductionCombination of low dose thiopurine with allopurinol can improve the clinical efficacy and bypass some of the adverse reactions of thiopurine monotherapy. Thiopurines can be used safely during pregnancy but...

PWE-117 Have Perianal Surgery Rates Decreased With The Rise In Thiopurine Use In Crohn’s Disease?

IntroductionAlthough thiopurines (TPs) have proven efficacy in the maintenance of remission in Crohn’s disease (CD) and may reduce the need for intestinal surgery, their impact on perianal disease is not...

Su1389 Successful Pregnancies With Thiopurine-Allopurinol Co-Therapy for Inflammatory Bowel Disease

Introduction Combination of low dose thiopurine with allopurinol can improve the clinical efficacy and bypass some of the adverse reactions of thiopurine monotherapy. Thiopurines can be used safely during pregnancy but there is scarce data regarding allopurinol. We report twelve cases of safe use of thiopurine and allopurinol co-therapy to manage IBD during pregnancy. Methods Patients were retrospectively identified at two hospitals in the UK and in Australia, using our local IBD databases. All pregnancies of co-therapy patients were included. TPMT activity and pre-pregnancy weight were used to calculate thiopurine dosing. Data regarding pregnancy and fetal outcomes were collected from patient notes. Results Eleven females on co-therapy became pregnant, totalling twelve pregnancies with eight live births (Table 1) and four ongoing pregnancies. There were no reported terminations, miscarriages or spontaneous pre-term deliveries ( Conclusion All twelve cases were treated successfully with co-therapy without any adverse pregnancy related events or adverse fetal outcomes. Intrauterine exposure of the fetus to thiopurine metabolites is not greater with combination therapy compared with thiopurine monotherapy. There are only two reports of congenital malformations with maternal allopurinol use. The case for an association based on two cases is weak, moreover a negative publication bias with respects to successful maternal allopurinal use is suspected. Our study provides support for clinicians and patients wishing to continue thiopurine-allopurinol co-therapy during pregnancy. Disclosure of Interest None Declared.

Impact of preoperative immunosuppressive agents on postoperative outcomes in Crohn's disease.

Immunosuppressive agents are essential in the management of Crohn's disease. Their safety before surgery, however, is still controversial. The aim of this study is to evaluate whether the preoperative use of immunosuppressive agents is associated with increased postoperative complications in Crohn's disease. A literature search of PubMed, EMBASE, and The Cochrane Library was undertaken in February 2013. All studies describing postoperative outcomes of patients undergoing bowel resections for Crohn's disease were included if they reported data comparing patients on preoperative immunosuppressive agents with an appropriate control group. All immunosuppressive agents used to manage Crohn's disease were studied. The main outcomes measured were total overall complications and total infectious complications. Twenty-one eligible studies (20 retrospective and 1 prospective) with 6899 patients were included. When individual studies were examined, only 2/14 (14%), 4/13 (31%), and 1/8 (13%) studies found an association between postoperative complications and preoperative anti-tumor necrosis factor agents, corticosteroids, and thiopurines. In meta-analyses, patients on anti-tumor necrosis factor agents (risk ratio, 1.29; 95% CI, 1.07-1.55), and corticosteroids (risk ratio, 1.55; 95% CI, 1.23-1.95) were found to have a higher risk of postoperative infectious complications. The use of anti-tumor necrosis factor agents was also significantly associated with wound infection (risk ratio, 1.62; 95% CI, 1.12-2.34) and septic shock (risk ratio, 1.81; 95% CI, 1.03-3.17). There was no association between the use of thiopurines or combined immunomodulator drugs and postoperative complications. Most studies were retrospectively designed, and there were large variations in the patient populations and outcome definitions. Patients with Crohn's disease on preoperative immunosuppressive agents are at higher risk for complications. Both corticosteroids and anti-tumor necrosis factor agents may increase the risk of infections and septic shock. A preoperative drug-free interval, when feasible, might be considered to reduce the risk of infections. The adoption of any operative strategies that modify these outcomes may additionally counter these risks.

Mo1184 Meta-Analysis of Thiopurine Exposure and Risk of Colonic Neoplasia in Inflammatory Bowel Disease

Background: Immunosuppressive medications play an important role in the management of inflammatory bowel disease (IBD). However, elderly patients are excluded from clinical trials and there is a paucity of data regarding the safety of immunosuppressive medications among elderly patients with IBD. The aim of this study was to examine the association between medication exposure and related complications and among elderly patients with IBD. Methods: We performed a cross sectional study of adults patients with IBD who received care at Baylor College of Medicine from July 2009 to June 2013. We identified IBD patients using ICD-9 codes for Crohn's disease (555.xx) and ulcerative colitis (556.xx). Demographic and clinical data were abstracted bymanual chart review using a standardized data abstraction form. Current and past medication exposure were classified as aminosalicylate/sulfasalazine, systemic steroids (prednisone/methylprednisolone), thiopurines (azathioprine, 6-mercaptopurine), methotrexate and biologics (infliximab, adalimumab, and certolizumab pegol). Potential medication-related complications were classified as infection, leukopenia, pancreatitis, hepatitis, osteoporosis/osteopenia, and cancer. The primary endpoint was association of medication exposure with the composite endpoint of any complication. Associations of medications with complications were assessed using univariate and multivariate logistic regression. Results: From a total of 1,525patients with IBD, we identified 144 patients who were 65 years or older at the time of data abstraction; mean age of 71.6 years (SD+6.1); 55% female; 38% with ulcerative colitis, 57% with Crohn's disease, and 5% with IBD unclassified. 32% of patients were observed to have at least one complication. In univariate analyses, thiopurine exposure was associated with an increased odds of any medicationrelated complication (OR 3.23 95% CI 1.53-6.80). On analysis of specific complications, thiopurine exposure was associated with higher rates on infection (OR 2.89 95% CI 1.087.76), but not other complications. None of the other examined medications, including biologics, were associated with medication-related complications. On multivariate analysis adjusting for gender, race, duration of disease and smoking, thiopurine exposure remained statistically significantly associated with the composite endpoint of any complication (OR 4.21 95%CI 1.84-9.65). Conclusions: One third of elderly patients with IBDwere observed to have a complication. Thiopurine exposure was associated with a 3-fold risk of complications compared to all other medication exposures. Biologic exposure was not associated with immediate medication-related complications. Thiopurine use in elderly patients with IBD requires close monitoring for infectious complications.

Mo1183 Prevalence of Serum JC Virus Antibody in Refractory Crohn's Disease Patients

Background: Immunosuppressive medications play an important role in the management of inflammatory bowel disease (IBD). However, elderly patients are excluded from clinical trials and there is a paucity of data regarding the safety of immunosuppressive medications among elderly patients with IBD. The aim of this study was to examine the association between medication exposure and related complications and among elderly patients with IBD. Methods: We performed a cross sectional study of adults patients with IBD who received care at Baylor College of Medicine from July 2009 to June 2013. We identified IBD patients using ICD-9 codes for Crohn's disease (555.xx) and ulcerative colitis (556.xx). Demographic and clinical data were abstracted bymanual chart review using a standardized data abstraction form. Current and past medication exposure were classified as aminosalicylate/sulfasalazine, systemic steroids (prednisone/methylprednisolone), thiopurines (azathioprine, 6-mercaptopurine), methotrexate and biologics (infliximab, adalimumab, and certolizumab pegol). Potential medication-related complications were classified as infection, leukopenia, pancreatitis, hepatitis, osteoporosis/osteopenia, and cancer. The primary endpoint was association of medication exposure with the composite endpoint of any complication. Associations of medications with complications were assessed using univariate and multivariate logistic regression. Results: From a total of 1,525patients with IBD, we identified 144 patients who were 65 years or older at the time of data abstraction; mean age of 71.6 years (SD+6.1); 55% female; 38% with ulcerative colitis, 57% with Crohn's disease, and 5% with IBD unclassified. 32% of patients were observed to have at least one complication. In univariate analyses, thiopurine exposure was associated with an increased odds of any medicationrelated complication (OR 3.23 95% CI 1.53-6.80). On analysis of specific complications, thiopurine exposure was associated with higher rates on infection (OR 2.89 95% CI 1.087.76), but not other complications. None of the other examined medications, including biologics, were associated with medication-related complications. On multivariate analysis adjusting for gender, race, duration of disease and smoking, thiopurine exposure remained statistically significantly associated with the composite endpoint of any complication (OR 4.21 95%CI 1.84-9.65). Conclusions: One third of elderly patients with IBDwere observed to have a complication. Thiopurine exposure was associated with a 3-fold risk of complications compared to all other medication exposures. Biologic exposure was not associated with immediate medication-related complications. Thiopurine use in elderly patients with IBD requires close monitoring for infectious complications.

Adalimumab Monotherapy Is Not Associated with Increased Cancer Risk

Mounting evidence suggests that thiopurine use for treatment of Crohn disease is associated with increased risks for nonmelanoma skin cancer (NMSC) and

Systematic review: The use of thiopurines or anti-TNF in post-operative Crohn's disease maintenance--progress and prospects.

Post-operative recurrence of Crohn's disease is an important management challenge, with 2-year recurrence rates defined by clinical, endoscopic and radiological parameters of up to 77%, 64% and 49%. Clinical and severe endoscopic recurrence vary widely in controlled trials from 13% to 36% and 22% to 56% with thiopurine treatment or 0% and 9% with infliximab treatment respectively at 1year. To provide a review of the evidence for thiopurine or anti-TNF use in post-operative Crohn's disease, and to assess the ability to identify those patients at highest risk of recurrent disease. A literature search was undertaken using Medline, Embase and Cochrane databases to identify studies using search terms 'thiopurine', 'azathioprine', 'mercaptopurine', 'Infliximab', 'adalimumab', 'Anti-TNF', 'Crohn's disease', 'post-operative' and 'recurrence'. Trials to examine this important area have proved difficult to execute, with recruitment and retention of patients posing major challenges to randomised clinical trials. There have been four RCTs of 433 patients of thiopurine therapy (with three meta-analyses of these data), and one of anti-TNF therapy involving 24 patients. Overall the efficacy data for thiopurine use in this setting are inconclusive, and other than smoking, there are no consistent predictors of post-operative relapse. At present, evidence for routine use of thiopurine treatment in post-operative Crohn's disease is heterogeneous and unconvincing. Stratification by risk of relapse emerges as a key challenge in post-operative management that needs to be addressed, using clinical parameters and emerging biomarkers. The evidence for prophylactic anti-TNF use is limited though promising, with its routine use guided by early assessment of relapse.

La nutrición enteral exclusiva continua siendo el tratamiento de primera línea en la enfermedad de Crohn pediátrica en la era de los biológicos

IntroductionExclusive enteral nutrition (EEN) has been to be more effective than corticosteroids in achieving mucosal healing without their side effects. ObjectivesTo determine the efficacy of EEN in terms of inducing clinical remission in newly diagnosed CD children and to study the efficacy of this therapeutic approach in improving the degree of intestinal mucosa inflammation. Materials and methodsThe medical records of patients with newly diagnosed Crohn's disease treated with EEN were reviewed retrospectively. The degree of mucosal inflammation was assessed by fecal calprotectin (FC). Remission was defined as a PCDAI<10. ResultsForty patients (24 males) were included, the age at diagnosis was 11.6±3.6 years. Of the 34 patients who completed the EEN period, 32 (94% per-protocol analysis) achieved clinical remission. This percentage fell to 80% in the intention-to-treat analysis. The compliance rate was 95%. Duration of EEN was 6.42 weeks (IQR 6.0–8.14). FC was significantly higher in patients with moderate and severe disease. Median baseline FC levels (680μg/g) decreased significantly to 218μg/g (P<0.0001) after EEN. We found a statistically significant correlation between FC and PCDAI (rho=0.727; P<0.0001). Early use of thiopurines (< 8 weeks) versus subsequent use was not associated with improved outcomes during the follow-up. ConclusionsEEN administered for 6-8 weeks is effective for inducing clinical remission and decreasing the degree of mucosal inflammation. We did not find differences in terms of maintenance of remission in patients treated early with thiopurines.

Fecal Microbial Composition of Ulcerative Colitis and Crohn’s Disease Patients in Remission and Subsequent Exacerbation

BackgroundLimited studies have examined the intestinal microbiota composition in relation to changes in disease course of IBD over time. We aimed to study prospectively the fecal microbiota in IBD patients developing an exacerbation during follow-up.DesignFecal samples from 10 Crohn’s disease (CD) and 9 ulcerative colitis (UC) patients during remission and subsequent exacerbation were included. Active disease was determined by colonoscopy and/or fecal calprotectine levels. Exclusion criteria were pregnancy, antibiotic use, enema use and/or medication changes between consecutive samples. The microbial composition was assessed by 16S rDNA pyrosequencing.ResultsAfter quality control, 6,194–11,030 sequences per sample were available for analysis. Patient-specific shifts in bacterial composition and diversity were observed during exacerbation compared to remission, but overarching shifts within UC or CD were not observed. Changes in the bacterial community composition between remission and exacerbation as assessed by Bray-Curtis dissimilarity, were significantly larger in CD versus UC patients (0.59 vs. 0.42, respectively; p = 0.025). Thiopurine use was found to be a significant cause of clustering as shown by Principal Coordinate Analysis and was associated with decreases in bacterial richness (Choa1 501.2 vs. 847.6 in non-users; p<0.001) and diversity (Shannon index: 5.13 vs. 6.78, respectively; p<0.01).ConclusionShifts in microbial composition in IBD patients with changing disease activity over time seem to be patient-specific, and are more pronounced in CD than in UC patients. Furthermore, thiopurine use was found to be associated with the microbial composition and diversity, and should be considered when studying the intestinal microbiota in relation to disease course.

P598 Proton pump inhibitor use and risk of microscopic colitis – A nationwide Danish case-control study with 5751 cases

Methods: Data on medication prescription and phenotypic appearance in 513 individuals [ulcerative colitis (UC) n = 300, Crohn’s disease (CD) n = 213] diagnosed in 2003 2004 with a follow-up time of 7 years were defined as baseline factors. Cumulative probabilities of recurrences were estimated and the association of baseline factors, medication use and time to first recurrence were examined by Cox regression. Results: In CD the cumulative risk of first all type recurrence was 42%, 67% and 69% after 1, 5 and 7 years. 55% of the patients at risk had a second relapse within 2 years of the first and of these 53% had third relapse within one year of the second. The cumulative risk of medical relapses were 38%, 62% and 65% after 1, 5 and 7 years. There was a trend of a protective factor in having male gender (HR 0.73 95%CI: 0.51 1.04) and use of thiopurines (HR 0.69, 95%CI: 0.44 1.06) in medical relapses. Stricturing behaviour at diagnosis (HR 3.5; 95%CI: 3.5 7.2), use of systemic corticosteroids (HR 3.77; 95%CI: 1.17 12.15), thiopurines (HR 1.90 95%CI: 1.03 3.50) and antiTNF agents (HR 2.37; 95%CI: 1.21 4.65) were associated with first surgical recurrence. Localization in the colon (HR 0.37; 95%CI: 0.18 0.72) and ileocolon (HR 0.41; 95%CI: 0.19 0.90) were protective. In UC the cumulative risk of first all type recurrence was 53%, 76% and 80% in 1, 5 and 7 years. The cumulative risk of a medical recurrence was 52%, 74% and 78% in 1, 5 and 7 years. Age above 40 was protective in first all type recurrence (HR 0.64; 95%CI: 0.49 0.84), in medical recurrence (HR 0.69; 95%CI: 0.52 0.90) and against colectomy (HR 0.49 95%CI: 0.22 1.09). Use of systemic corticosteroids in the first three months after diagnosis (HR 4.56; 95%CI: 2.09 9.95), use of thiopurines (HR 9.71; 95%CI: 4.58 20.57) and use of anti-TNF (HR 12.38; 95%CI: 4.33 35.37) were all significantly associated to risk of colectomy. Conclusions: The cumulative risk of first all type recurrence has decreased in CD compared to previous studies but patients with a relapse are at risk of a second and third relapse. Stricturing behaviour, systemic corticosteroids, thiopurines and anti-TNF were associated with first surgical recurrence. In UC the cumulative recurrence rate was unaltered. Age above 40 was protective against any type of recurrence.

Continuing Medical Education: February 2014

Association Between Thiopurine Use and Nonmelanoma Skin Cancers in Patients With Inflammatory Bowel Disease: A Meta-Analysis The American College of Gastroenterology is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The American College of Gastroenterology designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 Credit™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Use of thiopurines in inflammatory bowel disease: Safety issues.

Thiopurines are widely used for maintenance treatment of inflammatory bowel disease. Inter-individual 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.

Inflammatory bowel disease in children of middle eastern descent.

Increasing rates of inflammatory bowel disease (IBD) are now seen in populations where it was once uncommon. The pattern of IBD in children of Middle Eastern descent in Australia has never been reported. This study aimed to investigate the burden of IBD in children of Middle Eastern descent at the Sydney Children's Hospital, Randwick (SCHR). The SCHR IBD database was used to identify patients of self-reported Middle Eastern ethnicity diagnosed between 1987 and 2011. Demographic, diagnosis, and management data was collected for all Middle Eastern children and an age and gender matched non-Middle Eastern IBD control group. Twenty-four patients of Middle Eastern descent were identified. Middle Eastern Crohn's disease patients had higher disease activity at diagnosis, higher use of thiopurines, and less restricted colonic disease than controls. Although there were limitations with this dataset, we estimated a higher prevalence of IBD in Middle Eastern children and they had a different disease phenotype and behavior compared to the control group, with less disease restricted to the colon and likely a more active disease course.

Canadian Association of Gastroenterology position statement regarding the use of thiopurines for the treatment of inflammatory bowel disease.

Canadian Association of Gastroenterology position statement regarding the use of thiopurines for the treatment of inflammatory bowel disease.