Use Of Thiopurines Research Articles

Cancer and immunomodulators in inflammatory bowel diseases.

The widespread use of thiopurines and anti-tumor necrosis factors (TNFs) in inflammatory bowel disease (IBD) is a rising concern regarding their potential cancer risk. MEDLINE, EMBASE, and the Cochrane Library database were searched for articles regarding immunomodulators anti-TNF agents in IBD, hematologic malignancies, and solid tumors. Current evidences support that thiopurines and anti-TNFs used alone or in combination do not increase the overall cancer risk in IBD. Thiopurines use, with or without anti-TNFs, is associated with an increased risk of lymphoma, particularly non-Hodgkin lymphoma, in Crohn's disease. Combined treatment significantly increases the risk of a rare hepatosplenic T-cell lymphoma, particularly in young male patients with Crohn's disease. An increased risk of nonmelanotic skin cancer is also observed when using thiopurines in IBD, whereas a slightly increased risk of melanoma is observed when using anti-TNFs. The role played by immunomodulators in the development of other cancer types (i.e., urinary) as also by the severity of IBD is under investigation. Although the incidence of specific malignancies (lymphoma, skin cancers) seems to be increased by immunomodulators, their absolute number is low. As thiopurines and anti-TNFs are highly effective in IBD, current evidences support that in appropriate hands, their benefits overwhelm the cancer risk. However, a careful selection of both patients and timing of treatment is mandatory, particularly in young male patients with Crohn's disease. Immunomodulators should therefore be handled by experienced and dedicated gastroenterologists who aware of the potential, although low, cancer risk associated with their use in patients with IBD.

ACP journal club. In ulcerative colitis, current use of thiopurines was associated with nonmelanoma skin cancer.

Source Citation Abbas AM, Almukhtar RM, Loftus EV, Lichtenstein GR, Khan N. Risk of melanoma and non-melanoma skin cancer in ulcerative colitis patients treated with thiopurines: a nationwide retro...

P390. Thiopurines are more effective in Crohn's Disease than in Ulcerative Colitis, despite a global high rate of treatment failure: A single centre experience in the use of thiopurines in the era of biologics

P390. Thiopurines are more effective in Crohn's Disease than in Ulcerative Colitis, despite a global high rate of treatment failure: A single centre experience in the use of thiopurines in the era of biologics

DOP050. Early thiopurine use is associated with a reduced risk of surgery in children and young people with Crohn's disease but not in ulcerative colitis

DOP050. Early thiopurine use is associated with a reduced risk of surgery in children and young people with Crohn's disease but not in ulcerative colitis

Impact of timing and duration of thiopurine treatment on first perianal surgery in Crohn's disease: UK population-based study (1995-2009).

The impact of thiopurine (TP) use on perianal surgery is uncertain. Our aim was to determine trends in perianal surgery and the impact of timing and duration of TPs on the risk of first perianal surgery. We identified a population-based cohort of incident cases of Crohn's disease between 1995 and 2009. We used Kaplan-Meier analysis to determine trends in TP usage and first perianal surgery by era of diagnosis: era 1 (1995-2002) and era 2 (2003-2009). We quantified the impact of duration and timing of TPs on the risk of perianal surgery using a Cox regression model. We identified a cohort of 5235 incident cases of Crohn's disease. The 5-year cumulative probability of first perianal surgery decreased from 2.7% to 1.7% between era 1 and era 2, respectively (P = 0.03). TP use for greater than 18 months was associated with a 40% risk reduction for first perianal surgery (hazard ratio: 0.60, 95% confidence interval: 0.39-0.95) and 49% if TPs were used for 2 years or more (hazard ratio: 0.51, 95% confidence interval: 0.32-0.99). There was no demonstrable additional benefit from early TP use within the first year after diagnosis (hazard ratio: 0.85, 95% confidence interval: 0.52-1.40, P = 0.53). Over the past 15 years, TP use has increased by 50%, whereas perianal surgery rates have decreased by 37% among UK population with Crohn's disease. Sustained use for 18 months was associated with a reduced risk of perianal surgery by almost a half in the first 5 years after diagnosis.

Safety of Immunomodulators and Anti-TNF Therapy in Pregnancy.

Biologics have proved to be extremely effective therapies for active, difficult to treat ulcerative colitis and Crohn's disease. Given that active disease appears to be what drives worse outcomes in conception and pregnancy, understanding of the potential risks of continued biologic therapy during pregnancy is important. Knowledge of the mechanisms of placental transfer helps clinicians explain to patients the timing of potential cessation of therapy, and the ongoing data collection from the efforts of the Crohn's and Colitis Pregnancy Registry have helped immensely to move this field forward. The body of evidence for use of thiopurines as well has supported their continued use during pregnancy in patients, despite their category D rating. Family planning and counseling have come a long way with our efforts in understanding that the real enemy is active inflammation, not the therapies we use to treat it.

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

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

Efficacy of Thiopurines in Biologic-Naive Japanese Patients With Crohn's Disease: A Single-Center Experience.

Background/AimsEarly use of biologics in patients with Crohn's disease (CD) improves quality of life. However, the effects of the early use of immunomodulators on long-term outcomes remain unclear. This study aimed to evaluate the effects of immunomodulators in patients with CD.MethodsBetween January 2004 and December 2011, 47 biologic-naive CD patients treated with thiopurines alone for remission maintenance were analyzed. The patients were classified into 2 groups depending on the presence or absence of digestive complications. We evaluated the efficacy of and predictive factors for thiopurine use for remission maintenance.ResultsThe cumulative relapse rates at 24 and 60 months were 13.7% and 35.4%, respectively. Regarding patient characteristics, there was a significant difference in patient history of surgery between the non-relapse and relapse groups (P=0.021). The cumulative relapse rate was lower in patients without a history of surgery than in those with such a history (27.2% and 52.9% at 60.0 months, respectively). Multivariate analysis suggested that the prevalence of stricturing and penetrating complications is an independent factor for relapse. The cumulative relapse rate in patients without a history of surgery was significantly lower in the non-stricturing and non-penetrating group than in the stricturing and penetrating group (11.8% at 85.0 months vs. 58.5% at 69.0 months; P=0.036).ConclusionsThiopurine use might be beneficial for the long-term maintenance of remission in biologic-naive Crohn's disease patients without digestive complications and a history of surgery.

Is Long-Term Therapy With Thiopurines Effective for Maintaining Remission in Patients With Moderate-To-Severe Ulcerative Colitis?

The thiopurines, azathioprine and 6-mercaptopurine, have been in clinical use for 50 years. Prospective studies and meta-analyses suggest that thiopurines are effective for the maintenance of remission in UC.1,2 By maintaining remission, hospitalization and colectomy rates can be reduced, and long-term complications prevented. However, in the biologic era, the long-term efficacy of thiopurine needs to be better understood. In this issue of Intestinal Research, Yamada et al. tried to assess the long-term efficacy and safety of maintenance treatment with thiopurines in UC.3 They enrolled a total of 59 bio-naive patients who maintained remission by treatment with thiopurine and 5-aminosalicylate after induction. The cumulative remission-maintenance rates at 24, 48, and 84 months were reported as approximately 69%, 55%, and 44%, respectively. Recent meta-analyses of trial data revealed remission maintenance rates of 56-76% during thiopurine treatment.1,2 The remission maintenance rate of Yamada et al. was similar to that of meta-analyses, considering that the mean follow-up period of these studies was shorter. Yamada et al. also demonstrated that high-dose corticosteroid treatment (≥40 mg/day) was a negative predictive factor for maintenance treatment with thiopurine. This could be inferred from the fact that other maintenance treatments such as biologics should be considered in refractory UC patients treated with high-dose corticosteroids. Mucosal healing (MH) is becoming more widely accepted as a relevant outcome marker for UC. In a Norwegian population-based cohort study examining effects between the presence or absence of MH and long-term outcomes, MH at 1 year was confirmed in 50% of UC patients, and the colectomy rate at 5 years was 1.7%. MH at 1 year significantly decreased the need for colectomy at 5 years,4 and this association was significant after adjusting for factors that may influence colectomy, such as age, smoking, education level, and disease extent. Therefore, the previous study provides evidence that MH is strongly associated with the clinical outcomes of UC. Yamada et al. reported MH rates of >60% at 26.8 months, and a colectomy rate of 3.6%. Compared to that of Western studies, this result was not significantly different. However, only two-thirds of study patients underwent colonoscopy to evaluate MH and the time interval between initiating thiopurine therapy and performing the colonoscopy to assess MH was different in each patient due to the retrospective design of the study. Therefore, the results of Yamada et al. should be interpreted while considering the limitations of the study, such as the small number of patients included and the lack of adjustment for potential confounding factors. Efficacy must be balanced against safety and tolerability. In the Yamada et al. study, the median dose of thiopurine was 50 mg. Traditionally, the dose-escalating approach is used in East Asian patients.5,6 Several trials, including this study, have suggested that lower doses of azathioprine or 6-mercaptopurine may be effective and safe for the treatment of UC patients,7,8 contrary to the results of Western studies. According to previous studies, approximately 10-28% of patients reported adverse events (AEs), and 25.6% of patients had to discontinue thiopurine therapy due to AEs.9,10 A similar rate of AEs (28.8%) was reported in the study by Yamada et al. In this study, the discontinuation rate due to AEs was reported as low as 10.2%, probably due to low thiopurine dose they used. Although there were no severe AEs such as lymphoma and non-melanoma skin cancer in the Yamada et al. study, and the absolute risks of these malignancies remain low, the risks and benefits of continuing or ceasing thiopurine therapy should be weighed for each individual patient. Despite the fact that clinical trials (including the Yamada et al. study) concerning the use of thiopurines for UC have been heterogeneous in design, the evidence is sufficient to conclude that thiopurines are effective for maintenance of remission.

The positive influences of increasing age at diagnosis of inflammatory bowel disease on disease prognostication in asian perspective.

The positive influences of increasing age at diagnosis of inflammatory bowel disease on disease prognostication in asian perspective.

A practical guide to the use of thiopurines in oral medicine.

Thiopurines are widely used as first-line immunosuppressive therapies in the management of chronic inflammatory oral disease. However, despite over half a century of clinical experience, the evidence base for their use is limited. The aims of this paper were to review the evidence for the use of thiopurines in oral medicine and provide a contemporary model of thiopurine metabolism and mechanism of action and a rationale for clinical use and safe practice.

P-055 YI Thiopurine Methyltransferase Testing and Thiopurine Use in Inflammatory Bowel Disease Patients Amongst Gastroenterologists

Inflammatory bowel disease (IBD) is a chronic disease that often requires immunosuppressive and/or immunomodulatory therapy, in particular thiopurines such as Azathioprine (AZA) and 6-Mercaptopurine (6-MP). Numerous guidelines and organizations such as the World Gastroenterology Organization, American College of Gastroenterology, American Gastroenterology Association, National Institute for Health and Clinical Excellence and Federal Drug Association recommend routine evaluation of thiopurine methyltransferase testing (TPMT) for enzyme levels in order to identify at-risk patients for thiopurine-induced leukopenia. Therefore, we administered an electronic survey to Gastroenterologists to evaluate practice patterns and guideline adherence in TPMT testing for thiopurine use in inflammatory bowel disease patients. We designed a 21-question electronic survey that was provided to the Canadian Association of Gastroenterology (CAG). The survey was distributed to all CAG members on July 14, 2014 via e-mail and subsequently posted on the CAG website. The survey was created using online software from www.surveymonkey.com and results were analyzed using online software. To date, there have been 38 respondents. Majority (68.4%) of the Gastroenterologists were in the 30-49 age range, 71.1% were male and 57.9% are practicing in academic institutions. The most commonly prescribed thiopurine is Azathioprine (92.1%) and the most influential prescribing factor is personal familiarity (60.5%). Only 44.7% of Gastroenterologists routinely order TPMT testing and 15.8% of Gastroenterologists were unaware TPMT testing was available in Canada. Amongst those that are aware, 55.3% are unaware which laboratories offer TPMT testing. Amongst Gastroenterologists, 29.0% order TPMT testing on all newly diagnosed IBD patients while 31.6% order it on IBD patients just prior to starting therapy with a thiopurine. The most common reason Gastroenterologists do not order TPMT testing is because they believe testing is not available locally (15.8%). Additionally, Gastroenterologists believe TPMT testing costs anywhere from $11 to over $200 and believe result take anywhere from 1 day to over 4 weeks to attain. Based on our survey and analysis of initial responses, there is considerable variability in practice patterns with TPMT testing for thiopurine use in IBD patients. We have highlighted that there are several misconceptions amongst TPMT testing. We believe that this data can aid in creating an educational initiative aimed at clarifying common misconceptions and provide greater adherence to current guidelines.

A screening instrument to identify ulcerative colitis patients with the high possibility of current non-adherence to aminosalicylate medication based on the Health Belief Model: a cross-sectional study.

BackgroundNon-adherence to aminosalicylates is observed among 30% to 45% of patients with ulcerative colitis and increases the risk of relapse. The Health Belief Model is a theoretical model that could offer a broader perspective to improve patients’ self-medication adherence. This study aimed to develop a screening instrument based on the Health Belief Model to screen patients with ulcerative colitis who had a high possibility of current non-adherence to aminosalicylates. The study was also designed to allow examination of factors of non-adherence.MethodsA multicenter, cross-sectional study was conducted in outpatients diagnosed with ulcerative colitis and prescribed aminosalicylates. Non-adherence was defined as taking less than 80% of the prescribed dose. We hypothesized that there was a significant relationship between current aminosalicylate non-adherence and five components of the HBM: beliefs about taking aminosalicylates, disease characteristics, medication characteristics, abdominal symptoms, and sociodemographic characteristics. A logistic regression model was applied and the coefficients converted to a numeric scores in order to develop a screening instrument which could reliably discriminate non-adherent and adherent subjects.ResultsNon-adherence was observed in 127 (29.6%) of the 429 enrolled subjects. Lower perceptions of belief in taking aminosalicylates, absence of visible bleeding, eight daily tablets or less taken, and no concomitant use of thiopurines were related to non-adherence. We then developed a screening instrument comprising 22 items. When the cut-off point was set at 60, the instrument showed 85.0% sensitivity and 69.2% specificity with an area under the curve of 0.84 (95% confidence interval = 0.79–0.91).ConclusionsThe instrument appeared to be reliable for identifying patients with a high possibility of current non-adherence to aminosalicylates. Further, the instrument may provide useful information for detecting patients with a high possibility of current non-adherence and for assessing factors of non-adherence. On the other hand, we need to evaluate disease activity more strictly and examine whether it is included in the screening instrument in the future.Electronic supplementary materialThe online version of this article (doi:10.1186/s12876-014-0220-z) contains supplementary material, which is available to authorized users.

How thiopurines are used for the treatment of inflammatory bowel diseases: An Italian survey

BackgroundThe ideal manner of thiopurine use in inflammatory bowel disease has not been defined. We aimed at investigating the attitudes of Italian gastroenterologists on thiopurine use. MethodsA web-based survey was performed among 295 gastroenterologists. ResultsOverall, 70 surveys were completed. At baseline, thiopurine methyltransferase genotype and phenotype were not assessed by 87.1% and 97.1% of respondents, respectively. At treatment onset, 17.1% adopted full weight-calculated dose while 80.0% preferred escalating the dose. During treatment, 87.1% and 64.3% reduced the dose for myelo- and liver toxicity, respectively; 48.6% for increased pancreatic enzymes, 17.1% for fever, and 5.7% for arthralgia. A systematic shift from one thiopurine to the other was reported by 4.3% of respondents in case of failure, and by 5.7% for adverse effects. Forty-four gastroenterologists (62.9%) stopped thiopurine treatment after 5–7 years. ConclusionsSeveral discrepancies regarding the use of thiopurines in clinical practice were found, deviating from available guidelines. A more standardised attitude is needed in clinical practice.

The impact of timing and duration of thiopurine treatment on colectomy in ulcerative colitis: a national population-based study of incident cases between 1989-2009.

The role of thiopurines in altering the risk of colectomy in ulcerative colitis (UC) remains unclear. To examine predictors of colectomy in UC and determine the impact of thiopurines on the risk of colectomy. We constructed a population-based cohort of incident cases of UC in the United Kingdom between 1989 and 2009. We determined trends in thiopurine usage and colectomy for three defined cohorts: era 1 (1989-1995), era 2 (1996-2002), era 3 (2003-2009). We used Cox regression to determine predictors of colectomy and quantified the impact of duration and timing of thiopurine use on the risk of colectomy. We identified 8673 incident cases of UC. 5-year colectomy rates increased from 4.2%, 5.1% to 6.9% (P=0.001) for era 1, era 2 and era 3, respectively, despite increasing thiopurine use. This was not significant after adjustment for predictors of colectomy (P=0.06). There was a higher risk of colectomy in men (HR 1.44, 95% CI: 1.19-1.73), those diagnosed at an early age (HR 1.35, 95% CI: 1.04-1.75; 16-24 vs. 25-64) and early steroid users (HR 1.94, 95% CI: 1.59-2.37). 5-ASA users were less likely to require a colectomy (HR 0.35, 95% CI: 0.28-0.44). Amongst thiopurine users, those treated for greater than 12months had a 71% reduction in risk of colectomy (HR 0.29, 95% CI: 0.21-0.40). Early thiopurines offered no additional benefit. Thiopurine exposure for greater than 12months reduces the likelihood of colectomy by 71%. Young men and those requiring steroids within 3months of diagnosis are at greatest risk of colectomy, and most likely to benefit from sustained thiopurine use.

Pregnancy outcomes in women with inflammatory bowel disease following exposure to thiopurines and antitumor necrosis factor drugs: a systematic review with meta-analysis.

Several studies have indicated the harmful effect of flare-up periods in pregnant women with inflammatory bowel disease (IBD) on their newborns. Therefore, an effective and safe medical treatment during pregnancy is of great concern in IBD patients. The aim of this study was to perform a meta-analysis on the outcomes of thiopurines use and a systematic review of antitumor necrosis factor (anti-TNF) drugs used during pregnancy in women with IBD. The results of cohorts evaluating the safety of anti-TNF drugs during pregnancy up to July 2013 were collected and analyzed. In the meta-analysis, a total of 312 pregnant women with IBD who used thiopurines were compared with 1149 controls (women with IBD who were not treated with any medication and women who were exposed to drugs other than thiopurines) to evaluate the drug effect on different pregnancy outcomes, including prematurity, low birth weight, congenital abnormalities, spontaneous abortion, and neonatal adverse outcomes. Results of statistical analysis demonstrated that congenital abnormalities were increased significantly in thiopurine-exposed group in comparison with control group who did not receive any medicine for IBD treatment. The summary odds ratio was 2.95 with 95% confidence interval = 1.03-8.43 (p = 0.04). We observed no significant differences in occurrence of other adverse pregnancy outcomes between compared groups. The results of cohorts evaluated the safety of anti-TNF drugs during pregnancy demonstrated no increase in occurrence of adverse pregnancy outcomes in comparison with controls except for the significant decrease in gestational age of newborns of drug-exposed mothers in one trial. In conclusion, a benefit-risk ratio should be considered in prescribing or continuing medicinal therapy during pregnancy of IBD patients.

Thiopurine withdrawal during sustained clinical remission in inflammatory bowel disease: relapse and recapture rates, with predictive factors in 237 patients.

BackgroundThiopurines (azathioprine and mercaptopurine) remain integral to most medical strategies for maintaining remission in Crohn's disease (CD) and ulcerative colitis (UC). Indefinite use of these drugs is tempered by long-term risks. While clinical relapse is noted frequently following drug withdrawal, there are few published data on predictive factors.AimTo investigate the success of planned thiopurine withdrawal in patients in sustained clinical remission to identify rates and predictors of relapse.MethodsThis was a multicentre retrospective cohort study from 11 centres across the UK. Patients included had a definitive diagnosis of IBD, continuous thiopurine use ≥3 years and withdrawal when in sustained clinical remission. All patients had a minimum of 12 months follow-up post drug withdrawal. Primary and secondary end points were relapse at 12 and 24 months respectively.Results237 patients were included in the study (129 CD; 108 UC). Median duration of thiopurine use prior to withdrawal was 6.0 years (interquartile range 4.4–8.4). At follow-up, moderate/severe relapse was observed in 23% CD and 12% UC patients at 12 months, 39% CD and 26% UC at 24 months. Relapse rate at 12 months was significantly higher in CD than UC (P = 0.035).Elevated CRP at withdrawal was associated with higher relapse rates at 12 months for CD (P = 0.005), while an elevated white cell count was predictive at 12 months for UC (P = 0.007).ConclusionThiopurine withdrawal in the context of sustained remission is associated with a 1-year moderate-to-severe relapse rate of 23% in Crohn's disease and 12% in ulcerative colitis.

The Risk of a Second Non-Melanoma Skin Cancer With Thiopurine and Anti-TNF Use in Inflammatory Bowel Disease

The Risk of a Second Non-Melanoma Skin Cancer With Thiopurine and Anti-TNF Use in Inflammatory Bowel Disease

Risk of melanoma and non-melanoma skin cancer in ulcerative colitis patients treated with thiopurines: a nationwide retrospective cohort.

There are limited data on the risk of non-melanoma skin cancer (NMSC) and melanoma skin cancer (MSC) among thiopurine-treated patients with ulcerative colitis (UC). Our aim was to investigate the risk while on, by cumulative years, and after stopping thiopurine therapy. Nationwide data were obtained from the Veterans Affairs (VA) health-care system during 2001-2011. We performed a retrospective cohort study evaluating patients with UC. Cox regression was used to investigate the association between thiopurines use and time to NMSC while adjusting for demographics, ultraviolet radiation exposure, and VA visiting frequency. A matched nested case-control study was conducted to investigate the association between thiopurine use and MSC. We included 14,527 patients with UC in the analysis, with a median follow-up of 8.1 years. A total of 3,346 (23%) patients used thiopurines for a median duration of 1.6 years. We identified 421 NMSC and 45 MSC cases. The adjusted hazard ratios of developing NMSC while on and after stopping thiopurines were 2.1 (P<0.0001) and 0.7 (P=0.07), respectively, as compared with unexposed patients. The incidence rate of NMSC among those who never used thiopurines was 3.7 compared with 5.8, 7.9, 8.3, 7.8, and 13.6 per 1,000 person-years for the 1st, 2nd, 3th, 4th, and 5th year of thiopurine use, respectively. No statistically significant association was observed between thiopurine use and MSC, odds ratio 0.8 (P=0.6). In this predominantly white male nationwide cohort, there was a twofold increase in the risk of NMSC while on thiopurines. The incidence rate of NMSC significantly increased with subsequent years of cumulative exposure to thiopurines. Stopping thiopurines reduced the risk of NMSC to pre-exposure levels irrespective of the prior exposure duration.

P-090: Use of thiopurines in Swiss pediatric IBD patients

became normal. The condition was assessed as posterior reversible encephalopathy syndrome that developed as a complication of treatment with infliximab. PRES is defined as vasogenic brain edema in connection with neurotoxic impairments. Predisposing factors are hypertension, eclampsia, immunosuppressive therapy, chemotherapy, biological treatment. Pathogenetic is hyperperfusion, arterial hypertension, endothelial dysfunction, direct cytotoxic effect of drugs on endothelium etc. Clinical manifestation include headache, visual disturbances, convulsions and coma. 80% of patients have moderate to severe arterial hypertension. The diagnosis provides characteristic findings on magnetic resonance imaging of the brain. The prognosis is usually good, the disease heals ad intergum, but are also described cases with neurological consequences.