Treatment of inflammatory bowel disease with azathioprine and 6-mercaptopurine

6-Mercaptopurine and azathioprine have become important therapeutic options for patients with inflammatory bowel disease (IBD). Although accumulating data in the literature have supported the use of these immunomodulators in the management of IBD, marked variation exists in the pattern of clinical practice regarding azathioprine or 6-mercaptopurine therapy in patients with IBD. This article provides a critical review of the data on the clinical efficacy and toxicities of 6-mercaptopurine and azathioprine in the management of IBD. Emerging literature on the potential application of pharmacogenetic testing and metabolite monitoring are also discussed.     

Efficacy of 6-mercaptopurine treatment after azathioprine hypersensitivity in inflammatory bowel disease

AIM：To investigate the efficacy of 6-mercaptopurine （6-MP） in cases of azathioprine （AZA） hypersensitivity in patients with inflammatory bowel disease. METHODS： Twenty nine previously confirmed Crohn’s disease （CD） （n = 14） and ulcerative colitis （UC） （n = 15） patients with a known previous （AZA） hypersensitivity reaction were studied prospectively. The 6-MP doses were gradually increased from 0.5 up to 1.0-1.5 mg/kg per day. Clinical activity indicies （CDAI/CAI）, laboratory variables and daily doses of oral 5-ASA, corticosteroids, and 6-MP were assessed before and in the first, sixth and twelfth months of treatment. RESULTS： In 9 patients, 6-MP was withdrawn in the first 2 wk due to an early hypersensitivity reaction. Medication was ineffective within 6 mo in 6 CD patients, and myelotoxic reaction was observed in two. Data were evaluated at the end of the sixth month in 12 （8 UC, 4 CD） patients, and after the first year in 9 （6 UC, 3 CD） patients. CDAI decreased transiently at the end of the sixth month, but no significant changes were observed in the CDAI or the CAI values at the end of the year. Leukocyte counts （P = 0.01）, CRP （P = 0.02）, and serum iron （P = 0.05） values indicated decreased inflammatory reactions, especially in the UC patients at the end of the year, making the possibility to taper oral steroid doses. CONCLUSION： About one-third of the previously AZA- intolerant patients showed adverse effects on taking 6MP. In our series, 20 patients tolerated 6MP, but it was ineffective in 8 CD cases, and valuable mainly in ulcerative colitis patients.     

6-mercaptopurine in patients with inflammatory bowel disease and previous digestive intolerance of azathioprine

OBJECTIVE: Azathioprine and 6-mercaptopurine are useful therapies in inflammatory bowel diseases. Despite their efficacy, their use is limited owing to treatment intolerance or toxicity in 10-15% of patients. It has been suggested that both drugs could be interchangeable. MATERIAL AND METHODS: All patients treated with 6-mercaptopurine because of previous digestive intolerance of azathioprine in four Spanish hospitals were reviewed. Tolerance of 6-mercaptopurine therapy was assessed. RESULTS: Fifteen patients (11 Crohn's disease, 4 ulcerative colitis) were included. Immunosuppressant therapy was prescribed for steroid-dependent disease in 13 cases, and for perianal disease in 2. Main symptoms of digestive intolerance were epigastric pain, nausea and vomiting, which developed within the first weeks of treatment. Acute pancreatitis was ruled out in all the cases. Five patients commenced 6-mercaptopurine immediately after azathioprine discontinuation and 7 patients within the first month. Eleven patients (73.3%) tolerated 6-mercaptopurine and reached the therapeutic goals; only two patients had to discontinue 6-mercaptopurine because of adverse effects. CONCLUSIONS: Treatment with 6-mercaptopurine is a safe alternative in patients with inflammatory bowel diseases and previous digestive intolerance of azathioprine.     

Severe pulmonary toxicity after azathioprine/6-mercaptopurine initiation for the treatment of inflammatory bowel disease

Azathioprine and 6-mercaptopurine (6-MP) are effective in inflammatory bowel disease (IBD). However, between 10% and 29% of patients treated with these drugs are forced to stop therapy due to side effects. Pulmonary toxicity due to azathioprine/6-MP has been reported infrequently. We describe 3 patients who developed severe, noninfectious pulmonary toxicity within 1 month after the initiation of azathioprine or 6-MP for the treatment of IBD colitis (2 Crohn's disease and 1 ulcerative colitis). All patients presented with dyspnea, cough, and fever after initiation of azathioprine/6-MP. Evaluation for infectious etiologies, including bronchoscopy (3/3 patients) and open-lung biopsy (2/3 patients) was negative. Histopathologic examination of the lung biopsies revealed bronchiolitis obliterans organizing pneumonia in one, and usual interstitial pneumonitis in another patient. Cessation of purine analog therapy resulted in clinical improvement in all 3 cases. Azathioprine/6-MP-related pulmonary toxicity is a rare but serious side effect, and it is important for clinicians to have a high index of suspicion for this adverse reaction which occurs within 1 month after initiation of treatment for IBD.     

Shingles during the course of treatment with 6-mercaptopurine for inflammatory bowel disease

OBJECTIVE: Our aim was to study the frequency, severity, and outcome of patients with Crohn's disease and ulcerative colitis treated with 6-mercaptopurine (6MP) who developed shingles during treatment, and to recommend management. While varicella can be severe in young people immunocompromised by steroids, the incidence of herpes zoster in older people with inflammatory bowel disease (IBD) and whether its severity is influenced by 6MP and azathioprine are unknown. METHODS: Data were collected from our IBD Center on 550 patients with IBD to identify those who developed shingles while on 6MP, its severity, the dose and duration of 6MP, and the management of the 6MP. RESULTS: Twelve of 550 patients with IBD treated with 6MP developed shingles. In two with herpes zoster ophthalmicus the pain was prolonged, and one patient developed encephalitis which was brief and uncomplicated; in nine patients the course was benign. Acyclovir should be the treatment of choice even though it was available in only three cases. CONCLUSIONS: Shingles occurs more often in IBD patients treated with 6MP than in those who are not, but the course is usually benign and there has been no mortality. The 6MP should be stopped temporarily until severity is established but if the underlying disease warrants further treatment the 6MP should be restarted.     

Increased risk of lymphoma among inflammatory bowel disease patients treated with azathioprine and 6-mercaptopurine

BACKGROUND: Inflammatory bowel disease (IBD) is commonly treated with immunomodulators such as azathioprine and 6-mercaptopurine (6-MP). Studies examining lymphoma risk in IBD patients treated with these medications have been underpowered and have yielded conflicting conclusions. AIMS: The purpose of this meta-analysis was to provide a more precise estimate of the relative risk of lymphoma among IBD patients treated with azathioprine or 6-MP. METHODS: Studies were included if they were English language, full article, cohort studies specifically designed to evaluate cancer as an adverse outcome of treatment with azathioprine or 6-MP. Pooled standardised incidence ratios were calculated to estimate the relative risk of lymphoma associated with therapy. Heterogeneity was assessed using Poisson regression. Sensitivity analyses examined the influence of individual studies on risk estimate and heterogeneity statistics. RESULTS: Six studies were identified that met our inclusion criteria. When the data were combined across all studies, the pooled relative risk was 4.18 (95% confidence interval 2.07-7.51; 11 observed cases, 2.63 expected). Sensitivity analysis showed that exclusion of any one study had a relatively small effect on the pooled relative risk estimate (range 3.49-5.21) but excluding either the study with the highest or lowest estimated relative risk eliminated the statistically significant heterogeneity. CONCLUSIONS: Our data suggest an approximate fourfold increased risk of lymphoma in IBD patients treated with azathioprine/6-MP. The increased risk of lymphoma could be a result of the medications, the severity of the underlying disease, or a combination of the two.     

Optimizing 6-mercaptopurine and azathioprine therapy in the management of inflammatory bowel disease

The thiopurine drugs,6-mercaptopurine(6-MP) and azathioprine,are efficacious in the arsenal of inflammatory bowel disease(IBD) therapy.Previous reports indicate that 6-thioguanine nucleotide(6-TGN) levels correlate with therapeutic efficacy,whereas high 6-methylmercaptopurine(6-MMP) levels are associated with hepatotoxicity and myelotoxicity.Due to their complex metabolism,there is wide individual variation in patient response therein,both in achieving therapeutic drug levels as well as in developing advers...     

Epstein-Barr virus-positive lymphoma in patients with inflammatory bowel disease treated with azathioprine or 6-mercaptopurine.

BACKGROUND & AIMS: The use of azathioprine and 6-mercaptopurine for inflammatory bowel disease increased in the early 1990s. We sought to determine the effect of this change in therapy on the risk of lymphoma in patients with inflammatory bowel disease. METHODS: All patients with inflammatory bowel disease at a single tertiary care medical center who developed lymphoma between 1985-2000 were identified and the pathologic features of the lymphoma including presence of Epstein- Barr virus were determined. The patients were divided into two 8-year periods (1985-1992, 1993-2000) corresponding with the introduction of azathioprine and 6-mercaptopurine in 1993. RESULTS: Eighteen patients with lymphoma were identified, 6 between 1985-1992 and 12 between 1993-2000. Six of 18 lymphomas occurred in patients treated with azathioprine or 6-mercaptopurine, all between 1993-2000. Seven patients developed Epstein-Barr virus-positive lymphoma (1 from 1985-1992, 6 from 1993-2000). Five of 7 Epstein-Barr virus-positive lymphomas occurred in patients treated with azathioprine or 6-mercaptopurine compared with 1 of 11 Epstein-Barr virus-negative lymphomas (P = 0.01). Approximately 1200 patients with inflammatory bowel disease were treated with these agents between 1993-2000. CONCLUSIONS: Treatment of inflammatory bowel disease with azathioprine or 6-mercaptopurine appears to be associated with a small increased risk of Epstein-Barr virus-positive lymphoma.     

Glutathione-S-transferase genotypes and the adverse effects of azathioprine in young patients with inflammatory bowel disease

BACKGROUND: Adverse drug reactions to azathioprine, the prodrug of 6-mercaptopurine, occur in 15%-38% of patients and the majority are not explained by thiopurine-S-methyltransferase (TPMT) deficiency. Azathioprine is known to induce glutathione depletion and consumption of glutathione is greater in cells with high glutathione-S-transferase (GST) activity compared with those with low activity; moreover, some reports indicate that GST might play a direct role in the reaction of glutathione with azathioprine. The association between polymorphisms of GST-M1, GST-P1, GST-T1, and TPMT genes and the adverse effects of azathioprine was therefore investigated. METHODS: Seventy patients with inflammatory bowel disease (IBD), treated with azathioprine, were enrolled and clinical data were retrospectively determined. TPMT and GST genotyping were performed by polymerase chain reaction (PCR) assays on DNA extracted from blood samples. RESULTS: Fifteen patients developed adverse effects (21.4%); there was a significant underrepresentation of the GST-M1 null genotype among patients developing adverse drug reactions to azathioprine (odds ratio [OR] = 0.18, 95% confidence interval [CI] = 0.037-0.72, P = 0.0072) compared with patients who did not develop adverse effects. Patients heterozygous for TPMT mutations presented a marginally significant increased probability of developing adverse effects (OR = 6.38, 95% CI = 0.66-84.1, P = 0.062). Moreover, among the 55 patients who did not develop adverse effects, there was a significant underrepresentation of the GST-M1 null genotype among patients who displayed lymphopenia as compared with those that did not display this effect of azathioprine (OR = 0.15, 95% CI = 0.013-1.08, P = 0.032). CONCLUSION: Patients with IBD with a wildtype GST-M1 genotype present increased probability of developing adverse effects and increased incidence of lymphopenia during azathioprine treatment.     

Thiopurine S-methyltransferase and inosine triphosphate pyrophosphohydrolase genes in Japanese patients with inflammatory bowel disease in whom adverse drug reactions were induced by azathioprine/6-mercaptopurine treatment

Background  The main cause of azathioprine (AZA)/6-mercaptopurine (6MP)-induced adverse reactions is a reduction in the activities of the metabolizing enzymes thiopurine S-methyltransferase (TPMT) and inosine triphosphate pyrophosphohydrolase (ITPA). Adverse reactions develop at a high frequency in Japanese patients at half the dose required for European and American patients; however, the association with TPMT and ITPA gene polymorphisms in Japanese has not been fully investigated. Methods  Gene mutations of TPMT and ITPA, the major AZA/6-MP -metabolizing enzymes, were investigated retrospectively in 16 Japanese patients with inflammatory bowel disease (IBD) in whom AZA/6MP treatment induced adverse reactions. Results  The TPMT gene was found to have a wild-type sequence in all patients, but in the ITPA gene a mutation, 94C>A, was detected at a rate of 50% (8/16), with 83.3% (5/6) occurring in patients with acute bone marrow suppression and 75% (3/4) in those with agranulocytosis. The 94C>A allele frequency was 10 of 32 (0.313; 95% CI, 0.180–0.486). Adverse reactions developed earlier in patients with the 94C>A mutation. However, in half the patients, no gene polymorphism was noted. Conclusions  It is suggested that the ITPA gene mutation is closely related to the adverse reactions of AZA/6-MP in Japanese patients, and screening for the mutant allele is useful for predicting the most serious adverse reactions, agranulocytosis and acute bone marrow suppression.     

Long term efficacy and safety of allopurinol and azathioprine or 6-mercaptopurine in patients with inflammatory bowel disease

Background and aimsWe previously reported that IBD patients who are non-responders to thiopurines with preferential shunting of metabolites to hepatotoxic 6-methylmercaptopurine ribonucleotides compared to 6-thioguanine nucleotides can reverse the ratio of 6-MMP/6-TGN and respond to thiopurines with the addition of allopurinol. The objective of this study is to report long term efficacy and safety, along with results for an additional 11 patients.MethodsRetrospective chart review of patients at the University of Chicago IBD Center treated with allopurinol in addition to thiopurines.ResultsTwenty five patients with Crohn's disease or ulcerative colitis were enrolled. Within the first month of therapy 6-TGN metabolite levels increased from a mean of 186.5 ± 17.4 (SE) to 352.8 ± 37.8 pmol/8 × 10⁸ (p = 0.0001). Over the same period 6-MMP levels decreased from a mean of 11,966 ± 1697 to 2004 ± 536 pmol/8 × 10⁸ (p < 0.0001). The mean daily dosage of prednisone decreased from 19.8 ± 3.8 mg to 5.3 ± 2.7 mg (p = 0.03). Thirteen patients have a minimum of one year follow-up. Nine of these thirteen patients have continued on therapy for at least 2 years. All thirteen of these patients continue to be in clinical remission at the last follow-up visit. No patients have had evidence of sustained thrombocytopenia or abnormal liver enzymes.ConclusionsIn AZA/6-MP non-responders with increased 6-MMP/6-TGN ratios, addition of allopurinol continues to demonstrate safety and efficacy for long-term maintenance and steroid-sparing in IBD.     

Increased dosing requirements for 6-mercaptopurine and azathioprine in inflammatory bowel disease patients six years and younger

BACKGROUND: 6-Mercaptopurine (6-MP) and its prodrug azathioprine (AZA) are effective for the induction and maintenance of remission and reduction of corticosteroid exposure for pediatric inflammatory bowel disease (IBD). The standard dose of 6-MP is 1.0-1.5 mg/kg/day and for AZA is 2.0-2.5 mg/kg/day. The aim of this study was to determine whether IBD patients 6 years of age and younger require higher than standard doses of 6-MP/AZA to achieve clinical remission. METHODS: Clinical data was collected retrospectively for all IBD patients 6 years of age or younger treated with 6-MP/AZA at The Children's Hospital of Philadelphia. RESULTS: Thirty patients met the inclusion criteria. IBD was diagnosed at a median age of 3.3 years (25-75th %ile 2.3-4.6 years) and 6-MP/AZA was initiated at a median age of 3.9 years (range 0.8-6.8 years). After dose escalation, the median AZA-equivalent dose was 3.1 mg/kg/day (25-75th %ile 2.5-3.5, max. dose 5.1 mg/kg/day). At the final recorded dose, 8/13 (62%) patients receiving AZA >3.0 mg/kg/day achieved clinical remission, compared to 2/12 (17%) receiving 2-3 mg/kg/day (P = 0.02). The risk of having active disease was on average 85% lower if the AZA-equivalent dose was >3.0 mg/kg/day (95% confidence interval [CI] 72%-93%). Adverse events were experienced by 4/30 patients (hepatitis, n = 2; leukopenia, n = 2). No patients had to discontinue 6-MP/AZA, and all laboratory abnormalities improved spontaneously or with dose reduction. CONCLUSIONS: The standard dose of 6-MP/AZA may not be adequate for IBD patients 6 years of age and younger. Closely monitored dose escalation beyond the standard dosing range is effective and well-tolerated.     

Nature and course of pancreatitis caused by 6-mercaptopurine in the treatment of inflammatory bowel disease

6-Mercaptopurine (6-MP) has an important role in the treatment of inflammatory bowel disease. Its most frequent short-term complication has proven to be pancreatitis, which we have now seen in 13 of 400 (3.25%) patients (12 Crohn's disease, 1 ulcerative colitis) and which we here describe. The timing of the pancreatitis was such that it could not be attributed to sulfasalazine, which was also being taken by 9 patients, or corticosteroids, which were being taken by 7 patients. The dosage of 6-MP ranged from 50 to 100 mg daily, and the pancreatitis, which was uncomplicated in all cases, occurred within 8-32 days with one exception (6.5 mo). Symptoms included epigastric pain, back pain, fever, and nausea. The serum amylase was elevated in 12 patients. The average elevation was 5.9 times normal. In all cases, the 6-MP was discontinued and symptoms and signs returned to normal over a period of 1-11 days. No other complications of 6-MP occurred; there was no leukopenia. Of 7 patients rechallenged with 6-MP, all developed recurrent pancreatitis, including 4 in less than 24 h. In 3 patients, desensitization attempted by a gradual increase in dose from 1/8 tablet (approximately 6 mg) daily also led to recurrence. The timing of the initial pancreatitis and the recurrence at rechallenge are best explained by an allergic reaction. 6-Mercaptopurine should not be reinstituted once it has caused pancreatitis.     

The ten-year single-center experience with 6-mercaptopurine in the treatment of inflammatory bowel disease

GOALS: To report the 10-year experience of a single center in treating patients with refractory inflammatory bowel disease (IBD) with relatively lower dose of 6-mercaptopurine (6-MP). STUDY: The charts of 285 patients with IBD (Crohn's disease 160 and ulcerative colitis 125) receiving 6-MP were reviewed. Clinical response, subsequent breakthrough while taking 6-MP, and relapse rates when 6-MP was discontinued and side effects were assessed. RESULTS: Ninety-three percent of the patients were taking 50 to 75 mg/day of 6-MP. Complete remission was achieved in 62%, partial remission in 14.5%, and failure to achieve remission in 23.5% of the patients. Of complete responders, 27.5% had breakthrough while continuing 6-MP. Nine percent of those that achieved a complete remission experienced a relapse after 6-MP was discontinued. Side effects included leukopenia (11.2%), abnormal liver function tests (3.8%), various infections, including pneumonia (3.1%), pancreatitis (2.5%), nausea (2.1%), headache (2.8%), fever (1.4%), hair loss (1%), and rash (0.7%). Two cancers occurred while taking 6-MP: melanoma on the finger and a fatal colonic lymphoma. Four patients continued 6-MP throughout pregnancies and had normal outcomes. CONCLUSIONS: In our experience 6-MP is relatively safe and appears to be as effective at a lower dosage (0.84 mg/kg per day) compared with the recommended higher dosage (1-1.5 mg/kg per day), when leukopenia was more frequent. Serious side effects, although rare, need to be monitored.     

Malignant neoplasms subsequent to treatment of inflammatory bowel disease with 6-mercaptopurine

OBJECTIVE: Most complications of 6-mercaptopurine (6MP) used in the treatment of inflammatory bowel disease (IBD) occur early, whereas neoplasms occur late in the course. Concern persists that the risk is increased when 6MP is used. We report our experience with malignant tumors developing over 27 yr of treating IBD patients with 6MP. METHODS: A total of 591 patients with IBD treated with 6MP between 1969 and 1997 were followed or traced until present to identify all malignant tumors and blood dyscrasias that had developed to determine the type, distribution, and duration of the IBD, the dose and duration of 6MP therapy, the concurrent versus previous use of 6MP, the incidence and probable relationship of 6MP to specific neoplasms, and whether the 6MP had been effective in treatment. RESULTS: A total of 550 patients (93%) fulfilled the criteria for follow-up; these included 380 with Crohn's disease (CD) and 170 with ulcerative colitis (UC). Twenty-five patients had developed neoplasms (16 of 380 CD and nine of 170 UC) (p = 0.66). In half of the cases, the goal of therapy had been achieved with 6MP. In 10 patients, the neoplasm was diagnosed while the patients were taking 6MP (40%) and in 15, many years after the 6MP had been terminated (60%). The incidence of neoplasms (25 of 550) was 2.7/1000 patient-years of follow-up. The most common neoplasms were found in the bowel (eight of 550, 1.6%; five CD, and three UC), and breast (three, 0.5%; two CD, and one UC). Non-Hodgkins lymphomas occurred in two patients with CD; one was cerebral and the other abdominal. One patient with CD developed leukemia. The duration of 6MP therapy ranged from 5 months to 22 yr, with a mean of 5 yr. The dose of 6MP ranged from a quarter of a tablet/day (12.5 mg) to 100 mg/day, with the majority in a range from 50 to 75 mg/day. CONCLUSION: In no instance could a neoplasm be attributed to the use of 6MP. The incidence of colon cancer is not greater than that with long standing colitis. Suspicion of a relationship between 6MP and leukemia/lymphoma persists, but the incidence is low. This must be weighed against the improved quality of life due to 6MP for patients with IBD.     

Expert opinion:Experience with 6-mercaptopurine in the treatment of inflammatory bowel disease

Arbitrarily, modern day treatment of inflammatory bowel disease begins with the introduction of immuno- suppressives for ulcerative colitis. Clinical improvement with sulfasalazine had been meaningful but modest. Treatment with adrenocorticotropic hormone and corti- costeroids led to clinical responses never before realized but it took much too long to recognize that they were not capable of maintaining remission, that adverse reactions were subtle but potentially devastating and that some other agent would be necessary to capitalize on their transient advantage. This of course was true in the treatment of Crohn’s disease as well. Not much was ever made of the role of sulfasalazine for Crohn’ s disease, but with the severing of the diazobond and the elimination of the sulphur component, the 5-ami- nosalacylic acid (5-ASA) products clearly led to clinical improvement, especially in cases of Crohn’s colitis and those with ileitis where the 5-ASA product was released in the terminal ileum and more proximal in the small bowel as well as in ulcerative colitis. The induction of remission was first demonstrated by 6-mercaptopurine (6-MP) with case reports and uncontrolled trials in pa- tients with ulcerative colitis, but its placebo controlled trial for Crohn’s disease firmly established its role in inducing remission. No subsequent trial has confirmed its similar role for ulcerative colitis, but nevertheless cli- nicians know well that 6-MP works at least as well and probably more effectively for ulcerative colitis than for Crohn’s disease. What changes have taken place utiliz- ing 6-MP in the management of inflammatory bowel disease since its introduction in the 1960’s and 1970’s and its trial for Crohn’s disease published in the New England Journal of Medicine in 1980?