Thiopurine Methyltransferase Levels Research Articles

P397 Can upskilling pharmacy technicians support a robust and cost-effective Inflammatory Bowel Disease patient review process? A single-centre prospective study

Abstract Background Immunomodulators are key to the management of Inflammatory bowel disease (IBD). To ensure safety and efficacy, UK guidance recommend immunomodulator review. At University Hospitals Sussex (UHS), reviews are completed by a multi-disciplinary team (MDT), with specialised IBD pharmacists and nurses leading on autonomous blood monitoring and symptom review (figure 1). This workload puts considerable strain on the UHS IBD team. Upskilling and task shifting is recognised as legitimate strategy for service enhancement, care access, cost effectiveness and sustainability plus ensures team flexibility, boosted morale and career progression. The UHS IBD team includes a highly motivated pharmacy technician (PT). In the UK, PT are registered non-prescribing healthcare professionals, but training does not include autonomous blood monitoring and symptom review. Methods To ensure competency of autonomous blood monitoring and symptom review, a training package was developed and was approved by UHS Medicines Governance Group. Once accredited, PT prospectively recorded blood monitoring and symptom review activity over, 10-weeks (figure 2 and, 3) and referrals completed (figure 4). Results The training package was completed in, 10 weeks. Over, 10 weeks, PT completed, 699 distinct monitoring activities, with, 57 (8%) needing referral to the specialised pharmacist. The highest proportion of workload was observed in the IBD infusion clinic (314, 45%), followed by thiopurine monitoring (250, 36%) and then ‘others’ (135, 19%). ‘Others’ were essential IBD activities including faecal calprotectin levels (FCPL), pre-initiation tests (e.g. thiopurine methyltransferase levels (TPMT), viral screening, t-spots) and medication levels to optimise therapy. All referrals to the specialised pharmacist were appropriate as needed action by a prescribing professional. In addition, PT contributed substantially to data collection for virtual biologic clinic (VBIC) reviews;, 32 patients. Feedback has been overwhelmingly positive from all effected stakeholders (PT, IBD pharmacy and nursing team and gastroenterologists). Conclusion Identifying appropriate tasks and upskilling the IBD PT has enabled a more cost-effective and efficient use of IBD workflow, care standardisation, team robustness and staff morale. Approved training and support are required to enable upskilling and continued service safety and we recommend that skills are recognised locally and nationally.

Predictors of azathioprine toxicity in children with autoimmune hepatitis

Aim of the studyAzathioprine (AZA) is an important steroid-sparing drug in the management of autoimmune hepatitis (AIH). Avoidance of its adverse events that could be severe and carry a risk of mortality in a few cases is important, preferably with cheap and easy assessments that could be feasible in developing countries with the unavailability of molecular assays. Assessment of thiopurine methyltransferase (TPMT), the key enzyme for the inactivation of AZA, as a predictor of AZA toxicity had been a matter of conflict. This work aimed to study the role of TPMT serum level assessment and other host-, disease-, and treatment-related factors in predicting AZA toxicity.Material and methodsSixty-six children with AIH, divided into two groups, were recruited. Group 1 included twelve children with AZA toxicity and group 2 included fifty-four children without AZA toxicities. Both groups were compared for demographic, clinical, laboratory, histopathological, and treatment-related factors, and serum TPMT level, measured by ELISA.ResultsTPMT serum level was comparable in both groups (p = 0.363). Duration of treatment until enzyme normalization and duration of AZA therapy were significantly associated with AZA toxicity (p = 0.007 and p = 0.01, respectively). At the first follow-up treatment with AZA, total leucocyte count (TLC) and neutrophil counts were significantly lower in group 1 (p = 0.005 and p = 0.002, respectively). Moreover, the percentage reduction of TLC and neutrophil counts were significantly higher in group 1 (p < 0.001, for both).ConclusionsMonitoring for AZA adverse events in those with the defined predictors of AZA-related adverse events is more important than TPMT assessment.

S3509 Aplastic Anemia Following Autoimmune Hepatitis Treated With Azathioprine

INTRODUCTION: Aplastic anemia is a serious and potentially fatal disease where bone marrow suppression leads to pancytopenia. Azathioprine, an immunosuppressive drug used to treat various autoimmune disorders, can cause aplastic anemia. Here we present a case of aplastic anemia following azathioprine treatment of autoimmune hepatitis. CASE DESCRIPTION/METHODS: A 24 Y.O. Male presented with no significant past medical history presented with elevated liver enzymes and bilirubin. Ultrasound and CT confirmed mild hepatomegaly and diagnosis of acute hepatitis was given. A liver biopsy was performed and was noted for necrotic tissue. Acute hepatitis resolved spontaneously but relapsed 6 months later. Upon relapse, Anti Smooth Muscle Antibodies were found suggesting autoimmune hepatitis. The patient was treated with prednisone and 4 weeks later, azathioprine was started. 2 months after beginning azathioprine, labs revealed low hematocrit and platelet count, so the dose was lowered. By 4 months labs revealed pancytopenia and azathioprine treatment was stopped. The patient had a bone marrow biopsy done and was diagnosed with aplastic anemia. The patient began treatment to receive a bone marrow transplant but died of a systemic fungal infection. DISCUSSION: It is well documented that aplastic anemia, as a side effect of azathioprine treatment, is highly correlated to polymorphisms in the Thiopurine methyltransferase (TPMT) gene which occurs in 0.3%–0.5% of the population. Current treatment guidelines call for consideration of screening TPMT levels but considering the potential severity of the side effect and ease of testing, screening TPMT levels should be more common practice. However, it is also noted that the patient had low hematocrit levels starting about 1 month before the second episode of hepatitis. This suggests that the azathioprine may not have been the causative factor leading to pancytopenia, and it may have been a progression of Hepatitis Associated Aplastic Anemia (HAAA). HAAA is characterized by auto-immune hepatitis followed by aplastic anemia 2–3 months later. Testing for TPMT levels before starting azathioprine treatment for autoimmune hepatitis can help identify patients at risk for developing aplastic anemia as well as help rule out azathioprine as the causative agent for the aplastic anemia.

A drug‐repositioning screen for primary pancreatic ductal adenocarcinoma cells identifies 6‐thioguanine as an effective therapeutic agent for TPMT‐low cancer cells

Pancreatic cancer is one of the most difficult cancers to cure due to the lack of early diagnostic tools and effective therapeutic agents. In this study, we aimed to isolate new bioactive compounds that effectively kill pancreatic ductal adenocarcinoma (PDAC) cells, but not untransformed, human pancreatic ductal epithelial (HPDE) cells. To this end, we established four primary PDAC cell lines and screened 4141 compounds from four bioactive‐compound libraries. Initial screening yielded 113 primary hit compounds that caused over a 50% viability reduction in all tested PDAC cells. Subsequent triplicate, dose‐dependent analysis revealed three compounds with a tumor cell‐specific cytotoxic effect. We found that these three compounds fall into a single category of thiopurine biogenesis. Among them, 6‐thioguanine (6‐TG) showed an IC50 of 0.39–1.13 μm toward PDAC cells but had no effect on HPDE cells. We propose that this cancer selectivity is due to differences in thiopurine methyltransferase (TPMT) expression between normal and cancer cells. This enzyme is responsible for methylation of thiopurine, which reduces its cytotoxicity. We found that TPMT levels were lower in all four PDAC cell lines than in HPDE or Panc1 cells, and that knockdown of TPMT in HPDE or Panc1 cells sensitized them to 6‐TG. Lastly, we used a patient‐derived xenograft model to confirm that 6‐TG has a significant antitumor effect in combination with gemcitabine. Overall, our study presents 6‐TG as a strong candidate for use as a therapeutic agent against PDAC with low levels of TPMT.

57-Year-Old Man With Hip Pain and Lytic Bone Lesions

57-year-old man presented to his primary care physician with a 2-year history of progressive right hip pain. His medical history was notable for hyperlipidemia. He was up-to-date on sex- and agespecific cancer screening. The patient had no history of chest pain, palpitations, shortness of breath, cough, or other cardiac, respiratory, neurologic, or visual symptoms. He had no recent travel history or occupational or social contact with persons who were ill. Physical examination revealed an obese man (body mass index [calculated as weight in kilograms divided by height in meters squared], 40.34 kg/m 2 ) with normal vital signs and unremarkable findings on cardiac, respiratory, abdominal, neurologic, and lymphatic examination. No pain or tenderness was elicited on examination. He was treated initially with nonopioid pain medications. Sacroiliac corticosteroid injections were minimally beneficial. Results of a complete blood cell count (CBC) and electrolyte panel were normal with the exception of an elevated serum calcium level of 11.7 mg/dL (reference range, 8.9-10.1 mg/dL). Ultimately, magnetic resonance imaging (MRI) of his lumbar spine revealed numerous punched-out lytic lesions in the lumbar vertebra and pelvis. He underwent computed tomography (CT) of his chest, abdomen, and pelvis that identified further lytic lesions as well as multiple splenic lesions concerning for metastases. Two separate CT-guided bone biopsy samples of the lytic lesions in the lumbar vertebra did not elicit an etiology of the lesions.

Sa1272 Thiopurine Prescribing and Monitoring Behavior, Including Metabolites Testing and Allopurinol Co-Therapy: An Australian Perspective From 2008 to 2013

Background: Thiopurines (TP) are a mainstay of inflammatory bowel disease (IBD) therapy. Thiopurine methyltransferase (TPMT) and TP metabolites testing have been suggested to predict variation in metabolism and response to therapy. However, prospective data to confirm clinical benefits of metabolites guided dosing is still limited, as are guidelines for TP monitoring. We aimed to evaluate current Australian gastroenterologists' (GEs) practice in TP use for IBD, including TPMT testing, full blood count (FBC) monitoring, metabolites testing, allopurinol co-therapy, effects on clinical outcomes, and how practices have changed over time. Methods: An anonymous survey was distributed to GEs by email and at meetings across Australia over 6 months in 2013. The results were compared with a similar survey conducted in 2008. The Chi-squared test was used to calculate statistical significance. Results: Most GEs started TP at escalating rather than full doses (76.6%). FBC monitoring intervals varied most in the first 3 months. Compared to 2008, TPMT had become more frequently tested (79.1% vs 44.5%, p 1 week for the majority (87.6%), and >2 weeks for a large minority (41.1%). The majority of GEs perceived that TP metabolites had improved clinical outcomes: improved response rates (80.6%), reduced complication rates (60.4%) and altered clinical practice (79.2%). Allopurinol co-therapy was used by the majority (71%), although not all for the same indications [82.8% for shunters with abnormal liver function tests (LFTs), 24.7% for shunters irrespective of LFTs, and 36.6% for side effects irrespective of LFTs]. Conclusions: Over the past 5 years, the practices of TPMT and TP metabolites testing have increased markedly and have altered TP prescribing practice amongst Australian GEs. However, variability exists in FBC monitoring and TP dosing, especially in context of reduced TPMT levels, as well as indications for TP metabolites testing and allopurinol cotherapy. Despite these, the subjective appraisals of the majority of Australian GEs were that TP metabolites testing had improved clinical outcomes. Further studies to objectively confirm these, and evidence to inform standardization of TP prescribing and monitoring practices are keenly awaited.

P442 Infliximab versus combination infliximab and immunosuppressant therapy for patients with active ulcerative colitis: a meta-analysis

Background: Thiopurines (TP) are a mainstay of inflammatory bowel disease (IBD) therapy. Thiopurine methyltransferase (TPMT) and TP metabolites testing have been suggested to predict variation in metabolism and response to therapy. However, prospective data to confirm clinical benefits of metabolites guided dosing is still limited, as are guidelines for TP monitoring. We aimed to evaluate current Australian gastroenterologists' (GEs) practice in TP use for IBD, including TPMT testing, full blood count (FBC) monitoring, metabolites testing, allopurinol co-therapy, effects on clinical outcomes, and how practices have changed over time. Methods: An anonymous survey was distributed to GEs by email and at meetings across Australia over 6 months in 2013. The results were compared with a similar survey conducted in 2008. The Chi-squared test was used to calculate statistical significance. Results: Most GEs started TP at escalating rather than full doses (76.6%). FBC monitoring intervals varied most in the first 3 months. Compared to 2008, TPMT had become more frequently tested (79.1% vs 44.5%, p 1 week for the majority (87.6%), and >2 weeks for a large minority (41.1%). The majority of GEs perceived that TP metabolites had improved clinical outcomes: improved response rates (80.6%), reduced complication rates (60.4%) and altered clinical practice (79.2%). Allopurinol co-therapy was used by the majority (71%), although not all for the same indications [82.8% for shunters with abnormal liver function tests (LFTs), 24.7% for shunters irrespective of LFTs, and 36.6% for side effects irrespective of LFTs]. Conclusions: Over the past 5 years, the practices of TPMT and TP metabolites testing have increased markedly and have altered TP prescribing practice amongst Australian GEs. However, variability exists in FBC monitoring and TP dosing, especially in context of reduced TPMT levels, as well as indications for TP metabolites testing and allopurinol cotherapy. Despite these, the subjective appraisals of the majority of Australian GEs were that TP metabolites testing had improved clinical outcomes. Further studies to objectively confirm these, and evidence to inform standardization of TP prescribing and monitoring practices are keenly awaited.

Letter: international IBD practice guidelines - authors’ reply

SIRS, We thank Drs Mowat and Bloom for their comments concerning our manuscript 2 We agree that clinical practice guidelines require greater attention to transparency regarding potential conflicts of interest (COI) and grading of evidence for the recommendations. However, we do not agree with the critique regarding the decision to assign a Grade D to highlight recommendations that did not provide any indication of the supporting evidence. We felt that any statement marked with a bullet point separated from the body of the manuscript could be considered a recommendation. These statements could have been graded, even if the level of evidence was only expert opinion. When a guideline does not cite the level of evidence, there is no way for the clinician to know the quality of evidence or the strength of the recommendation. While many recommendations lack evidence from randomised control trials, we suggest that it is not acceptable to make recommendations without an indication of the grade of evidence. The example cited by Mowat and Bloom regarding methotrexate exemplifies this point. Despite a lack of randomised trials, there is an abundance of data concerning the dangers associated with taking methotrexate during pregnancy. Had the GRADE system (Grading of Recommendations, Assessment, Development and Evaluation) been used, it would have graded ‘methotrexate is absolutely contra-indicated in pregnancy’ as a strong recommendation based on the certainty of the available evidence. We disagree that we misquoted the BSG level of evidence regarding checking thiopurine methyltransferase levels. The British Society of Gastroenterology (BSG) cites evidence level EL4. Evidence level 4 refers to case– control study or poor/non-independent reference standards. This merges into a level C evidence – consensus opinions of experts, case studies or standard of care. With regard to use of methotrexate in ulcerative colitis (UC) and the BSG’s discordant recommendation, the European Crohn’s and Colitis Organisation (ECCO) guideline cites seven manuscripts related to methotrexate in UC. The additional paper that the BSG references is the Cochrane review from 2009 that comments “the available evidence is not sufficient to recommend the use of methotrexate,” which is identical to the ECCO guidelines. BSG is alone in recommending methotrexate in UC. Lastly, we fully agree that potential conflicts of interest (COI) do not equate to bias. However, when COI are present in the development process there is the potential for the COI to bias recommendations. 11 Having a rigorous review process of the manuscript’s drafts does not obviate the need for transparency regarding COI and a well-defined process to mitigate potential bias prior to guideline development. We all agree that the goal of practice guidelines is to create a safer and more effective medical system. To this end, the guidelines development process must be transparent regarding potential COI, have a system in place to minimise potential bias, base recommendations on the best available evidence, and provide a grading of the quality of the evidence for all recommendations.

PWE-102 The use of TPMT Enzyme Testing in Managing Thiopurine Therapy

IntroductionThiopurine methyl transferase (TPMT) enzyme deficiency is associated with azathioprine-induced myelosuppression and hepatotoxicity. We aimed to assess thiopurine methyl transferase levels (TPMT) in patients with inflammatory bowel disease (IBD) and...

The Utility of Thiopurine Methyltransferase Enzyme Testing in Inflammatory Bowel Disease

To assess the levels of red blood cell thiopurine methyltransferase (TPMT) in subjects with inflammatory bowel disease (IBD) and to determine how these levels impacted thiopurine dosing and leukopenia over the first six months of therapy. A retrospective chart review was performed on all adult IBD patients (n=423, 88.2% Caucasian) who had TPMT levels measured by 11 participating gastroenterologists in Manitoba between 2008 and 2010. In addition to descriptive data, white blood cell count, dose and reason for discontinuation were analyzed for the first six months of therapy. Patients receiving ≥2.0 mg/kg of azathioprine (AZA) or ≥1.0 mg/kg of 6-mercapatopurine were considered to be 'substantially' dosed. Of the 423 patients, 8.3% had intermediate levels and 93.4% had normal levels of TPMT. Only one subject had a low level. A total of 216 patients had sufficient data to be included for full analysis. Patients with intermediate TPMT levels were generally started at lower doses of thiopurine than patients with normal TPMT levels (mean [± SD] 1.0±0.6 mg/kg versus 1.8±0.5 mg/kg). Of the subjects with normal TPMT levels, only 37.8% were dosed with ≥2.0 mg/kg of AZA. Each month, approximately 5% of subjects were leukopenic. These subjects received a mean overall AZA dose of 1.9±0.3 mg/kg and had a mean white blood cell count of 3.8±0.4×10(9)/L. Normal TPMT levels did not prevent the development of leukopenia, although life-threatening leukopenia was rare. Physicians are not using TPMT levels to substantially dose thiopurines at the outset, which may limit the speed at which adequate doses are reached to facilitate remission.

PTU-104 Thioguanine nucleotides: optimising thiopurine therapy in inflammatory bowel disease (a DGH perspective)

IntroductionAzathioprine (AZA) and 6-mercaptopurine (6MP) have been used in treatment of inflammatory bowel disease since introduction in the 1960s.1 6-thioguanine nucleotides (TGN) levels are related to therapeutic response with likely...

Systemic Treatment of Pediatric Atopic Dermatitis with Azathioprine and Mycophenolate Mofetil

Severe forms of atopic dermatitis (AD) cause significant morbidity in vulnerable pediatric populations and necessitate treatment with systemic therapy. The existing literature concerning the treatment of severe pediatric AD with azathioprine (AZ) and mycophenolate mofetil (MM) is sparse. The purpose of this case series is to examine the use of these two drugs in the treatment of severe pediatric AD. Medical records of 28 pediatric patients with AD from the University of North Carolina at Chapel Hill pediatric dermatology clinic treated using these two drugs were analyzed for laboratory values, thiopurine methyltransferase (TPMT) levels, symptoms, infections, and other relevant data. Patients were also contacted via the telephone to ascertain outcomes and any missing data. Treatment outcomes were scored into three categories: significant improvement, some improvement, and no improvement. AZ dosing was correlated to TPMT levels successfully, with comparable levels of improvement in the heterozygous and homozygous wild-type groups. Absolute eosinophil count corresponded to AD activity and treatment response across both treatment modalities in 18 of 26 (69%) patients. Seventeen of 28 (61%) patients treated with AZ and eight of 12 (66%) treated with MM reported significant improvement. We had lower rates of laboratory abnormalities and side effects with MM than with AZ but similar rates of cutaneous infections. Treatment outcomes did not appear to differ with race, sex, or TPMT level. We experienced success with AZ and MM in the treatment of severe pediatric AD. Coordinating treatment to each patient's unique morbidities is the best way to choose systemic treatments.

MRI Guided Biologic Therapy for Crohn's Perianal Fistulae: 3 Year Follow up Data

Background: Thiopurine methyltransferase (TPMT) is a cytosolic enzyme involved in the metabolism of azathioprine and 6-mercaptopurine. Higher TPMT activity is associated with lower levels of the therapeutic metabolite 6-thioguanine (6-TG). Some therapeutic studies in patients with inflammatory bowel disease have excluded those with intermediate TPMT activity. A small difference in TPMT enzyme activity has been reported between AfricanAmericans and Caucasians. Our own preliminary data suggested that this difference may be more pronounced. We sought to further assess racial differences in TPMT activity to help determine optimal treatment strategies for patients with inflammatory bowel disease. Methods: A retrospective chart review from the electronic medical records of Henry Ford Health System was conducted for patients who had undergone testing for TPMT enzyme activity from June 2004 through September 2010. Testing was performed at Prometheus Laboratories (San Diego, CA). TPMT activity was categorized into low ( 21 EU). Results: 394 patients underwent TPMT testing during the study period. Race was available for 388 patients (246 women and 142 men). The population was composed of 223 Caucasians, 134 African-Americans, and 31 patients of other race. Mean TPMT level was 28.3 EU (SD 9.6) for Caucasians, 23.3 EU(SD 8.2) for African-Americans, and 27.5 EU (SD 9.0) for others (p <0.001). Mean TPMT activity for the 13 Middle Eastern patients in the population was 22.1 (SD 7.8) which was significantly lower than that of Caucasians (p = 0.024). Analysis by TPMT activity category showed that low activity was seen in only 2 patients, and both were Caucasians. Intermediate activity was seen in 37 of the 223 Caucasians (16.6%), 52 of 134 African-Americans (38.8%), and 7 of 31 other race patients (22.6%). Normal TPMT activity was seen for 184 of the 223 Caucasians (82.5%), 82 of the 134 African-Americans (61.2%), and 24 of the 31 patients of other race (77.4%). This distribution was statistically significant (p <0.001). Conclusions: Mean TPMT activity is lower in African-American and Middle Eastern patients compared to Caucasians. African-Americans are more likely to have intermediate TPMT activity compared to Caucasians. Therapeutic studies using 6-mercaptopurine and azathioprine that exclude patients with intermediate TPMT activity may exclude a high proportion of AfricanAmerican patients.

Significant Racial Differences in Thiopurine Methyltransferase Enzyme Activity in a Metropolitan Population

Background: Thiopurine methyltransferase (TPMT) is a cytosolic enzyme involved in the metabolism of azathioprine and 6-mercaptopurine. Higher TPMT activity is associated with lower levels of the therapeutic metabolite 6-thioguanine (6-TG). Some therapeutic studies in patients with inflammatory bowel disease have excluded those with intermediate TPMT activity. A small difference in TPMT enzyme activity has been reported between AfricanAmericans and Caucasians. Our own preliminary data suggested that this difference may be more pronounced. We sought to further assess racial differences in TPMT activity to help determine optimal treatment strategies for patients with inflammatory bowel disease. Methods: A retrospective chart review from the electronic medical records of Henry Ford Health System was conducted for patients who had undergone testing for TPMT enzyme activity from June 2004 through September 2010. Testing was performed at Prometheus Laboratories (San Diego, CA). TPMT activity was categorized into low ( 21 EU). Results: 394 patients underwent TPMT testing during the study period. Race was available for 388 patients (246 women and 142 men). The population was composed of 223 Caucasians, 134 African-Americans, and 31 patients of other race. Mean TPMT level was 28.3 EU (SD 9.6) for Caucasians, 23.3 EU(SD 8.2) for African-Americans, and 27.5 EU (SD 9.0) for others (p <0.001). Mean TPMT activity for the 13 Middle Eastern patients in the population was 22.1 (SD 7.8) which was significantly lower than that of Caucasians (p = 0.024). Analysis by TPMT activity category showed that low activity was seen in only 2 patients, and both were Caucasians. Intermediate activity was seen in 37 of the 223 Caucasians (16.6%), 52 of 134 African-Americans (38.8%), and 7 of 31 other race patients (22.6%). Normal TPMT activity was seen for 184 of the 223 Caucasians (82.5%), 82 of the 134 African-Americans (61.2%), and 24 of the 31 patients of other race (77.4%). This distribution was statistically significant (p <0.001). Conclusions: Mean TPMT activity is lower in African-American and Middle Eastern patients compared to Caucasians. African-Americans are more likely to have intermediate TPMT activity compared to Caucasians. Therapeutic studies using 6-mercaptopurine and azathioprine that exclude patients with intermediate TPMT activity may exclude a high proportion of AfricanAmerican patients.

The value of tpmt measurement in the routine clinical management of patients with IBD

IntroductionThe measurement of thiopurine methyl transferase (TPMT) can be used to identify patients at risk of marrow suppression from azathioprine. Across the medical specialities, there is no clear consensus or...

Monitoring thiopurine methyltransferase (TPMT) activity in inflammatory bowel disease: is it worth it?

IntroductionAzathioprine and 6-mercaptopurine are immunosuppressants used to treat inflammatory bowel disease (IBD). Marrow toxicity occurs in 3% of patients receiving these drugs. Some practitioners propose that checking Thiopurine methyltransferase (TPMT)...

Disseminated Histoplasmosis and Pneumocystis Pneumonia in a Child With Crohn Disease Receiving Infliximab

Disseminated Histoplasmosis and Pneumocystis Pneumonia in a Child With Crohn Disease Receiving Infliximab

PWE-028 Thiopurine-induced neutropaenia in IBD patients with normal TPMT levels: a warning for gastroenterologists

<h3>Introduction</h3> Myelotoxicity occurs in approximately 3% of patients receiving Azathioprine (AZA) or Mercaptopurine (MP). Manufacturers recommend weekly blood testing for the first 8 weeks of therapy but BSG guidelines state that “less frequent monitoring (within 4 weeks) may be sufficient”. Some gastroenterologists elect to monitor patients with normal thiopurine methyl transferase (TPMT) levels less intensively, believing that neutropaenia is less frequently encountered in this group. We performed a retrospective review to determine the proportion of IBD patients on our unit with AZA/MP-induced neutropaenia who had low TPMT levels. <h3>Methods</h3> We reviewed the medical records of our IBD patients who had become neutropenic on AZA/MP over the last 2 years. Patients received standard recommended doses: 2–2.5 mg/kg AZA, 1–1.5 mg/kg MP. TPMT had been measured prior to therapy in all patients. All patients had blood tests done at fixed intervals according to a local protocol to monitor myelotoxicity. <h3>Result</h3> Over the last 2 years, 8 patients were identified, who had developed myelosupression on AZA/MP therapy. Five patients had Ulcerative colitis. Average age at start of AZA/MP was 51.8 years (range 31–74 years). Average disease duration prior to immunosuppression was 8.7 years (range 1–21 years). MP was used in 7 patients. Only one of the patients had a low TPMT level 24 (normal range 26–50 PM/h/mgH). Mean time to myelosupression was 4.7 weeks (range 2–7 weeks). Lowest recorded WCC ranged from 0.6–2.7×10⁹/L (median-1.8×10⁹/L) and neutrophils ranged from 0–1.4×10⁹/L (median 0.75×10⁹/L). <h3>Conclusion</h3> The majority (7 of 8) of our patients with thiopurine-induced myelotoxicty had normal TPMT levels. Half of our patients developed neutropaenia within 4 weeks of treatment. The results of TPMT level should not influence the frequency of blood test monitoring in the first 8 weeks of therapy. The current BSG guidelines should be amended to emphasise the importance of frequent blood test monitoring. We advise caution when using thiopurine and suggest weekly FBC for the first 8 weeks, even if the TPMT is normal.

Black Americans are More Likely to have Intermediate TPMT Enzyme Levels than White Americans

Purpose: Thiopurine methyltransferase (TPMT) metabolizes azathioprine (AZA) and mercaptopurine (6MP) into active and inactive metabolites. Optimal therapeutic effect is achieved at 6-thioguanine levels (6TG) between 230-400. Achieving therapeutic levels of 6TG is limited by the concurrent production of the inactive hepatotoxic metabolite 6-methylmercaptopurine (6MMP). A patient's TPMT enzyme activity is related to the ratio of production of these metabolites. Black Americans and Caucasians have differing frequencies of mutant alleles resulting in similar phenotypes of low, intermediate and normal levels. It is unclear whether there are racial differences in TPMT levels. Such differences could affect both medication choices and dosage regimens in the management of patients with inflammatory bowel disease. We sought to investigate ethnic variations in TMPT levels. Methods: We performed a retrospective chart review of patients who underwent TPMT level or genetic testing at our institution from June 2004 to June 2009. TPMT testing was performed at Prometheus Laboratories (San Diego, CA). Results: We identified 272 patients who had TPMT levels drawn (96 males, 176 females). Of the patients with quantitative TPMT levels available for review, 80 were self-described black American, 133 Caucasian, and 18 other. These levels are categorized into low, intermediate and normal (with less than 6.0 EU being low, 6.0- 21.0 EU intermediate and greater than 21.0 EU normal). The mean TPMT level for black Americans was 23.2 EU (SD 8.1), for Caucasians 27.7 EU (SD 9.4) and for other patients 25.7 EU (SD 8.7) (p=0.002). The mean levels are all within the normal range. Categorization of these levels into low, intermediate and normal showed that 0/80 (0.0%) of black Americans, 1/133 (0.8%) of Caucasians and 0/18 (0.0%) of others had low enzyme levels. 31/80 (38.8%) of black Americans, 26/133 (19.6%) of Caucasians and 5/18 (27.3%) of others had intermediate levels. 49/80 (61.3%) of black Americans, 106/133 (79.7%) of Caucasians and 13/18 (72.2%) of others had normal levels. The difference among the three categories is statistically significant (Fisher exact test p-value=0.017). Conclusion: Significant racial differences exist in mean TPMT enzyme levels among different American ethnic groups. While mean levels fall within the normal enzyme range, there was a statistically significant difference in the distribution of patients who fall into the intermediate versus the normal enzyme level between black and white Americans with a higher percentage of black Americans in the intermediate range and higher percentage of Caucasians in the normal range. Such differences may have important clinical implications insofar as ability to achieve therapeutic levels of 6TG.

Timing of Myelosuppression During Thiopurine Therapy for Inflammatory Bowel Disease: Implications for Monitoring Recommendations

Thiopurines (azathioprine and 6-mercaptopurine) can induce life-threatening myelosuppression. This study determined the frequency, timing, and outcomes of mild and severe myelosuppression after initiation of thiopurine therapy. This retrospective cohort study included patients with inflammatory bowel disease who were new users of thiopurines; those tested for thiopurine methyltransferase levels before therapy were excluded. Patients were followed from their first thiopurine prescription until the earliest of severe leukopenia (white blood cell count, <1.0 x 10(9)/L), severe thrombocytopenia (platelet level, <20 x 10(9)/L), the end of therapy, the first gap in therapy, disenrollment, or December 31, 2006. Among 1997 new users, the incidence of severe leukopenia per 100 person-months was 0.16 (95% confidence interval [CI], 0.03-0.29; n = 6) in weeks 0 to 8, 0.00 in weeks 9 to 24, and 0.01 (95% CI, 0-0.03; n = 3) after week 26 of therapy. The incidence of severe neutropenia and severe thrombocytopenia per 100 person-months during the first 8 weeks of therapy was 0.51 (95% CI, 0.31-0.80; n = 19) and 0.08 (95% CI, 0.02-0.23; n = 3), respectively. During the first 8 weeks, the median duration from a normal white blood cell count to severe leukopenia was 13 days (range, 8-26 d) and to severe neutropenia was 14 days (range, 7-23 d). The high incidence of severe myelosuppression justifies frequent monitoring during the first 8 weeks of therapy. Subsequently, the rate of severe myelosuppression and the proportion of patients who progress from mild to severe myelosuppression decrease, justifying less-frequent monitoring.