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Azathioprine (AZA) and its metabolites 6-mercaptopurine (6MP) are thiopurine drugs used widely in the management of various rheumatologic conditions such as rheumatoid arthritis, systemic lupus erythematosis (notably lupus nephritis), systemic vasculitis and other autoimmune connective tissue disorders.1,2,3 It is also used in acute lymphoblastic leukaemia, organ transplantation, inflammatory bowel disease and inflammatory dermatologic disease. Azathioprine has no indigenous immunosuppressive activity; it is a prodrug. The first step in biotransformation is non-enzymic cleavage to form mercaptopurine which in turn undergoes extensive metabolism.4 Mercaptopurine can be oxidised, methylated, or formed into a variety of active thionucleotide metabolites. Azathioprine, as with all thioguanines, is metabolized to the active metabolites referred to collectively as 6-thioguanine nucleotide (6-TGN), which in turn is inactivated by thiopurine-6-methyltransferase (TPMT).5-7 TPMT is a cytosolic enzyme that preferentially catalyzes the inactivation (S-methylation) of the active metabolites of the thiopurines (6-mercaptopurine, AZA, and thioguanine).8 TPMT activity in erythrocytes are trimodal9; 90% of people exhibit high TPMT activity (homozygous for wild-type alleles), 10% have intermediate activity (mutation on one chromosome), 0.3% have low or no activity (mutation is found on both chromosomes).10 About 1 in 300 Caucasians are homozygous for TPMT and are at highest risk of life threatening myeolotoxicity if standard thiopurine doses are used. This myelotoxicity is thought to be due to elevated concentration of the cytotoxic metabolites, 6-thioguanine nucleotides (6-TGNs), which occur when 6-MP is unable to be metabolized by TPMT to 6-MMP. British Society of Rheumatology (BSR) recommends the initial dose of AZA should be 1mg/kg/day with dose increment of 0.5 mg/kg every 4-6 weeks until the desired response achieved or a maximum total dose of 2-3 mg/kg/day is achieved. Pre-treatment assessment of TPMT level is also recommended.11 AZA treatment discontinuation due to dose-related toxicities has been reported in up to 20% patients.12 Polymorphism in the TPMT gene predicted haematological adverse drug reactions in 5-10% of patients treated with thiopurine drugs.13 TPMT testing prior to AZA therapy has been shown to be cost-effective, when modelled in various theoretical situations.14,15 British Association of Dermatology (BAD) recommends pre-treatment measurement of TPMT in all patients prescribed azathioprine.16 Measurement of TPMT activity prior to initiation of thiopurine therapy can identify the select group of patients at risk of severe myelosuppression with standard dose of the drugs. Adjusting AZA dose on the basis of individual patients' TPMT activity can potentially minimise this risk. Estimated number of patients who would need TPMT analysis in order to avoid one serious adverse event over 6 months was 20 in one study.12 TPMT measurement costs NZ$64.52 per assay in New Zealand and it is performed by Canterbury Health Laboratories. We undertook this retrospective audit to determine the local practice of AZA dosing and pre-treatment TPMT testing and compared it with the BSR guideline for AZA dosing regimen. Methods Retrospective review of rheumatology patients receiving azathioprine, between January' 2003 to January' 2007, at Middlemore Hospital in Auckland, New Zealand was undertaken. Patients who had a minimum follow-up of 6 months were identified using the Read code MO1C (other DMARDs) from the inpatient and outpatient database. Data were collected on patient's demographics, previous and current treatment, AZA dosing regimen, TPMT testing, AZA-related toxicity profile and their management. Major AZA-related side-effects involving gastrointestinal tract, liver and bone marrow, were identified and documented. An increase of more than twice the upper limit of the normal range in the levels of serum alanine aminotransferase (ALT) was considered as hepatotoxicity. AZA related myelotoxicity was defined as neutrophil count <1.5×109 or total white cell count <3.5×109. Efficacy was defined as both clinical and biochemical improvement as well as reduction or complete withdrawal of all corticosteroids. Statistical analysis—Data are presented as mean (SD), median (IQR), or percentage as appropriate. Comparisons between groups for categorical data were made using Fishers exact test for 2×2 tables, or chi-square analysis for higher level tables. Normally distributed continuous variables were compared using Student's t-test. P 0.05 was considered significant, all tests are two tailed. Results Sixty patients on AZA were identified; majority of the patients were female (73%) and of European ethnicity. 42% of the patients had systemic lupus erythromatosis and 22% had rheumatoid arthritis, forming the majority of the cohort (Table 1). Forty-three (72%) patients were on at least one other DMARD prior to initiation of azathioprine- 17 patients from group 1 and 22 patients from group 2. Majority were on hydroxychloroquine, methotrexate or sulphasalazine either as monotherapy or combination therapy. The mean initial dose of prescribed AZA for our patient was 100 mg; the mean patient weight was 70 kg. BSR recommended starting dose (1 mg/kg) and dose incrementation was followed in 32% and 15% cases, respectively (Table 2). TPMT status was tested on six patients; of whom three had low TPMT levels requiring dose adjustment. Twenty-six patients (43%) of our cohort suffered at least one AZA-related side-effect. 42% suffered hepatoxicity, 39% had bone marrow toxicity and 19% had gastrointestinal intolerance. AZA was withdrawn in 21 patients (35%) either due to adverse effects or inefficacy. Two patients required hospital admission; one patient required rescue therapy for leucopenia and the other patient was admitted with urosepsis and leucopenia (Table 3). Comparison of patients who suffered AZA-related toxicity (group 1) with those who tolerated the drug well (group 2), showed no statistically significant difference except group 1 patients were prescribed higher initial dose compared to group 2 (p<0.005) (Table 4). Table 1. Patient's demographics (values are number [%] or mean ± SD) Sex: Male Female 16 (27%) 44 (73%) Age: mean±SD 53 ± 16 Ethnicity European NZ Māori Polynesian Fijian Others 26 10 9 9 6 SLE RA Vasculitis Inflammatory myopathy Others 25 (42%) 13 (22%) 8 (13%) 5 (8%) 9 (15%) Table 2. AZA dosing and pre-treatment TPMT testing regimen (values are number (%) or mean ± SD) Initial dose (mean ± SD) Optimum dosing Under dosing Over dosing 100 ± 38 mg 19 (32%) 13 (22%) 28 (46%) Escalating dose Guideline followed: Too rapidly No clear plan 9 (15%) 13 (22%) 38 (63%) Patients weight (mean ± SD) 70 ± 25 kg TPMT status 6 (10%) Table 3. Patient outcome on AZA Interval of adverse reaction 95±40 days Adverse reaction Hepatotoxicity: Bone marrow toxicity: GIT intolerance: 26 (43%) 11 (42%) 10 (39%) 5 (19%) Drug withdrawn Adverse effects Inefficacy 21 (35%) 16 5 Management of adverse reaction: Dose reduction: Drug withdrawn: 38% 62% Table 4. Comparison between patients with AZA related toxicity (group 1) and patients who tolerated the drug (group 2) Variables Group 1 (n=26) Group 2 (n=34) P-value Age 58 (IQR40-67) 53 (IQR 39-61) 0.71 Sex (M:F) 7:19 9:25 0.99 Ethnicity: Caucasian NZ Māori Polynesian Fijian 13 3 5 5 13 7 4 4 0.36 0.49 0.48 0.48 Rheumatological diagnosis: SLE RA 12 5 13 8 0.54 0.69 Other DMARDs Yes 17 26 0.35 Weight (kg) 72 ±18 kg 78±29 kg 0.57 AZA dose: Recommended dose Higher dose Lower dose 100±40mg 6 18 2 100±35mg 13 10 11 0.99 0.60 <0.005 0.37 Dose escalation regimen: Too quickly Guideline No clear plan 5 3 18 8 6 20 0.47 0.72 0.60 WCC: Baseline Post drug exposure 7.5±2.7 2±0.8 8±3.9 7.5±3 0.56 <0.0001 Neutrophil: Baseline Post drug exposure 5.3±2.6 0.9±0.5 5 ±3.5 5.5±3 0.70 <0.0001 Discussion This study reviewed local practice of AZA dosing, frequency of pre-treatment TPMT testing, and evaluated AZA-related toxicity in a select group of rheumatologic patients. Our study shows that BSR guideline for initial dosing regimen was followed in 32% cases and the dose increment regimen was followed in 19% cases. TPMT test was requested in six (10%) patients only; three had low TPMT level requiring reduced dose of AZA. Available data suggests that by optimizing the maximum dose of AZA (between 0.75 and 3 mg/kg/day), depending on TPMT testing (with a drastic reduction in dosage for patients homozygous for mutant TPMT alleles), considerable cost savings can be made by avoiding hospitalization and rescue therapy for leucopenic events.12 In treating rheumatological disease, the commonest cause for withdrawal of AZA is lack of therapeutic effect.17,18 This study has shown AZA was prescribed in low dose in 22% of patients and the drug was stopped in five patients (13%) as considered to be ineffective. One important observation in our study was the high rate of toxicity (43%) necessitating either the withdrawal or dose reduction of the AZA. However, this was not unusually high compared to observations reported in some other published studies.19,20 In all patients, the toxicities were reversible on discontinuation of AZA treatment. Pre-treatment measurement of TPMT activity has a role in identifying the 1 in 300 patients who are at risk of severe myelosuppression and also to identify the heterozygote intermediate individual who are at risk of early leucopenic episodes when treated with standard thiopurine dosages. Thus knowledge of TPMT status warns of early bone marrow toxicity. In our study there was no observed consistency in requesting TPMT level prior to initiation of AZA, despite reported benefits of pre-treatment testing and adverse consequences related to non-testing. Of the 6 patients who were tested for TPMT, had AZA dose adjustment accordingly, none had adverse events. The proportion of patients who could have avoided AZA related toxicities if screening TPMT tests were carried out cannot be inferred from our data. We assume this would be significant and translate into substantial cost saving by preventing toxicity related hospitalizations. Economic analysis has indicated that the prevention of myelo-suppression in TPMT homozygotes, by adjusting thiopurine dosage is cost-benefitial.21 Intracellular level of thiopurine metabolites, 6-TGN and 6-MMP can also be used as a guide to optimize drug dose. The therapeutic window of 6-TGN levels for optimal treatment of rheumatic disorders remains to be determined. In summary, our data suggest a need for greater awareness, both regarding the practice of guideline based dosing regimen of azathioprine as well as TPMT test as a pre-treatment assessment tool to avoid life-threatening myelosuppression.

Summary

Abstract

Azathioprine (AZA) is a commonly used drug for the management of various rheumatologic disorders. Due to individual variation of the metabolism of AZA, related to genetic polymorphism of the thiopurine methyl transferase (TPMT), serious toxic effects can result if inappropriate dose is administered. AZA dosing according to patients TPMT status can reduce drug-induced morbidity and can be cost effective.

Aim

To determine the current local practice of AZA dosing, identify AZA-related toxicity and to compare the local practice with the British Society of Rheumatology (BSR) recommendations.

Method

Retrospective review of patients on AZA for various rheumatologic conditions from inpatient (n=22) and outpatient (n=38) database at Middlemore Hospital, from January 2003 to January 2007. Data were collected on patients demographics, treatment history including AZA dosing regimen, TPMT testing, drug-related toxicities and their management.

Results

The mean age was 53 years; 73% were females. 43% of European ethnicity; mean weight of patient was 75 00b125 kg. 42% had SLE, 22% had rheumatoid arthritis, and 13% had systemic vasculitis. Average initial dose of AZA prescribed was 100 00b137 mg. 45% developed AZA related toxicity. AZA was withdrawn in 35 % of patients due to drug-related side-effects and inefficacy.15% of the patients required dose reduction. TPMT status was tested in 6 (10%) patients; three had low TMPT level, needing dose reduction. BSR recommendation for AZA dosing was followed in 15% cases.

Conclusion

A significant proportion of the studied cohort of rheumatologic patients on AZA had drug-related toxicity resulting in discontinuation of AZA. Our data suggests that better pre-treatment assessment including TPMT testing and the practice of guideline based dosing regimen would reduce the incidence of undue side-effects and discontinuation of such treatment.

Author Information

Dinar Jabin, Rheumatology Registrar; Sunil Kumar, Physician and Rheumatologist; Peter J Gow, Rheumatologist and Associate Professor; Department of Rheumatology, Middlemore Hospital, Otahuhu, South Auckland

Acknowledgements

Correspondence

Dr Dinar Jabin, Department of Rheumatology, Middlemore Hospital, Counties Manukau District Health Board, Private Bag 93311, Otahuhu, Auckland, New Zealand.

Correspondence Email

dr_djab@hotmail.com

Competing Interests

None known.

- Gaffney K, Scott DG. Azathioprine and cyclophosphamide in the treatment of rheumatoid arthritis. Br J Rheumatol 1998 Aug;37(8):824-36.-- Carette S, Klippel JH, Decker JL, et al. Controlled studies of oral immunosuppressive drugs in lupus nephritis. A long-term follow-up. Ann Intern Med 1983 Jul;99(1):1-8.-- Adu D, Pall A, Luqmani RA, et al. Controlled trial of pulse versus continuous prednisolone and cyclophosphamide in the treatment of systemic vasculitis. QJM. 1997 Jun;90(6):401-9.-- Evans WE, Horner M, Chu YQ, et al. Altered mercaptopurine metabolism, toxic effects, and dosage requirement in a thiopurine methyltransferase-deficient child with acute lymphocytic leukemia. J Pediatr. 1991 Dec;119(6):985-9. J Pediatr. 1991 Dec;119(6):985-9.-- Guidelines for monitoring drug therapy in rheumatoid arthritis. American College of Rheumatology Ad Hoc Committee on Clinical Guidelines. Arthritis Rheum. 1996 May;39(5):723-31.-- Stolk JN, Boerbooms AM, de Abreu RA, et al. Reduced thiopurine methyltransferase activity and development of side effects of azathioprine treatment in patients with rheumatoid arthritis. Arthritis Rheum. 1998 Oct;41(10):1858-66.-- Krynetski EY, Evans WE. Pharmacogenetics as a molecular basis for individualized drug therapy: the thiopurine S-methyltransferase paradigm. Pharm Res. 1999 Mar;16(3):342-9.-- Yates CR, Krynetski EY, Loennechen T, et al. Molecular diagnosis of thiopurine S-methyltransferase deficiency: genetic basis for azathioprine and mercaptopurine intolerance. Ann Intern Med. 1997 Apr 15;126(8):608-14.-- McLeod HL, Coulthard S, Thomas AE, et al. Analysis of thiopurine methyltranferase variant alleles in childhood acute lymphoblastic leukaemia. Br J Haematol 1999;105:696-700.-- Weinshilboum RM, Sladek SL. Mercaptopurine pharmacogenetics: monogenic inheritance of erythrocyte thiopurine methyltransferase activity. Am J Hum Genet. 1980 Sep;32(5):651-62.-- Chakravarty K, McDonald H, Pullar T, et al. BSR/BHPR guideline for disease-modifying anti-rheumatic drug (DMARD) therapy in consultation with the British Association of Dermatologists. Rheumatology (Oxford). 2008 Jun;47(6):924-5. Epub 2006 Aug 28.-- Seidman EG, Furst DE. Pharmacogenetics for the individualization of treatment of rheumatic disorders using azathioprine. J Rheumatol 2002 Dec;29(12):2484-7.-- Lennard L.TPMT in the treatment of Crohns disease with azathioprine. Gut 2002 Aug;51(2):143-6.-- Marra CA, Esdaile JM, Anis AH. Practical pharmacogenetics: The cost effectiveness of screening for thiopurine S-methytransferase polymorphisms in patients with rheumatological conditions treated with azathioprine. J Rheumatol. 2002 Dec;29(12):2507-12.-- Tavadia SMB, Mydlarski PR, Reis MD, et al. Screening for the azathioprine toxicity: a pharmacoeconomic analysis based on a target case. J Am Acad Dermatol. 2000 Apr;42(4):628-32.-- Anstey AV, Wakelin SW, Reynolds NJ. Guidelines for prescribing azathioprine in dermatology. Br J Dermatol. 2004 Dec;151(6):1123-32.-- Black AJ, Mcleod H, Capell HA, et al. Thiopurine methyltransferase genotype predicts therapy-limiting severe toxicity from azathioprine. Ann Intern Med. 1998 Nov 1;129(9):716-8.-- Corominas H, Domenech M, Laiz A, et al. Is thiopurine methyltransferase genetic polymorphism a major factor for withdrawal of azathioprine in rheumatoid arthritis patients? Rheumatology (Oxford). 2003 Jan;42(1):40-5.-- Ritchie DM, Boyle JA, McInnes JM, et al. Clinical studies with an articular index for the assessment of joint tenderness in patients with theumatoid arthritis. Q J Med. 1968 Jul;37(147):393-406.-- Woodland J, Chaput de Saintonge DM, Evans SJW, et al. Azathioprine in rheumatoid arthritis: double blind study of full versus half versus placebo. Ann Rheum Dis. 1981 Aug;40(4):355-9.-- Marshall E. Preventing toxicity with a gene test. Science. 2003 Oct 24;302(5645):588-90.-

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Azathioprine (AZA) and its metabolites 6-mercaptopurine (6MP) are thiopurine drugs used widely in the management of various rheumatologic conditions such as rheumatoid arthritis, systemic lupus erythematosis (notably lupus nephritis), systemic vasculitis and other autoimmune connective tissue disorders.1,2,3 It is also used in acute lymphoblastic leukaemia, organ transplantation, inflammatory bowel disease and inflammatory dermatologic disease. Azathioprine has no indigenous immunosuppressive activity; it is a prodrug. The first step in biotransformation is non-enzymic cleavage to form mercaptopurine which in turn undergoes extensive metabolism.4 Mercaptopurine can be oxidised, methylated, or formed into a variety of active thionucleotide metabolites. Azathioprine, as with all thioguanines, is metabolized to the active metabolites referred to collectively as 6-thioguanine nucleotide (6-TGN), which in turn is inactivated by thiopurine-6-methyltransferase (TPMT).5-7 TPMT is a cytosolic enzyme that preferentially catalyzes the inactivation (S-methylation) of the active metabolites of the thiopurines (6-mercaptopurine, AZA, and thioguanine).8 TPMT activity in erythrocytes are trimodal9; 90% of people exhibit high TPMT activity (homozygous for wild-type alleles), 10% have intermediate activity (mutation on one chromosome), 0.3% have low or no activity (mutation is found on both chromosomes).10 About 1 in 300 Caucasians are homozygous for TPMT and are at highest risk of life threatening myeolotoxicity if standard thiopurine doses are used. This myelotoxicity is thought to be due to elevated concentration of the cytotoxic metabolites, 6-thioguanine nucleotides (6-TGNs), which occur when 6-MP is unable to be metabolized by TPMT to 6-MMP. British Society of Rheumatology (BSR) recommends the initial dose of AZA should be 1mg/kg/day with dose increment of 0.5 mg/kg every 4-6 weeks until the desired response achieved or a maximum total dose of 2-3 mg/kg/day is achieved. Pre-treatment assessment of TPMT level is also recommended.11 AZA treatment discontinuation due to dose-related toxicities has been reported in up to 20% patients.12 Polymorphism in the TPMT gene predicted haematological adverse drug reactions in 5-10% of patients treated with thiopurine drugs.13 TPMT testing prior to AZA therapy has been shown to be cost-effective, when modelled in various theoretical situations.14,15 British Association of Dermatology (BAD) recommends pre-treatment measurement of TPMT in all patients prescribed azathioprine.16 Measurement of TPMT activity prior to initiation of thiopurine therapy can identify the select group of patients at risk of severe myelosuppression with standard dose of the drugs. Adjusting AZA dose on the basis of individual patients' TPMT activity can potentially minimise this risk. Estimated number of patients who would need TPMT analysis in order to avoid one serious adverse event over 6 months was 20 in one study.12 TPMT measurement costs NZ$64.52 per assay in New Zealand and it is performed by Canterbury Health Laboratories. We undertook this retrospective audit to determine the local practice of AZA dosing and pre-treatment TPMT testing and compared it with the BSR guideline for AZA dosing regimen. Methods Retrospective review of rheumatology patients receiving azathioprine, between January' 2003 to January' 2007, at Middlemore Hospital in Auckland, New Zealand was undertaken. Patients who had a minimum follow-up of 6 months were identified using the Read code MO1C (other DMARDs) from the inpatient and outpatient database. Data were collected on patient's demographics, previous and current treatment, AZA dosing regimen, TPMT testing, AZA-related toxicity profile and their management. Major AZA-related side-effects involving gastrointestinal tract, liver and bone marrow, were identified and documented. An increase of more than twice the upper limit of the normal range in the levels of serum alanine aminotransferase (ALT) was considered as hepatotoxicity. AZA related myelotoxicity was defined as neutrophil count <1.5×109 or total white cell count <3.5×109. Efficacy was defined as both clinical and biochemical improvement as well as reduction or complete withdrawal of all corticosteroids. Statistical analysis—Data are presented as mean (SD), median (IQR), or percentage as appropriate. Comparisons between groups for categorical data were made using Fishers exact test for 2×2 tables, or chi-square analysis for higher level tables. Normally distributed continuous variables were compared using Student's t-test. P 0.05 was considered significant, all tests are two tailed. Results Sixty patients on AZA were identified; majority of the patients were female (73%) and of European ethnicity. 42% of the patients had systemic lupus erythromatosis and 22% had rheumatoid arthritis, forming the majority of the cohort (Table 1). Forty-three (72%) patients were on at least one other DMARD prior to initiation of azathioprine- 17 patients from group 1 and 22 patients from group 2. Majority were on hydroxychloroquine, methotrexate or sulphasalazine either as monotherapy or combination therapy. The mean initial dose of prescribed AZA for our patient was 100 mg; the mean patient weight was 70 kg. BSR recommended starting dose (1 mg/kg) and dose incrementation was followed in 32% and 15% cases, respectively (Table 2). TPMT status was tested on six patients; of whom three had low TPMT levels requiring dose adjustment. Twenty-six patients (43%) of our cohort suffered at least one AZA-related side-effect. 42% suffered hepatoxicity, 39% had bone marrow toxicity and 19% had gastrointestinal intolerance. AZA was withdrawn in 21 patients (35%) either due to adverse effects or inefficacy. Two patients required hospital admission; one patient required rescue therapy for leucopenia and the other patient was admitted with urosepsis and leucopenia (Table 3). Comparison of patients who suffered AZA-related toxicity (group 1) with those who tolerated the drug well (group 2), showed no statistically significant difference except group 1 patients were prescribed higher initial dose compared to group 2 (p<0.005) (Table 4). Table 1. Patient's demographics (values are number [%] or mean ± SD) Sex: Male Female 16 (27%) 44 (73%) Age: mean±SD 53 ± 16 Ethnicity European NZ Māori Polynesian Fijian Others 26 10 9 9 6 SLE RA Vasculitis Inflammatory myopathy Others 25 (42%) 13 (22%) 8 (13%) 5 (8%) 9 (15%) Table 2. AZA dosing and pre-treatment TPMT testing regimen (values are number (%) or mean ± SD) Initial dose (mean ± SD) Optimum dosing Under dosing Over dosing 100 ± 38 mg 19 (32%) 13 (22%) 28 (46%) Escalating dose Guideline followed: Too rapidly No clear plan 9 (15%) 13 (22%) 38 (63%) Patients weight (mean ± SD) 70 ± 25 kg TPMT status 6 (10%) Table 3. Patient outcome on AZA Interval of adverse reaction 95±40 days Adverse reaction Hepatotoxicity: Bone marrow toxicity: GIT intolerance: 26 (43%) 11 (42%) 10 (39%) 5 (19%) Drug withdrawn Adverse effects Inefficacy 21 (35%) 16 5 Management of adverse reaction: Dose reduction: Drug withdrawn: 38% 62% Table 4. Comparison between patients with AZA related toxicity (group 1) and patients who tolerated the drug (group 2) Variables Group 1 (n=26) Group 2 (n=34) P-value Age 58 (IQR40-67) 53 (IQR 39-61) 0.71 Sex (M:F) 7:19 9:25 0.99 Ethnicity: Caucasian NZ Māori Polynesian Fijian 13 3 5 5 13 7 4 4 0.36 0.49 0.48 0.48 Rheumatological diagnosis: SLE RA 12 5 13 8 0.54 0.69 Other DMARDs Yes 17 26 0.35 Weight (kg) 72 ±18 kg 78±29 kg 0.57 AZA dose: Recommended dose Higher dose Lower dose 100±40mg 6 18 2 100±35mg 13 10 11 0.99 0.60 <0.005 0.37 Dose escalation regimen: Too quickly Guideline No clear plan 5 3 18 8 6 20 0.47 0.72 0.60 WCC: Baseline Post drug exposure 7.5±2.7 2±0.8 8±3.9 7.5±3 0.56 <0.0001 Neutrophil: Baseline Post drug exposure 5.3±2.6 0.9±0.5 5 ±3.5 5.5±3 0.70 <0.0001 Discussion This study reviewed local practice of AZA dosing, frequency of pre-treatment TPMT testing, and evaluated AZA-related toxicity in a select group of rheumatologic patients. Our study shows that BSR guideline for initial dosing regimen was followed in 32% cases and the dose increment regimen was followed in 19% cases. TPMT test was requested in six (10%) patients only; three had low TPMT level requiring reduced dose of AZA. Available data suggests that by optimizing the maximum dose of AZA (between 0.75 and 3 mg/kg/day), depending on TPMT testing (with a drastic reduction in dosage for patients homozygous for mutant TPMT alleles), considerable cost savings can be made by avoiding hospitalization and rescue therapy for leucopenic events.12 In treating rheumatological disease, the commonest cause for withdrawal of AZA is lack of therapeutic effect.17,18 This study has shown AZA was prescribed in low dose in 22% of patients and the drug was stopped in five patients (13%) as considered to be ineffective. One important observation in our study was the high rate of toxicity (43%) necessitating either the withdrawal or dose reduction of the AZA. However, this was not unusually high compared to observations reported in some other published studies.19,20 In all patients, the toxicities were reversible on discontinuation of AZA treatment. Pre-treatment measurement of TPMT activity has a role in identifying the 1 in 300 patients who are at risk of severe myelosuppression and also to identify the heterozygote intermediate individual who are at risk of early leucopenic episodes when treated with standard thiopurine dosages. Thus knowledge of TPMT status warns of early bone marrow toxicity. In our study there was no observed consistency in requesting TPMT level prior to initiation of AZA, despite reported benefits of pre-treatment testing and adverse consequences related to non-testing. Of the 6 patients who were tested for TPMT, had AZA dose adjustment accordingly, none had adverse events. The proportion of patients who could have avoided AZA related toxicities if screening TPMT tests were carried out cannot be inferred from our data. We assume this would be significant and translate into substantial cost saving by preventing toxicity related hospitalizations. Economic analysis has indicated that the prevention of myelo-suppression in TPMT homozygotes, by adjusting thiopurine dosage is cost-benefitial.21 Intracellular level of thiopurine metabolites, 6-TGN and 6-MMP can also be used as a guide to optimize drug dose. The therapeutic window of 6-TGN levels for optimal treatment of rheumatic disorders remains to be determined. In summary, our data suggest a need for greater awareness, both regarding the practice of guideline based dosing regimen of azathioprine as well as TPMT test as a pre-treatment assessment tool to avoid life-threatening myelosuppression.

Summary

Abstract

Azathioprine (AZA) is a commonly used drug for the management of various rheumatologic disorders. Due to individual variation of the metabolism of AZA, related to genetic polymorphism of the thiopurine methyl transferase (TPMT), serious toxic effects can result if inappropriate dose is administered. AZA dosing according to patients TPMT status can reduce drug-induced morbidity and can be cost effective.

Aim

To determine the current local practice of AZA dosing, identify AZA-related toxicity and to compare the local practice with the British Society of Rheumatology (BSR) recommendations.

Method

Retrospective review of patients on AZA for various rheumatologic conditions from inpatient (n=22) and outpatient (n=38) database at Middlemore Hospital, from January 2003 to January 2007. Data were collected on patients demographics, treatment history including AZA dosing regimen, TPMT testing, drug-related toxicities and their management.

Results

The mean age was 53 years; 73% were females. 43% of European ethnicity; mean weight of patient was 75 00b125 kg. 42% had SLE, 22% had rheumatoid arthritis, and 13% had systemic vasculitis. Average initial dose of AZA prescribed was 100 00b137 mg. 45% developed AZA related toxicity. AZA was withdrawn in 35 % of patients due to drug-related side-effects and inefficacy.15% of the patients required dose reduction. TPMT status was tested in 6 (10%) patients; three had low TMPT level, needing dose reduction. BSR recommendation for AZA dosing was followed in 15% cases.

Conclusion

A significant proportion of the studied cohort of rheumatologic patients on AZA had drug-related toxicity resulting in discontinuation of AZA. Our data suggests that better pre-treatment assessment including TPMT testing and the practice of guideline based dosing regimen would reduce the incidence of undue side-effects and discontinuation of such treatment.

Author Information

Dinar Jabin, Rheumatology Registrar; Sunil Kumar, Physician and Rheumatologist; Peter J Gow, Rheumatologist and Associate Professor; Department of Rheumatology, Middlemore Hospital, Otahuhu, South Auckland

Acknowledgements

Correspondence

Dr Dinar Jabin, Department of Rheumatology, Middlemore Hospital, Counties Manukau District Health Board, Private Bag 93311, Otahuhu, Auckland, New Zealand.

Correspondence Email

dr_djab@hotmail.com

Competing Interests

None known.

- Gaffney K, Scott DG. Azathioprine and cyclophosphamide in the treatment of rheumatoid arthritis. Br J Rheumatol 1998 Aug;37(8):824-36.-- Carette S, Klippel JH, Decker JL, et al. Controlled studies of oral immunosuppressive drugs in lupus nephritis. A long-term follow-up. Ann Intern Med 1983 Jul;99(1):1-8.-- Adu D, Pall A, Luqmani RA, et al. Controlled trial of pulse versus continuous prednisolone and cyclophosphamide in the treatment of systemic vasculitis. QJM. 1997 Jun;90(6):401-9.-- Evans WE, Horner M, Chu YQ, et al. Altered mercaptopurine metabolism, toxic effects, and dosage requirement in a thiopurine methyltransferase-deficient child with acute lymphocytic leukemia. J Pediatr. 1991 Dec;119(6):985-9. J Pediatr. 1991 Dec;119(6):985-9.-- Guidelines for monitoring drug therapy in rheumatoid arthritis. American College of Rheumatology Ad Hoc Committee on Clinical Guidelines. Arthritis Rheum. 1996 May;39(5):723-31.-- Stolk JN, Boerbooms AM, de Abreu RA, et al. Reduced thiopurine methyltransferase activity and development of side effects of azathioprine treatment in patients with rheumatoid arthritis. Arthritis Rheum. 1998 Oct;41(10):1858-66.-- Krynetski EY, Evans WE. Pharmacogenetics as a molecular basis for individualized drug therapy: the thiopurine S-methyltransferase paradigm. Pharm Res. 1999 Mar;16(3):342-9.-- Yates CR, Krynetski EY, Loennechen T, et al. Molecular diagnosis of thiopurine S-methyltransferase deficiency: genetic basis for azathioprine and mercaptopurine intolerance. Ann Intern Med. 1997 Apr 15;126(8):608-14.-- McLeod HL, Coulthard S, Thomas AE, et al. Analysis of thiopurine methyltranferase variant alleles in childhood acute lymphoblastic leukaemia. Br J Haematol 1999;105:696-700.-- Weinshilboum RM, Sladek SL. Mercaptopurine pharmacogenetics: monogenic inheritance of erythrocyte thiopurine methyltransferase activity. Am J Hum Genet. 1980 Sep;32(5):651-62.-- Chakravarty K, McDonald H, Pullar T, et al. BSR/BHPR guideline for disease-modifying anti-rheumatic drug (DMARD) therapy in consultation with the British Association of Dermatologists. Rheumatology (Oxford). 2008 Jun;47(6):924-5. Epub 2006 Aug 28.-- Seidman EG, Furst DE. Pharmacogenetics for the individualization of treatment of rheumatic disorders using azathioprine. J Rheumatol 2002 Dec;29(12):2484-7.-- Lennard L.TPMT in the treatment of Crohns disease with azathioprine. Gut 2002 Aug;51(2):143-6.-- Marra CA, Esdaile JM, Anis AH. Practical pharmacogenetics: The cost effectiveness of screening for thiopurine S-methytransferase polymorphisms in patients with rheumatological conditions treated with azathioprine. J Rheumatol. 2002 Dec;29(12):2507-12.-- Tavadia SMB, Mydlarski PR, Reis MD, et al. Screening for the azathioprine toxicity: a pharmacoeconomic analysis based on a target case. J Am Acad Dermatol. 2000 Apr;42(4):628-32.-- Anstey AV, Wakelin SW, Reynolds NJ. Guidelines for prescribing azathioprine in dermatology. Br J Dermatol. 2004 Dec;151(6):1123-32.-- Black AJ, Mcleod H, Capell HA, et al. Thiopurine methyltransferase genotype predicts therapy-limiting severe toxicity from azathioprine. Ann Intern Med. 1998 Nov 1;129(9):716-8.-- Corominas H, Domenech M, Laiz A, et al. Is thiopurine methyltransferase genetic polymorphism a major factor for withdrawal of azathioprine in rheumatoid arthritis patients? Rheumatology (Oxford). 2003 Jan;42(1):40-5.-- Ritchie DM, Boyle JA, McInnes JM, et al. Clinical studies with an articular index for the assessment of joint tenderness in patients with theumatoid arthritis. Q J Med. 1968 Jul;37(147):393-406.-- Woodland J, Chaput de Saintonge DM, Evans SJW, et al. Azathioprine in rheumatoid arthritis: double blind study of full versus half versus placebo. Ann Rheum Dis. 1981 Aug;40(4):355-9.-- Marshall E. Preventing toxicity with a gene test. Science. 2003 Oct 24;302(5645):588-90.-

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Azathioprine (AZA) and its metabolites 6-mercaptopurine (6MP) are thiopurine drugs used widely in the management of various rheumatologic conditions such as rheumatoid arthritis, systemic lupus erythematosis (notably lupus nephritis), systemic vasculitis and other autoimmune connective tissue disorders.1,2,3 It is also used in acute lymphoblastic leukaemia, organ transplantation, inflammatory bowel disease and inflammatory dermatologic disease. Azathioprine has no indigenous immunosuppressive activity; it is a prodrug. The first step in biotransformation is non-enzymic cleavage to form mercaptopurine which in turn undergoes extensive metabolism.4 Mercaptopurine can be oxidised, methylated, or formed into a variety of active thionucleotide metabolites. Azathioprine, as with all thioguanines, is metabolized to the active metabolites referred to collectively as 6-thioguanine nucleotide (6-TGN), which in turn is inactivated by thiopurine-6-methyltransferase (TPMT).5-7 TPMT is a cytosolic enzyme that preferentially catalyzes the inactivation (S-methylation) of the active metabolites of the thiopurines (6-mercaptopurine, AZA, and thioguanine).8 TPMT activity in erythrocytes are trimodal9; 90% of people exhibit high TPMT activity (homozygous for wild-type alleles), 10% have intermediate activity (mutation on one chromosome), 0.3% have low or no activity (mutation is found on both chromosomes).10 About 1 in 300 Caucasians are homozygous for TPMT and are at highest risk of life threatening myeolotoxicity if standard thiopurine doses are used. This myelotoxicity is thought to be due to elevated concentration of the cytotoxic metabolites, 6-thioguanine nucleotides (6-TGNs), which occur when 6-MP is unable to be metabolized by TPMT to 6-MMP. British Society of Rheumatology (BSR) recommends the initial dose of AZA should be 1mg/kg/day with dose increment of 0.5 mg/kg every 4-6 weeks until the desired response achieved or a maximum total dose of 2-3 mg/kg/day is achieved. Pre-treatment assessment of TPMT level is also recommended.11 AZA treatment discontinuation due to dose-related toxicities has been reported in up to 20% patients.12 Polymorphism in the TPMT gene predicted haematological adverse drug reactions in 5-10% of patients treated with thiopurine drugs.13 TPMT testing prior to AZA therapy has been shown to be cost-effective, when modelled in various theoretical situations.14,15 British Association of Dermatology (BAD) recommends pre-treatment measurement of TPMT in all patients prescribed azathioprine.16 Measurement of TPMT activity prior to initiation of thiopurine therapy can identify the select group of patients at risk of severe myelosuppression with standard dose of the drugs. Adjusting AZA dose on the basis of individual patients' TPMT activity can potentially minimise this risk. Estimated number of patients who would need TPMT analysis in order to avoid one serious adverse event over 6 months was 20 in one study.12 TPMT measurement costs NZ$64.52 per assay in New Zealand and it is performed by Canterbury Health Laboratories. We undertook this retrospective audit to determine the local practice of AZA dosing and pre-treatment TPMT testing and compared it with the BSR guideline for AZA dosing regimen. Methods Retrospective review of rheumatology patients receiving azathioprine, between January' 2003 to January' 2007, at Middlemore Hospital in Auckland, New Zealand was undertaken. Patients who had a minimum follow-up of 6 months were identified using the Read code MO1C (other DMARDs) from the inpatient and outpatient database. Data were collected on patient's demographics, previous and current treatment, AZA dosing regimen, TPMT testing, AZA-related toxicity profile and their management. Major AZA-related side-effects involving gastrointestinal tract, liver and bone marrow, were identified and documented. An increase of more than twice the upper limit of the normal range in the levels of serum alanine aminotransferase (ALT) was considered as hepatotoxicity. AZA related myelotoxicity was defined as neutrophil count <1.5×109 or total white cell count <3.5×109. Efficacy was defined as both clinical and biochemical improvement as well as reduction or complete withdrawal of all corticosteroids. Statistical analysis—Data are presented as mean (SD), median (IQR), or percentage as appropriate. Comparisons between groups for categorical data were made using Fishers exact test for 2×2 tables, or chi-square analysis for higher level tables. Normally distributed continuous variables were compared using Student's t-test. P 0.05 was considered significant, all tests are two tailed. Results Sixty patients on AZA were identified; majority of the patients were female (73%) and of European ethnicity. 42% of the patients had systemic lupus erythromatosis and 22% had rheumatoid arthritis, forming the majority of the cohort (Table 1). Forty-three (72%) patients were on at least one other DMARD prior to initiation of azathioprine- 17 patients from group 1 and 22 patients from group 2. Majority were on hydroxychloroquine, methotrexate or sulphasalazine either as monotherapy or combination therapy. The mean initial dose of prescribed AZA for our patient was 100 mg; the mean patient weight was 70 kg. BSR recommended starting dose (1 mg/kg) and dose incrementation was followed in 32% and 15% cases, respectively (Table 2). TPMT status was tested on six patients; of whom three had low TPMT levels requiring dose adjustment. Twenty-six patients (43%) of our cohort suffered at least one AZA-related side-effect. 42% suffered hepatoxicity, 39% had bone marrow toxicity and 19% had gastrointestinal intolerance. AZA was withdrawn in 21 patients (35%) either due to adverse effects or inefficacy. Two patients required hospital admission; one patient required rescue therapy for leucopenia and the other patient was admitted with urosepsis and leucopenia (Table 3). Comparison of patients who suffered AZA-related toxicity (group 1) with those who tolerated the drug well (group 2), showed no statistically significant difference except group 1 patients were prescribed higher initial dose compared to group 2 (p<0.005) (Table 4). Table 1. Patient's demographics (values are number [%] or mean ± SD) Sex: Male Female 16 (27%) 44 (73%) Age: mean±SD 53 ± 16 Ethnicity European NZ Māori Polynesian Fijian Others 26 10 9 9 6 SLE RA Vasculitis Inflammatory myopathy Others 25 (42%) 13 (22%) 8 (13%) 5 (8%) 9 (15%) Table 2. AZA dosing and pre-treatment TPMT testing regimen (values are number (%) or mean ± SD) Initial dose (mean ± SD) Optimum dosing Under dosing Over dosing 100 ± 38 mg 19 (32%) 13 (22%) 28 (46%) Escalating dose Guideline followed: Too rapidly No clear plan 9 (15%) 13 (22%) 38 (63%) Patients weight (mean ± SD) 70 ± 25 kg TPMT status 6 (10%) Table 3. Patient outcome on AZA Interval of adverse reaction 95±40 days Adverse reaction Hepatotoxicity: Bone marrow toxicity: GIT intolerance: 26 (43%) 11 (42%) 10 (39%) 5 (19%) Drug withdrawn Adverse effects Inefficacy 21 (35%) 16 5 Management of adverse reaction: Dose reduction: Drug withdrawn: 38% 62% Table 4. Comparison between patients with AZA related toxicity (group 1) and patients who tolerated the drug (group 2) Variables Group 1 (n=26) Group 2 (n=34) P-value Age 58 (IQR40-67) 53 (IQR 39-61) 0.71 Sex (M:F) 7:19 9:25 0.99 Ethnicity: Caucasian NZ Māori Polynesian Fijian 13 3 5 5 13 7 4 4 0.36 0.49 0.48 0.48 Rheumatological diagnosis: SLE RA 12 5 13 8 0.54 0.69 Other DMARDs Yes 17 26 0.35 Weight (kg) 72 ±18 kg 78±29 kg 0.57 AZA dose: Recommended dose Higher dose Lower dose 100±40mg 6 18 2 100±35mg 13 10 11 0.99 0.60 <0.005 0.37 Dose escalation regimen: Too quickly Guideline No clear plan 5 3 18 8 6 20 0.47 0.72 0.60 WCC: Baseline Post drug exposure 7.5±2.7 2±0.8 8±3.9 7.5±3 0.56 <0.0001 Neutrophil: Baseline Post drug exposure 5.3±2.6 0.9±0.5 5 ±3.5 5.5±3 0.70 <0.0001 Discussion This study reviewed local practice of AZA dosing, frequency of pre-treatment TPMT testing, and evaluated AZA-related toxicity in a select group of rheumatologic patients. Our study shows that BSR guideline for initial dosing regimen was followed in 32% cases and the dose increment regimen was followed in 19% cases. TPMT test was requested in six (10%) patients only; three had low TPMT level requiring reduced dose of AZA. Available data suggests that by optimizing the maximum dose of AZA (between 0.75 and 3 mg/kg/day), depending on TPMT testing (with a drastic reduction in dosage for patients homozygous for mutant TPMT alleles), considerable cost savings can be made by avoiding hospitalization and rescue therapy for leucopenic events.12 In treating rheumatological disease, the commonest cause for withdrawal of AZA is lack of therapeutic effect.17,18 This study has shown AZA was prescribed in low dose in 22% of patients and the drug was stopped in five patients (13%) as considered to be ineffective. One important observation in our study was the high rate of toxicity (43%) necessitating either the withdrawal or dose reduction of the AZA. However, this was not unusually high compared to observations reported in some other published studies.19,20 In all patients, the toxicities were reversible on discontinuation of AZA treatment. Pre-treatment measurement of TPMT activity has a role in identifying the 1 in 300 patients who are at risk of severe myelosuppression and also to identify the heterozygote intermediate individual who are at risk of early leucopenic episodes when treated with standard thiopurine dosages. Thus knowledge of TPMT status warns of early bone marrow toxicity. In our study there was no observed consistency in requesting TPMT level prior to initiation of AZA, despite reported benefits of pre-treatment testing and adverse consequences related to non-testing. Of the 6 patients who were tested for TPMT, had AZA dose adjustment accordingly, none had adverse events. The proportion of patients who could have avoided AZA related toxicities if screening TPMT tests were carried out cannot be inferred from our data. We assume this would be significant and translate into substantial cost saving by preventing toxicity related hospitalizations. Economic analysis has indicated that the prevention of myelo-suppression in TPMT homozygotes, by adjusting thiopurine dosage is cost-benefitial.21 Intracellular level of thiopurine metabolites, 6-TGN and 6-MMP can also be used as a guide to optimize drug dose. The therapeutic window of 6-TGN levels for optimal treatment of rheumatic disorders remains to be determined. In summary, our data suggest a need for greater awareness, both regarding the practice of guideline based dosing regimen of azathioprine as well as TPMT test as a pre-treatment assessment tool to avoid life-threatening myelosuppression.

Summary

Abstract

Azathioprine (AZA) is a commonly used drug for the management of various rheumatologic disorders. Due to individual variation of the metabolism of AZA, related to genetic polymorphism of the thiopurine methyl transferase (TPMT), serious toxic effects can result if inappropriate dose is administered. AZA dosing according to patients TPMT status can reduce drug-induced morbidity and can be cost effective.

Aim

To determine the current local practice of AZA dosing, identify AZA-related toxicity and to compare the local practice with the British Society of Rheumatology (BSR) recommendations.

Method

Retrospective review of patients on AZA for various rheumatologic conditions from inpatient (n=22) and outpatient (n=38) database at Middlemore Hospital, from January 2003 to January 2007. Data were collected on patients demographics, treatment history including AZA dosing regimen, TPMT testing, drug-related toxicities and their management.

Results

The mean age was 53 years; 73% were females. 43% of European ethnicity; mean weight of patient was 75 00b125 kg. 42% had SLE, 22% had rheumatoid arthritis, and 13% had systemic vasculitis. Average initial dose of AZA prescribed was 100 00b137 mg. 45% developed AZA related toxicity. AZA was withdrawn in 35 % of patients due to drug-related side-effects and inefficacy.15% of the patients required dose reduction. TPMT status was tested in 6 (10%) patients; three had low TMPT level, needing dose reduction. BSR recommendation for AZA dosing was followed in 15% cases.

Conclusion

A significant proportion of the studied cohort of rheumatologic patients on AZA had drug-related toxicity resulting in discontinuation of AZA. Our data suggests that better pre-treatment assessment including TPMT testing and the practice of guideline based dosing regimen would reduce the incidence of undue side-effects and discontinuation of such treatment.

Author Information

Dinar Jabin, Rheumatology Registrar; Sunil Kumar, Physician and Rheumatologist; Peter J Gow, Rheumatologist and Associate Professor; Department of Rheumatology, Middlemore Hospital, Otahuhu, South Auckland

Acknowledgements

Correspondence

Dr Dinar Jabin, Department of Rheumatology, Middlemore Hospital, Counties Manukau District Health Board, Private Bag 93311, Otahuhu, Auckland, New Zealand.

Correspondence Email

dr_djab@hotmail.com

Competing Interests

None known.

- Gaffney K, Scott DG. Azathioprine and cyclophosphamide in the treatment of rheumatoid arthritis. Br J Rheumatol 1998 Aug;37(8):824-36.-- Carette S, Klippel JH, Decker JL, et al. Controlled studies of oral immunosuppressive drugs in lupus nephritis. A long-term follow-up. Ann Intern Med 1983 Jul;99(1):1-8.-- Adu D, Pall A, Luqmani RA, et al. Controlled trial of pulse versus continuous prednisolone and cyclophosphamide in the treatment of systemic vasculitis. QJM. 1997 Jun;90(6):401-9.-- Evans WE, Horner M, Chu YQ, et al. Altered mercaptopurine metabolism, toxic effects, and dosage requirement in a thiopurine methyltransferase-deficient child with acute lymphocytic leukemia. J Pediatr. 1991 Dec;119(6):985-9. J Pediatr. 1991 Dec;119(6):985-9.-- Guidelines for monitoring drug therapy in rheumatoid arthritis. American College of Rheumatology Ad Hoc Committee on Clinical Guidelines. Arthritis Rheum. 1996 May;39(5):723-31.-- Stolk JN, Boerbooms AM, de Abreu RA, et al. Reduced thiopurine methyltransferase activity and development of side effects of azathioprine treatment in patients with rheumatoid arthritis. Arthritis Rheum. 1998 Oct;41(10):1858-66.-- Krynetski EY, Evans WE. Pharmacogenetics as a molecular basis for individualized drug therapy: the thiopurine S-methyltransferase paradigm. Pharm Res. 1999 Mar;16(3):342-9.-- Yates CR, Krynetski EY, Loennechen T, et al. Molecular diagnosis of thiopurine S-methyltransferase deficiency: genetic basis for azathioprine and mercaptopurine intolerance. Ann Intern Med. 1997 Apr 15;126(8):608-14.-- McLeod HL, Coulthard S, Thomas AE, et al. Analysis of thiopurine methyltranferase variant alleles in childhood acute lymphoblastic leukaemia. Br J Haematol 1999;105:696-700.-- Weinshilboum RM, Sladek SL. Mercaptopurine pharmacogenetics: monogenic inheritance of erythrocyte thiopurine methyltransferase activity. Am J Hum Genet. 1980 Sep;32(5):651-62.-- Chakravarty K, McDonald H, Pullar T, et al. BSR/BHPR guideline for disease-modifying anti-rheumatic drug (DMARD) therapy in consultation with the British Association of Dermatologists. Rheumatology (Oxford). 2008 Jun;47(6):924-5. Epub 2006 Aug 28.-- Seidman EG, Furst DE. Pharmacogenetics for the individualization of treatment of rheumatic disorders using azathioprine. J Rheumatol 2002 Dec;29(12):2484-7.-- Lennard L.TPMT in the treatment of Crohns disease with azathioprine. Gut 2002 Aug;51(2):143-6.-- Marra CA, Esdaile JM, Anis AH. Practical pharmacogenetics: The cost effectiveness of screening for thiopurine S-methytransferase polymorphisms in patients with rheumatological conditions treated with azathioprine. J Rheumatol. 2002 Dec;29(12):2507-12.-- Tavadia SMB, Mydlarski PR, Reis MD, et al. Screening for the azathioprine toxicity: a pharmacoeconomic analysis based on a target case. J Am Acad Dermatol. 2000 Apr;42(4):628-32.-- Anstey AV, Wakelin SW, Reynolds NJ. Guidelines for prescribing azathioprine in dermatology. Br J Dermatol. 2004 Dec;151(6):1123-32.-- Black AJ, Mcleod H, Capell HA, et al. Thiopurine methyltransferase genotype predicts therapy-limiting severe toxicity from azathioprine. Ann Intern Med. 1998 Nov 1;129(9):716-8.-- Corominas H, Domenech M, Laiz A, et al. Is thiopurine methyltransferase genetic polymorphism a major factor for withdrawal of azathioprine in rheumatoid arthritis patients? Rheumatology (Oxford). 2003 Jan;42(1):40-5.-- Ritchie DM, Boyle JA, McInnes JM, et al. Clinical studies with an articular index for the assessment of joint tenderness in patients with theumatoid arthritis. Q J Med. 1968 Jul;37(147):393-406.-- Woodland J, Chaput de Saintonge DM, Evans SJW, et al. Azathioprine in rheumatoid arthritis: double blind study of full versus half versus placebo. Ann Rheum Dis. 1981 Aug;40(4):355-9.-- Marshall E. Preventing toxicity with a gene test. Science. 2003 Oct 24;302(5645):588-90.-

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