This Article  • References  • Full text PDF  • Send to a friend  • Save in My Folder  • Save to citation manager  • Permissions  Citing Articles  • Citation map  • Citing articles on HighWire  • Citing articles on Web of Science (88)  • Contact me when this article is cited  Related Content  • Similar articles in this journal  Social Bookmarking   What's this?

John L. Snow, MB, ChB; Lawrence E. Gibson, MD

Arch Dermatol. 1995;131(2):193-197.

Abstract
Background
Thiopurine methyltransferase (TPMT) is one of three major enzymes involved in the metabolism of azathioprine and its active metabolite 6-mercaptopurine. Thiopurine methyltransferase activity is determined by an allelic polymorphism for either high (TPMT^H) or low (TPMT^L) enzyme activity. Homozygotes for the low activity allele are known to be at risk for profound myelosuppression with azathioprine. Heterozygotes may be at risk for myelosuppression. Homozygotes for the high activity allele may be inadequately immunosuppressed with conventional, empiric doses of azathioprine. We analyzed TPMT activity in red blood cell (RBC) lysates and determined the TPMT genotypes (based on normal population screening) of 28 dermatologic patients. This information was correlated with the observed efficacy and side effects of azathioprine therapy.

Observations
Two patients with TPMT levels of less than 12.5 U/mL RBCs (both TPMT^H heterozygotes) experienced leukopenia (white blood count <4.0x 10⁹/L) with azathioprine doses around 1.5 mg/kg. A third patient who experienced leukopenia had a TPMT level at the lower end of the homozygous range (15.5 U/mL RBCs) but received the highest dose of azathioprine (2.6 mg/ kg) of all patients in this series. Ten patients with TPMT levels of more than 18.5 U/mL RBCs (all TPMT^H homozygotes) receiving less than 1.5 mg/kg of azathioprine were judged to have a poor clinical response. In comparison, seven patients with TPMT levels between 12.5 and 18.5 U/mL RBCs (six TPMT^H homozygotes and one TPMT^H heterozygote) receiving 0.9 to 1.8 mg/kg of azathioprine had a favorable clinical response. Adverse effects of gastrointestinal upset and liver function test abnormalities did not appear to correlate with TPMT activity.

Conclusion
The TPMT^H heterozygotes may be at increased risk for myelosuppression with standard, empiric doses of azathioprine. On the other hand, homozygotes for TPMT^H, particularly those with TPMT levels at the upper end of the homozygous range, may have a poor clinical response to azathioprine due to inadequate empiric dosing.

(Arch Dermatol. 1995;131:193-197)

Author Affiliations
From the Department of Dermatology, Mayo Clinic and Mayo Foundation, Rochester, Minn.

CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    Twitter     What's this?

THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES

Thioguanine Nucleotides and Thiopurine Methyltransferase in Immunobullous Diseases: Optimal Levels as Adjunctive Tools for Azathioprine Monitoring
el-Azhary et al.
Arch Dermatol 2009;145:644-652.
ABSTRACT | FULL TEXT  

Optimizing Clinical Use of Azathioprine With Newer Pharmacogenetic Data
Wolverton
Arch Dermatol 2009;145:707-710.
FULL TEXT  

Role of Thiopurine Methyltransferase Activity in the Safety and Efficacy of Azathioprine in the Treatment of Pemphigus Vulgaris
Firooz et al.
Arch Dermatol 2008;144:1143-1147.
ABSTRACT | FULL TEXT  

A Comparison of Oral Methylprednisolone Plus Azathioprine or Mycophenolate Mofetil for the Treatment of Bullous Pemphigoid
Beissert et al.
Arch Dermatol 2007;143:1536-1542.
ABSTRACT | FULL TEXT  

A Comparison of Oral Methylprednisolone Plus Azathioprine or Mycophenolate Mofetil for the Treatment of Pemphigus.
Beissert et al.
Arch Dermatol 2006;142:1447-1454.
ABSTRACT | FULL TEXT  

Prediction of Survival for Patients With Bullous Pemphigoid: A Prospective Study
Joly et al.
Arch Dermatol 2005;141:691-698.
ABSTRACT | FULL TEXT  

Azathioprine-induced pancytopenia in a patient with pompholyx and deficiency of erythrocyte thiopurine methyltransferase
Konstantopoulou et al.
BMJ 2005;330:350-351.
FULL TEXT  

Relevance of thiopurine methyltransferase status in rheumatology patients receiving azathioprine
Clunie and Lennard
Rheumatology (Oxford) 2004;43:13-18.
ABSTRACT | FULL TEXT  

Pharmacogenetics in rheumatology: the prospects and limitations of an emerging field
Siva et al.
Rheumatology (Oxford) 2002;41:1273-1279.
ABSTRACT | FULL TEXT  

Erythrocyte thiopurine methyl transferase assessment prior to azathioprine use in the UK
Holme et al.
QJM 2002;95:439-444.
ABSTRACT | FULL TEXT  

Thiopurine methyltransferase activity in a Spanish population sample: decrease of enzymatic activity in multiple sclerosis patients
Menor et al.
Mult Scler 2002;8:243-248.
ABSTRACT  

The First International Consensus on Mucous Membrane Pemphigoid: Definition, Diagnostic Criteria, Pathogenic Factors, Medical Treatment, and Prognostic Indicators
Chan et al.
Arch Dermatol 2002;138:370-379.
ABSTRACT | FULL TEXT  

A Comparison of Oral and Topical Corticosteroids in Patients with Bullous Pemphigoid
Joly et al.
NEJM 2002;346:321-327.
ABSTRACT | FULL TEXT  

Bullous Pemphigoid: The Latest in Diagnosis, Prognosis, and Therapy
Korman
Arch Dermatol 1998;134:1137-1141.
FULL TEXT  

Management of Acquired Bullous Skin Diseases
Fine
NEJM 1995;333:1475-1484.
FULL TEXT  

The Role of Genetic Variation in Thiopurine Methyltransferase Activity and Efficacy and/or Side Effects of Azathioprine Therapy in Dermatologic Patients
Anstey and Lennard
Arch Dermatol 1995;131:1087-1088.
ABSTRACT