title: Thiopurine methyltransferase activity in Spain: a study of 14,545 patients.
abstract: We sought to assess the activity of thiopurine methyltransferase (TPMT) in 14,545 Spanish patients with different diseases amenable to treatment with azathioprine/6-mercaptopurine (6-MP), and to evaluate the proportion of patients with low TPMT activity and therefore a higher risk of myelotoxicity with these drugs. TPMT activity in red blood cells (RBCs) was measured by a radiochemical method. The association between several clinical variables and TPMT activity was assessed by multiple linear regression. We included 14,545 patients: autoimmune hepatitis (n=359 patients), inflammatory bowel disease (n=7,046), multiple sclerosis (n = 814), myasthenia gravis (n=344), pemphigus (n=133), and other diseases (n=5,849). Mean TPMT activity was 20.1 +/- 6 U/mL, but differed depending on the disease (P<.001). TPMT distribution was low (<5) in 0.5%; intermediate (5.0-13.7) in 11.9%; or high (>or=13.8) in 87.6%. Only when TPMT activity was considered separately in each disease did it reveal a normal distribution. In the multivariate analysis, gender, hematocrit, and treatment with 5-aminosalicylates/steroids/azathioprine/6-MP statistically influenced TPMT activity, although, probably, in a clinically irrelevant manner. This study shows, in a large sample of 14,545 patients, that 0.5% had low TPMT activity, indicating a higher risk of myelotoxicity with azathioprine/6-MP, a figure similar or slightly higher than that reported in other areas. Nevertheless, the trimodal distribution of TPMT activity varied depending on disease, and the proportion of patients with low activity values ranged from 0-0.8%. The drugs prescribed for the treatment of autoimmune diseases, including azathioprine/6-MP, modified TPMT activity, but the magnitude of this effect was very small and the differences found are probably irrelevant from the clinical point of view.
authors.affiliation: Servicio de Aparato Digestivo, Hospital Universitario de la Princesa, Universidad Autónoma, Playa de Mojácar 29, Urb, Bonanza, 28669, Boadilla del Monte, Madrid, Spain. gisbert@meditex.es
authors.forename: Javier P
authors.initials: JP
authors.lastname: Gisbert
authors.forename: Fernando
authors.initials: F
authors.lastname: Gomollón
authors.forename: Carlos
authors.initials: C
authors.lastname: Cara
authors.forename: Marta
authors.initials: M
authors.lastname: Luna
authors.forename: Yago
authors.initials: Y
authors.lastname: González-Lama
authors.forename: José María
authors.initials: JM
authors.lastname: Pajares
authors.forename: José
authors.initials: J
authors.lastname: Maté
authors.forename: Luis G
authors.initials: LG
authors.lastname: Guijarro
mesh_terms: D000328:Adult; D001327:Autoimmune Diseases / Q000188:drug therapy* / Q000201:enzymology; D001379:Azathioprine / Q000009:adverse effects* / Q000378:metabolism; D001855:Bone Marrow Diseases / Q000139:chemically induced*; D004912:Erythrocytes / Q000201:enzymology*; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects* / Q000378:metabolism; D016014:Linear Models; D008297:Male; D015122:Mercaptopurine / Q000009:adverse effects* / Q000378:metabolism; D008780:Methyltransferases / Q000097:blood / Q000378:metabolism*; D008875:Middle Aged; D018570:Risk Assessment; D012307:Risk Factors; D013030:Spain
chemical_list: D007166:Immunosuppressive Agents; D015122:Mercaptopurine; D008780:Methyltransferases; C022745:thiopurine methyltransferase; D001379:Azathioprine