The efficacy of the
immunosuppressants azathioprine and
6-mercaptopurine has been well established in the
therapy of
inflammatory bowel diseases (IBD). However, its use has been complicated by a high incidence of serious
adverse drug reactions such as hematotoxicity, hepatotoxicity,
pancreatitis and gastrointestinal disturbances. Whereas
azathioprine-related
pancytopenia has been clearly linked to
thiopurine S-methyltransferase (TPMT) polymorphism limited data are available to explain gastrointestinal side effects. In a retrospective analysis of 93 adults with IBD and
azathioprine therapy both phenotyping and genotyping was used to explore systematically the relationship between TPMT and
azathioprine-related adverse reactions. At time of inclusion, 69 patients were still receiving
azathioprine therapy and had never experienced side effects.
Azathioprine had been withdrawn in 10 patients for non-medical reasons or lack of response and 14 patients (15%) had stopped medication or were on reduced dose due to severe
azathioprine-related side effects. Nine of these 14 patients had developed gastrointestinal side effects (hepatotoxicity, n = 3;
pancreatitis, n = 3; others, n = 3), but their normal red blood cell TPMT activities were in accordance to TPMT wild-type.
TPMT deficiency in one patient had led to
pancytopenia whereas only two of the remaining four patients with hematotoxicity displayed an intermediate phenotype of TPMT. This study demonstrates that
azathioprine-related gastrointestinal side effects are independent of the TPMT polymorphism. Nevertheless pharmacogenetic testing for TPMT prior to commencing
thiopurine therapy should become routine practice in order to avoid severe hematotoxicity in TPMT deficient patients and lowering the incidence of hematological side effects in individuals heterozygous for TPMT.