Optimising use of thiopurines in inflammatory bowel disease

Abstract

Azathioprine (AZA) and 6-mercaptopurine (6-MP) are the most widely used immunosuppressive therapies in inflammatory bowel disease. Pretreatment measurement of thiopurine methyltransferase (TPMT) activity is recommended and although conventional practice is to use a dose of 2 mg/kg AZA (1 mg/kg 6-MP), higher doses of 2.5 mg/kg AZA or more may be required in some patients, particularly if TPMT activity is high. Dose raising is limited by toxicity, and a robust monitoring system is mandatory. Patients with side effects to AZA may tolerate 6-MP but pancreatitis is a contraindication to switching. Metabolite monitoring is not widely available but may be useful, particularly if non-compliance is possible or where metabolite shunting to 6-methylmercaptopurine is suspected, on the basis of non-response or toxicity. It may allow dose optimisation before switching to alternative immunosuppressants. The drug appears safe in pregnancy and breast feeding. Long term duration of therapy is a balance between benefits in relation to the underlying disease extent, activity and aggressiveness, and the risk of neoplasia, particularly lymphoma.

Figure 1

Pathway for thiopurine metabolism. 6-Me-TIMP, 6-methyl thioinosine monophosphate; 6-MMP, 6-methylmercaptopurine; 6-MMPR, 6-methylmercaptopurine ribonucleotides; 6-MP, 6-mercaptopurine; 6-TGDP, 6-thioguanosine diphosphate; 6-TGMP, 6-thioguanosine monophosphate; 6-TGTP, 6-thioguanosine triphosphate; 6-TIMP, 6-thioinosine monophosphate; 6-TU, 6-thiouracil; 6-TXMP, 6-thioxanthine monophosphate; AZA, azathioprine; GMPS, guanosine monophosphate synthetase; HGPRT, hypoxanthine guanine phosphoribosyl transferase; IMPDH, inosine monophosphate dehydrogenase; TPMT, thiopurine S-methyltransferase; XO, xanthine oxidase. 6-TGMP, 6-TGDP and 6-TGTP together are called 6-thioguanine nucleotides.

Figure 2

Time to bone marrow toxicity. Delay (months) between the first administration of azathioprine/6-mercaptopurine and the occurrence of bone marrow toxicity. Patients were classified as low methylators (LM; n=4), intermediate methylators (IM; n=7) and high methylators (HM; n=20) (courtesy of Colombel et al16).