Poor response to thiopurine in inflammatory bowel disease: How to overcome therapeutic resistance? Commentary

The thiopurine antimetabolites azathioprine and 6-mercaptopurine are commonly used to treat inflammatory bowel disease; however, their administration at conventional doses is associated with adverse events and a lack of response in some patients. Although there is an abundance of data on thiopurine-S-methyltransferase (TPMT) deficiency and adverse hematologic events during treatment with thiopurines, there is still a paucity of information on the molecular causes for nonresponse. Chouchana et al. present a patient with ulcerative colitis who was unresponsive to therapy with thiopurines and had both a high TPMT activity and an unfavorable ratio of thiopurine metabolites, i.e., a high concentration of methylmercaptopurine nucleotides (MMPNs)2 relative to thioguanine nucleotides (TGNs). Higher MMPN and lower TGN concentrations are associated with a reduced thiopurine response; a high TPMT activity may be involved in determining this unfavorable metabolic ratio (1). Recent evidence has provided additional promising genetic determinants for a high TPMT activity and a lack of thiopurine response; however, these molecular features still need further validation before their clinical use. Polymorphisms in the TPMT3 (thiopurine S-methyltransferase) promoter have been associated with increased TPMT activity. Moreover, trans effects of single-nucleotide polymorphisms that affect TPMT activity and mercaptopurine sensitivity have recently been discovered in the PACSIN2 (protein kinase C and casein kinase substrate in neurons 2) gene. These molecular factors influencing TPMT activity may identify patients with high TPMT activity. For azathioprine, deletion of the GSTM1 (glutathione S-transferase mu 1) gene, which encodes an enzyme involved in the conversion of azathioprine to 6-mercaptopurine, has been associated with reduced drug activation, a lower TGN concentration, and a reduced response to therapy. An increased understanding of the molecular features that lead to an unfavorable response to thiopurines may provide useful tools, via a multilocus genotype approach, for identifying patients with a lower probability of responding to thiopurine therapy. Clinical implementation of this multifactorial assessment may be possible via the use of computerized decision-support tools in combination with electronic medical records (2), which would improve patients' pharmacological treatment.