Thiopurines are an important drug for management of patients with IBD. Sixty per cent of patients with IBD receive thiopurines (azathioprine (AZA), 6-mercaptopurine (6-MP) and to a lesser extent tioguanine) with proven efficacy in maintaining steroid-free remission. There is considerable interest in thiopurine pharmacogenetics, and it has been demonstrated that thiopurine-induced bone marrow suppression is associated with reduced thiopurine methyltransferase (TPMT) activity. This has however not been demonstrated in Indian populations where frequency of TPMT mutations is lower. Instead another mutation NUDT15 has been commonly reported in Indian patients. Presence of NUDT15 mutation is associated with development of cytopenias. Also early AZA intolerance (nausea, vomiting, myalgia) may affect up to 28% of patients, causing many to cease therapy. This is a significant problem because of limited alternative therapies. The mechanism of early AZA intolerance is unclear. Following an oral dose, 6MP is rapidly released from AZA by a nonenzymatic reaction cleaving methyl-nitro-thioimidazole from the AZA molecule. 6MP is then metabolized by 1 of 3 competing enzyme pathways. (Fig. 1) Measuring TGNs provides a summary of epigenetic and genetic factors influencing thiopurine metabolism and, together with measurement of MeMP, offers a means for therapeutic drug monitoring. Measurement of TGNs and MeMP in red blood cells (RBCs) has been shown to be clinically useful after steady state is reached at 4–6 weeks. Meta-analyses suggest that a therapeutic range of TGN between 235 pmol/8×108 and 450 pmol/8×108 RBCs correlates best with a good clinical response. Subtherapeutic TGNs risk a poor response to therapy/relapse.

Nearly one third of patients suffer a relapse every year. Disease flares occur in a random way and are mostly unpredictable, and persistent inflammatory activity negatively affects the patient’s physical and psychological well-being, social performance and working capacity. Clinical and biochemical parameters including age of disease onset, gender, disease location, fecal calprotectin, hsCRP and serum albumin; environmental factors including smoking, use of NSAIDs, antibiotics, OCPs, hormonal replacement therapy, diet; gut microbiota and genetic predictors play an important role in influencing disease activity. It is important to understand and identify reasons as to why a thiopurine is ineffective or not tolerated. Dose changes, switching to another thiopurine/drug, and management of side effects are crucial to ensure thiopurines are used in the best way. In addition, the use of TPMT/NUDT15, TDM, diet and fecal microbiome are clinically relevant and can help optimize existing thiopurine treatment. A correlation of all these parameters will aid in guiding treatment and ensure thiopurines are used to maximize response.