Optimized use of Thiopurines in Inflammatory Bowel Disease

Thiopurines are an important drug for management ofpatients with IBD. Sixtyper cent of patients with IBD receive thiopurines (azathioprine (AZA),6-mercaptopurine (6-MP) and to a lesser extent tioguanine) with proven efficacyin maintaining steroid-free remission. There isconsiderable interest in thiopurine pharmacogenetics, and it has beendemonstrated that thiopurine-induced bone marrow suppression is associated withreduced thiopurine methyltransferase (TPMT) activity. This has however not beendemonstrated 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. Alsoearly AZA intolerance (nausea, vomiting, myalgia) may affect up to 28% of patients, causingmany to cease therapy. This is a significant problem because of limitedalternative therapies. The mechanism of early AZA intolerance is unclear. Followingan oral dose, 6MP is rapidly released from AZA by a nonenzymatic reactioncleaving methyl-nitro-thioimidazole from the AZA molecule. 6MP is thenmetabolized by 1 of 3 competing enzyme pathways. (Fig. 1) Measuring TGNsprovides a summary of epigenetic and genetic factors influencing thiopurinemetabolism and, together with measurement of MeMP, offers a means fortherapeutic drug monitoring. Measurement of TGNs and MeMP in red blood cells(RBCs) has been shown to be clinically useful after steady state is reached at4–6 weeks. Meta-analyses suggest that a therapeutic range of TGN between 235pmol/8×108 and 450 pmol/8×108 RBCs correlates best with a goodclinical response. Subtherapeutic TGNs risk a poor response to therapy/relapse.

Nearlyone third of patients suffer a relapse every year. Disease flares occurin a random way and are mostly unpredictable, and persistent inflammatoryactivity negatively affects the patient’s physical and psychologicalwell-being, social performance and working capacity. Clinical and biochemicalparameters including age of disease onset, gender, disease location, fecalcalprotectin, hsCRP and serum albumin; environmental factors including smoking,use of NSAIDs, antibiotics, OCPs, hormonal replacement therapy, diet; gutmicrobiota and genetic predictors play an important role in influencing diseaseactivity. It is important to understand and identify reasons as to why athiopurine is ineffective or not tolerated. Dose changes, switching to anotherthiopurine/drug, and management of side effects are crucial to ensurethiopurines are used in the best way. In addition, the use of TPMT/NUDT15, TDM,diet and fecal microbiome are clinically relevant and can help optimizeexisting thiopurine treatment. A correlation of all these parameters will aidin guiding treatment and ensure thiopurines are used to maximize response.