Thiopurine Drugs in the Treatment of Ulcerative Colitis: Identification of a Novel Deleterious Mutation in TPMT

Abstract

Chronic inflammatory bowel disease (IBD) includes Crohn’s disease and ulcerative colitis. Both are characterized by inflammation of part of the digestive tract lining. Azathioprine (AZA) is a well-known immunosuppressant that has been known for many years for its ability to provide long-term disease remission in IBDs, but has important side effects, most of which are related to a single nucleotide polymorphism in the gene for thiopurine methyltransferase (TPMT), which ensures the degradation and efficacy of AZA. Since a direct correlation between TPMT gene polymorphisms and the haematological toxicity of the AZA treatment has been widely demonstrated, TPMT genotyping has been made necessary prior to any introduction of AZA. The monitoring of thiopurine metabolites presents one of the factors that limit wide adaptation of these thiopurines in clinical practice. Thus, identifying patients with asymmetric metabolism could help clinicians provide an ideal treatment recommendation to improve response and reduce adverse effects. Here, we review the role of AZA in the treatment of IBD and discuss the usefulness of TPMT genotyping to guide clinical decision-making. In addition, we report the identification of a new molecular alteration, never described, TPMT mutation affecting the TPMT activity and responsible for deleterious side effects in a clinical case of a 20-year-old woman patient.

Probiotic Bacillus cereus Alleviates Dextran Sulfate Sodium-Induced Colitis in Mice through Improvement of the Intestinal Barrier Function, Anti-Inflammation, and Gut Microbiota Modulation

“…Current therapeutic agents for IBD involve corticosteroids, aminosalicylates, antibiotics, and immunomodulatory drugs . However, the chronic application of these drugs is associated with various side effects, such as allergic reactions, fever, hypertension, and hepatic problems . Therefore, the efficacy and safety of probiotics for the intervention of colitis have piqued the interest of the scientific community.…”

“…14 However, the chronic application of these drugs is associated with various side effects, such as allergic reactions, fever, hypertension, and hepatic problems. 15 Therefore, the efficacy and safety of probiotics for the intervention of colitis have piqued the interest of the scientific community. The probiotic Bacillus cereus (B. cereus) is reported to exhibit potential therapeutic properties, such as modulating gut microbiota composition, enhancing acid resistance, and promoting thermal stability.…”

Azathioprine and Biological Treatment Genetic Association With Clinical Response and Toxicity in Inflammatory Bowel Disease Patients

“…Figure (1). The involved genes in thiopurine metabolism include TMPT, ITPA, HPRT, XDH, GSTM1, XDH, GMPS, and NUDT15 97 . But, the impacts of TPMT and NUDT15 on thiopurines effects and toxicity have been reported.…”

Pharmacogenomic Determinants of Interindividual Drug Response Variability: From Discovery to Implementation

“…In addition to 6-MP treatment for pediatric ALL, thiopurine response was also studied by Harmond et al [ 4 ]; however, their research was focused on azathiopurine (AZA) treatment of chronic inflammatory bowel disease (IBD), including Crohn’s disease and ulcerative colitis. The authors reviewed the role of AZA in IBD treatment, which included an overview of the previously characterized association with TPMT and the potential for genotype-guided clinical management.…”