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.
Highlights
Inflammatory bowel disease (IBD) is a term expressed to define a set of intestinal disorders involved in the whole of the digestive tract, comprising two main pathologies: Ulcerative colitis (UC)
The European organization of IBD has published a consensus statement in which clinicians agree to the use of thiopurines as monotherapy or in addition to infliximab against corticosteroid-dependent IBDs, stating the significant efficacy of thiopurines compared with aminosalicylates to slow the rise of UC [17,18]
A novel class 5 deleterious mutation, c.483_484del, p.Asp162Serfs * 26, was found in exon 7 (Figure 3). This deletion involves a shift in the reading frame of the sequence and induces a STOP codon located at position 188 of the amino acids (Tyrosine → Stop) in the middle of exon 8
Summary
Inflammatory bowel disease (IBD) is a term expressed to define a set of intestinal disorders involved in the whole (or part) of the digestive tract, comprising two main pathologies: Ulcerative colitis (UC). The immune system of people with IBD does not respond well to environmental triggers, activating T-cells and triggering chronic inflammation of the gastrointestinal tract [3] Aminosalicylated derivatives such as mesalazine or sulfasalazine are drugs prescribed in first line to induce and maintain remission in UC; to which if necessary, glucocorticoids can be added. Genes 2020, 11, 1212 the mainstay of IBD treatment as steroid sparing agents thanks to their modulation of the immune system [4,5]. They are used to maintain the remission acquired during the use of corticosteroids, but especially in combination with biological therapy. We summarize the main pharmacological features of AZA and 6-MP, describe the genetic variants in TPMT that influence their toxicity, and report the identification of a new molecular alteration responsible for deleterious side effects in a clinical case
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