Predicting (side) effects for patients with inflammatory bowel disease: The promise of pharmacogenetics

Abstract

Inflammatory bowel disease (IBD) is a chronic and heterogeneous intestinal inflammatory disorder. The medical management of IBD aims for long-lasting disease remission to prevent complications and disease progression. Early introduction of immunosuppression forms the mainstay of medical IBD management. Large inter-individual variability in drug responses, in terms of both efficacy and toxicity, leads to high rates of therapeutic failure in the management of IBD. Better patient stratification is needed to maximize patient benefit and minimize the harm caused by adverse events. Pre-treatment pharmacogenetic testing has the potential to optimize drug selection and dose, and to minimize harm caused by adverse drug reactions. In addition, optimizing the use of cheap conventional drugs, and avoiding expensive ineffective drugs, will lead to a significant reduction in costs. Genetic variation in both TPMT and NUDT15, genes involved in thiopurine metabolism, is associated to an increased risk of thiopurine-induced myelosuppression. Moreover, specific HLA haplotypes confer risk to thiopurine-induced pancreatitis and to immunogenicity to tumor necrosis factor-antagonists, respectively. Falling costs and increased availability of genetic tests allow for the incorporation of pre-treatment genetic tests into clinical IBD management guidelines. In this paper, we review clinically useful pharmacogenetic associations for individualized treatment of patients with IBD and discuss the path from identification of a predictive pharmacogenetic marker to implementation into IBD clinical care.

Keywords: Inflammatory bowel disease; Crohn’s disease; Ulcerative colitis; Pharmacogenetics; Personalized medicine

Core tip: In recent years, strong pharmacogenetic associations for drugs used in the management of inflammatory bowel disease (IBD) have been identified. However, the implementation of pre-treatment pharmacogenetic testing into clinical guidelines has been challenging. Particular groups of patients are needlessly exposed to (expensive) drugs that are either ineffective or harmful. Pre-treatment screening for TPMT and NUDT15 genetic variation should be incorporated into clinical IBD management guidelines. Therapeutic recommendations based on HLA genetic variants, conferring risk for thiopurine-induced pancreatitis and immunogenicity to tumor necrosis factor-antagonists, respectively, should be further evaluated.