Pharmacogenetics of treatments for inflammatory bowel disease

ABSTRACT

Introduction: Inflammatory bowel disease is a chronic inflammation of the gut whose pathogenesis is still unclear. Although no curative therapy is currently available, a number of drugs are used in induction and maintenance therapy; however, for most of these drugs, a high inter-individual variability in response is observed. Among the factors of this variability, genetics plays an important role.

Areas covered: This review summarizes the results of pharmacogenetic studies, considering the most important drugs used and in particular aminosalycilates, glucocorticoids, thiopurines, monoclonal antibodies and thalidomide. Most studies used a candidate gene approach, even if significant breakthroughs have been obtained recently from applying genome-wide studies. When available, also investigations considering epigenetics and pharmacogenetic dosing guidelines have been included.

Expert opinion: Only for thiopurines, genetic markers identified as predictors of efficacy or adverse events have allowed the development of dosing guidelines. For the other drugs, encouraging results are available and great expectations rely on the study of epigenetics and integration with pharmacokinetic information, especially useful for biologics. However, to improve therapy of IBD patients with these drugs, for implementation in the clinics of pharmacogenetics, informatic clinical decision support systems and training about pharmacogenetics of health providers are needed.

KEYWORDS:

• Biologics
• glucocorticoids
• inflammatory bowel disease
• pharmacogenetics
• thalidomide
• thiopurines

Article highlights

• The role of pharmacogenetic factors to predict therapeutic effects in IBD has been largely demonstrated but only few genetic markers have been developed to the point of clinical guidelines to tailor therapy.

• For thiopurines, administration of the drug on the basis of a multilocus genotype considering variants in TPMT, NUDT15 and HLAs is promising in reducing adverse effects (myelosuppression and pancreatitis) and increasing efficacy of treatment.

• For all drugs and in particular glucocorticoids, based on their mechanism of action, epigenetic evaluations considering miRNAs and DNA methylation profiles are promising toward the identification of clinically useful pharmacogenetic markers.

• Biologic drugs and anti-drug antibodies concentrations are strongly associated with disease remission and proper integration of pharmacokinetic and pharmacogenetic markers may lead to the identification of strategies to prevent and overcome remission induction failure or loss of response.

• Improvement in the field of pharmacogenetics of IBD may depend on the development of large national and international collaborative groups to increase sample sizes of populations considered for analysis.

• Clinical implementation of pharmacogenetic biomarkers depend also on the development of tools that assist clinicians in handling these informations, such as informatic clinical decision support systems, and on training about pharmacogenetics of health providers.

This box summarizes key points contained in the article.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.