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

Abstract

Inflammatory Bowel Disease (IBD) involves a variety of conditions, particularly Crohn's disease (CD) and ulcerative colitis (UC). IBD is characterized by a chronic inflammatory process of the patient's gut. This review aims to summarize the pharmacogenetics of biologics approved for IBD and the correlation with azathioprine-metabolizing enzymes and adverse reactions, therefore highlighting a likely relationship between particular polymorphisms and therapeutic response. Therefore, we reviewed and discussed the activities of therapeutic drug monitoring (TDM) protocols that use monoclonal antibodies (mABs) with a particular attention to the integration of other actions aimed to exploit the most effective and safest medications for IBD cases. The pharmacotherapy of IBD (CD and UC) has experienced a great advancement with the advent of mABs which have peculiar pharmacokinetic properties differentiating them from chemical agents, like aminosalicylates, antimetabolites (e.g., azathioprine (AZA), 6mercaptopurine (6MP)), and methotrexate), and immunosuppressant agents (steroids and cyclosporine). But clinical studies showed that biologicals might have pharmacokinetic variability which can affect the anticipated clinical outcomes, beyond primary resistance phenomena. Thus, TDM protocols are applied to the doses of medications according to the required serum mABs levels. This aims to maximize the favourable effects of mABs and minimize the toxicity. But, the presence of particular genetic polymorphisms in patients might determine a different outcome in response to treatment, indicating the heterogeneity of the effectiveness among IBD cases. Indeed, many reports demonstrated significant associations between polymorphisms and response to biologics. In conclusion, the improvement of TNF-, TNFR and IL-1 pharmacogenetics could be the best approach toward a targeted treatment for IBD.Pretherapy genotyping has to be integrated with IBD therapeutic guidelines, as it is the most suitable approach to choose the most appropriate biologicals for each case. Also, the addition of pharmacodynamic markers (including serum, cellular, or tissue concentrations of TNF-alpha and IL-8) might boost the predictive performance of models and, eventually, control the disease with a significant improvement in quality of life (QOL).