Pharmacogenetics: Reality or Dream in Predicting the Response to TNF-α Inhibitor Treatment?

Abstract

Background: The ongoing progresses in the knowledge of the pathogenic mechanisms of various immunemediated or inflammatory diseases such as rheumatoid arthritis, systemic lupus erythematosus, Crohn's disease, ankylosing spondylitis, disseminated granuloma annulare, psoriasis and/or psoriatic arthritis, and the availability of innovative biotechnological approaches have lead to the development of new drugs which add to conventional treatments. There are five TNF-α inhibitors available for clinical use including anti-TNF-α monoclonal antibodies (infliximab, adalimumab, golimumab and certolizumab pegol) and a fusion protein that acts as a "decoy receptor" for TNF-α (etanercept). Pharmacogenetics has the potential of increasing drug efficiency by identifying genetic factors responsible for lack response or toxicities to TNF-α inhibitors. Methods: We analyzed the most recent studies in the literature relating to different genetic polymorphisms and their potential association with the therapeutic response to TNF-α inhibitors. Results: SNP at position-308 of the TNF-α promoter genes and particularly the-308 G/G genotype and HLA-DRB1-encoding shared epitope (allele *0404 and allele *0101) may predict a better response to etanercept. Polymorphisms of TNFR1 and TNFR2 decrease response to infliximab. By contrast, FCGR3A-158 polymorphism seems to favor the response to infliximab. G allele of SNP rs610604 located in the TNFAIP3 gene and its haplotype with the T allele of rs2230926 could be considered as markers of good response to etanercept, infliximab and adalimumab. Conclusion: Most of these studies are often small and not sufficiently powered to detect an effect and often examines only the effects of a single SNP, while it would be more useful to analyze more haplotypes in contemporary in the same patients. Candidate genes may be in linkage with other loci, thus, having a true influence upon the pharmacology of TNF-α inhibitors. Further studies are needed before a pharmacogenetic approach may be applicable in daily clinical therapeutic practice.