Pharmacogenomics of Tumor Necrosis Factor Antagonists in Rheumatoid Arthritis

Abstract

Tumor necrosis factor (TNF)-α plays a central role in the pathogenesis of rheumatoid arthritis (RA) and is instrumental in causing joint destruction, the clinical hallmark of the disease. Recognizing this, in recent years biological therapies have been developed that work by blocking the damaging effects of TNF-α on synovium and cartilage. Three such agents are currently approved for treatment in RA – etanercept, infliximab and adalimumab. Although these agents are very effective in slowing the clinical and structural progression in RA, they are expensive, totaling several thousand dollars in yearly costs. Furthermore, only about 60% of patients respond effectively to these agents. As RA is a chronic disease, with most patients expected to remain on these therapies for life, ways to prospectively identify patients most likely to benefit from these agents are being explored. Pharmacogenomic approaches form the basis of most such screening methods. Polymorphisms in genes encoding TNF-α, TNF-α receptors, other cytokines, and the major histocompatibility complex region, and their ability to predict response to anti-TNF therapies, have been the focus of many recent studies. The results from such studies are mixed, with some suggesting that single nucleotide polymorphisms (SNPs) in these genes are significant, while others conclude that such SNPs are irrelevant in predicting response. Such conflicting results are likely to be due to a variety of factors, as discussed in this article. Whether pharmacogenomics will allow prediction of anti-TNF therapy efficacy in RA remains a question with no clear answers to date. Large, prospective, multicenter studies with the examination of not just individual SNPs, but also multi-SNP haplotypes, are needed to address this question in the future.

Keywords::

• etanercept
• infliximab
• pharmacogenomics
• rheumatoid arthritis
• tumor necrosis factor antagonists

Acknowledgment

Funding: Dr Ranganathan’s work was supported by the BIRCWH Career Development Program, NIH 5 K12 HD01 459–05.

•	Pharmacogenomic studies offer novel approaches to prospectively screen patients for genetic markers for optimal drug selection with maximum efficacy and minimum toxicity.
•	The advent of the tumor necrosis factor (TNF) antagonists in the treatment of rheumatoid arthritis (RA) has caused a marked change because of their superior efficacy compared to existing agents.
•	Although highly effective, these agents are expensive, their costs being several fold higher than older disease-modifying antirheumatic drugs.
•	Also, response to anti-TNF therapies in RA is not uniform, with only approximately 60% of patients having a good response to these agents.
•	Polymorphisms in TNF, TNF-RSF1A and 1B, other cytokine genes, and the MHC class alleles have been described, although whether such polymorphisms are functionally significant remains controversial.
•	Recent studies have examined associations between these polymorphisms and the efficacy of anti-TNF therapies to help predict response to these agents.
•	There is no clear consensus based on the results of these studies, with some studies showing that these single nucleotide polymorphisms are predictive of response, while other studies show the opposite.
•	Such conflicting results are not surprising given the influence of multiple factors on these results, such as small sample sizes, high degree of linkage disequilibrium within the MHC region and the differing mechanisms of action of the various TNF antagonists.
•	Further prospective studies with large patient numbers, adequate powering and haplotype analyses are needed to determine which genetic markers are indicative of response to this new class of highly effective agents in RA.