Genetic Influences on Treatment Response in Rheumatoid Arthritis

The lack of clinical and laboratory markers that reliably predict response, side effects, or toxicity to therapeutic intervention poses a significant challenge in therapeutic decision-making. Consequently, rheumatologists and other physicians treating patients with rheumatoid arthritis (RA) must choose treatment regimens based on their own experience and assessment of the literature which usually consists of clinical trials of heterogeneous patient populations. With the US Food and Drug Administration’s (FDA) approval of tumor necrosis factor (TNF) inhibitors such as etanercept (1) and infliximab (2), the era of targeted biological agents for the treatment of RA has begun. Biologic agents differ from traditional medications used for RA in their capacity to target specific pathophysiological pathways not previously accessible to focused therapeutic intervention. However, the expense of these medications (>$10,000/yr), their lack of universally positive clinical responses, and the risk of immunosuppression with regard to infections make the identification of markers for clinically significant responses both clinically and practically important. Although the mechanism of action of biologic agents may be through molecular events “downstream” from those being directly inhibited, there is rationale for searching for genetic markers of disease within the targeted molecules or their ligands. By identifying genetic markers of treatment response (either positive or negative), rheumatologists hope to be able to stratify patients according to genetic determinants of likelihood of