Genetic predictors of response to treatment in RA patients

This review evaluated recent research into genetic predictors of response to treatments with methotrexate (MTX) and TNF-blocking agents.

The treatment of rheumatoid arthritis (RA) is based on drugs which modify the behavior of the immune system and reduce the extent of inflammation. Methotrexate (MTX), a commonly used anti-metabolite drug which inhibits the function of all highly active cells, including those of the immune system, is often the treatment of choice in RA. Since tumor necrosis factor (TNF) is an important signaling molecule involved in the regulation of immune and inflammatory processes and is known to play a key role in the progression of RA, TNF-blocking agents are another commonly used approach in the treatment of RA.

However, despite the proven success of these immune modifying therapies, only a fraction of patients responds to treatment, and the majority of patients withdraw from treatment over time due to ineffectiveness of the drug or adverse effects.

Several recently published studies have investigated genetic factors that might predict patient responsiveness to different treatments. Such genetic factors may include either gene variations (certain variants of the same gene found in different patients) or epigenetic variations (heritable changes in the DNA that affect gene expression, rather than alterations in the gene itself) that show correlation with a good or poor response to specific treatments. An example for an epigenetic variation is methylation. This is a specific chemical modification of regions within a gene known to inhibit its activity.

Prescribing the most appropriate initial treatment, on a personalized basis, is likely to be a key factor in providing patients with better and more cost-effective therapy. In addition, patient response to initial treatment is known to be associated with long-term patient outcomes, emphasizing the importance of first-line treatment selection.

Recent studies have reported several genetic mutations (variants of the same gene) suspected as being associated with treatment outcomes, however most showed conflicting results under further investigation. For example, mutations in the PTPRC gene, known to be associated with RA, were found to predict response to anti-TNF drugs in two large studies, each comprising over 1,000 patients. However, this association was not replicated in other large-scale studies. Variations in the CD84 gene, crucial for the proper development of immune cells, have been shown to be predictive of response to the anti-TNF drug etanercept (Enbrel) in a study including 733 patients. Similarly, variations in the PDE3A–SLCO1C1 gene were found to be associated with response to the TNF-inhibitors etanercept, infliximab (Remicade) and adali­mumab (Humira) in a study including 511 patients. However, neither of these associations appear sufficiently accurate to guide treatment selection for individual patients.

Since genetic studies to date have only identified markers with weak-to modest predictive value, new research is currently focused on epigenetic modifications (such as methylation) which may be associated with response to treatment. A study including 354 patients with RA revealed large differences in the methylation of genes within immune cells when compared to healthy individuals. Studies in cancer patients have showed that methylation of specific genes is associated with decreased response to methotrexate (which is used to treat RA as well as certain types of cancer). However, to date no studies have investigated the association between methotrexate responsiveness and methylation among patients with RA.

Several studies have previously demonstrated increased TNF production within cells with reduced methylation. A recent study among RA patients has also demonstrated a correlation between methylation of the TNF gene region and disease outcomes. The only study directly investigating treatment outcomes with TNF-inhibitors among RA patients is currently ongoing and compares the methylation pattern between 36 patients who achieved disease remission with etanercept treatment and 35 patients who did not. The study recently reported significant differences found in the methylation of four distinct genetic regions between the two groups.

This review suggests that genetic and epigenetic markers are a promising research avenue which may provide patients and physicians with valuable information optimizing treatment decisions in the future.

Despite promising progress, genetic and epigenetic markers are still not of sufficient predictive power to provide individual clinical information. The results of ongoing and future studies on this subject are awaited.