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Similar variations in response associated with genetic polymorphism have been reported for other RA therapies, including variation in toxicity to azathioprine, allopurinol hypersensitivity, and variability of tacrolimus pharmacokinetics.22
The use of genetic polymorphism as a predictive tool in clinical practice offers an important strategy to identify those who are likely to benefit from treatment. It has important economic and health outcomes implications as well, such as avoiding exposure to unnecessary adverse events or expensive treatment in those who are unlikely to respond. Indeed, variability in response to expensive anti-TNF-α agents has prompted efforts to identify biomarkers that are predictive of response.
This has included multiple genome-wide association studies intended to provide unbiased scans for variants associated with response, although studies to date have been inconclusive, with very few examples of clinically useful pharmacogenetic biomarkers.22
However, the potential of germ-line genetic variation as a biomarker of treatment response offers distinct advantages over conventional biomarkers because germ-line genetic variation is stable throughout a person’s lifespan such that genetic variants can be measured well ahead of clinical need using relatively inexpensive analytic assays. In fact, large-scale preemptive genotyping is already in progress across multiple healthcare systems.
Nongenetic biomarkers, such as gene-expression signatures, can show very strong correlation with clinical response to drug treatment, and combining genetic and nongenetic measurements is a promising path forward in the effort to develop predictive biomarkers. This may provide the best predictive signature of treatment outcome.22
The involvement of environmental risk factors suggests that behavior may account for a substantial proportion of RA risk, and these factors can be modified to change RA risk and outcomes. Risk models based on family history and epidemiologic and genetic factors show that seropositive and seronegative RA are highly discriminatory. Therefore, assessing epidemiologic and genetic factors among individuals with positive family history of RA may identify those suitable for RA prevention strategies.23
Personalized risk education may be an important method to encourage those at increased risk for RA to change behaviors and potentially modify their risk. The Personalized Risk Estimator for Rheumatoid Arthritis (PRE-RA) family study risk assessment and education study was designed to assess willingness to change RA-related behaviors.24,25
The investigators hypothesized that participants who received personalized RA risk tools and health education would be more willing to change RA risk behaviors compared with participants who received standard RA information. This study is important because it provides a rationale for RA prevention efforts in the clinical setting among individuals with genetic predisposition to the disease.
Summary and Clinical Applicability
Compelling evidence suggests a strong genetic association in the risk for RA, which is modified by environmental factors including smoking, alcohol consumption, sex, and age. Genetic polymorphism has been used to explain the variation in RA treatment response. Genotyping patients according to their genetic markers may have important clinical application in pretreatment predictions of treatment outcome. Determining the clinical utility of genotyping, however, requires more extensive research and large-scale multicenter studies. The influence of environmental factors in modifying genetic risk for RA suggests that personalized risk assessment and patient education to encourage modification of risk factors may reduce the risk for RA disease and improve outcomes.
References
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