Lowering Rheumatoid Arthritis Risk in Highly Susceptible Populations Through Patient Education

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Environmental factors such as cigarette smoking have been associated higher RA risk.
Environmental factors such as cigarette smoking have been associated higher RA risk.

Improved understanding of the underlying pathophysiologic mechanisms of rheumatoid arthritis (RA) has resulted in the development of an armamentarium of non-biologic and biologic disease-modifying anti-rheumatic drugs (DMARDs). Implementation of the well-established guideline, which recommended a strategy of early treatment to target to achieve low disease activity or disease remission, has resulted in significant improvement in disease management and patient outcomes.1 

Despite an improved understanding of the pathophysiologic mechanisms of RA, the underlying etiology remains less well defined and is poorly understood. However, it is thought to involve a complex interplay of genetic and environmental factors in susceptible individuals.

The genetic and environmental association of RA helps to explain the variation in treatment response from one patient to the next and offers an opportunity to modify individual risk factors and thereby influence patient outcomes. Indeed, the clustering of RA among family members suggests a strong genetic link, and this is supported by the identification of specific alleles within defined loci in the human leukocyte antigen (HLA) system that are associated with increased risk for the development of anti-citrullinated protein antibody-positive and anti-citrullinated protein antibody-negative RA. 

There is now compelling evidence from registries and from several studies, including those involving twins, that allude to family history as one of the strongest risk factors for RA, conferring a two- to four-fold increased risk among first-degree relatives. 

The heritability of RA has been estimated at approximately 60%.2-6 The presence of the shared epitope alleles at HLA-DRB1 and detectable levels of RA-related auto-antibodies (including rheumatoid factor and anti-cyclic citrullinated peptide antibodies) in the serum prior to symptom onset elevates the risk for RA.7-9 

The contribution of the HLA gene alone to RA heritability has been estimated to be 11% to 37%. Other genes such as PTPN22, STAT4, CTLA4, TRAF1, PADI4, IRF5, FCRL3, TNFIP3, TNF-α, miRNAs, CD28, CD40, and TYK2 have been associated with susceptibility to, severity of, activity of, and treatment response to RA.6 

Family history of related arthritic disease may also be a useful predictor of RA, although there is variation in the degree of association, and a family history of systemic lupus erythematosus or juvenile idiopathic arthritis is a better predictor of RA, compared with family history of osteoarthritis or unspecified joint pain.2

Despite a strong genetic association with the development of seropositive and seronegative RA, genetics does not explain all RA risk. Environmental factors such as cigarette smoking, alcohol consumption, body mass index, and physical activity have also been associated higher RA risk.10-14 

Sex and age at disease onset have been suggested as other factors that modify familial RA aggregation; however, evidence for the latter association is inconclusive because of the small and possibly non-generalizable samples that have been studied.15,16 Approximately 25% of RA risk may be from cigarette smoking alone, whereas a combination of risk factors (smoking, alcohol intake, obesity, and reproductive factors) may account for up to 41% of RA risk.17,18

The genetic association of RA can help explain the variation in treatment response from one patient to the next. Despite highly effective DMARDs and a treat-to-target strategy, not all patients respond optimally. Many continue to experience pain, disability, and joint destruction, even after treatment with the widely used and generally effective methotrexate and targeted biologic agents. 

In fact, between 30% and 40% of those with RA do not respond to anti-TNF-α agents, and in clinical trials of anti-TNF therapies, remission was achieved in fewer than 50% of patients.19,20 Single-nucleotide polymorphism has been identified as predictive of methotrexate response; non-response was associated with genetic polymorphism among SLC22A11 and ABCC1 carriers.21 

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 germline genetic variation as a biomarker of treatment response offers distinct advantages over conventional biomarkers because germline 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. 

Non-genetic biomarkers, such as gene expression signatures can show very strong correlation with clinical response to drug treatment, and combining genetic and non-genetic measurements is a promising path forward in the effort to develop predictive biomarkers. This avenue 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 pre-treatment predictions of treatment outcome. Determining the clinical utility of genotyping, however, requires more extensive research and large-scale multi-center 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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