Improved understanding of the underlying pathophysiologic mechanisms of rheumatoid arthritis (RA) has resulted in the development of an armamentarium of nonbiologic and biologic disease-modifying antirheumatic 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 anticitrullinated protein antibody-positive and anticitrullinated protein antibody-negative RA. 


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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 twofold to fourfold 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 autoantibodies (including rheumatoid factor and anticyclic 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

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Despite a strong genetic association for 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 with modifying 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 nongeneralizable 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; nonresponse was associated with genetic polymorphism among SLC22A11 and ABCC1 carriers.21