Genetic Polymorphisms Underlying Treatment Response Variations in RA

Slideshow

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  Genetic Polymorphisms and Rheumatoid Arthritis

  The genetic and environmental associations of rheumatoid arthritis (RA) help to explain the variation in treatment response from one patient to the next [1] and offers an opportunity to modify individual risk factors, and thereby influence patient outcomes.

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  Specific Human Leukocyte Antigen Alleles Associated With RA

  The clustering of RA among family members suggests a strong genetic link, 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. [3]

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  Family History: A Strong Determinant of RA Risk

  Family history is one of the strongest risk factors for RA, conferring a twofold to fourfold increased risk among first-degree relatives. [2] The heritability of RA has been estimated at approximately 60%. [2]

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  Shared Epitope Alleles and RA-Related Autoantibodies

  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. [2]

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  Human Leukocyte Antigen and the Genetic Predisposition to Developing RA

  The contribution of the HLA gene alone to RA heritability has been estimated to be 11% to 37%. [1] 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. [1]

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  The Use of Nongenetic Biomarkers in RA

  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.[6]

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  How Genetics Can Help Explain Variability in Treatment Responses

  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. [4]

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  Genetic Polymorphisms Predictive of Treatment Response

  Single nucleotide polymorphism has been identified as predictive of methotrexate response; nonresponse was associated with genetic polymorphism among SLC22A11 and ABCC1 carriers. [5] 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.

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  Personalized Medicine and Genetic Testing to Predict Treatment Response

  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. [6]

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  Are Biomarkers of Treatment Response the Future of RA Treatment?

  The potential of germ-line genetic variation as a biomarker of treatment response offers distinct advantages over conventional biomarkers; 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. [6]