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Genetic and epigenetic predictors of responsiveness to treatment in RA

Key Points

  • In rheumatoid arthritis (RA), patient responsiveness to the first-line treatment used is the most important predictor of long-term disease outcomes

  • Identifying predictive biomarkers of response to the drugs most commonly used in RA is, therefore, a research priority

  • Genetic studies of responsiveness to treatment in RA have revealed a small number of robust associations

  • Only two genetic polymorphisms, within CD84 and the PDE3A–SLCO1C1 locus, have been associated with responsiveness to treatment at or approaching accepted levels of genome-wide significance

  • In general, epigenetic changes in RA remain underexplored, and studies investigating this aspect hold promise for correlating genetics and gene expression data with outcomes of treatment

  • Responsiveness to treatment is probably multifactorial, and thus accurate measurement of therapeutic responses will be a key factor in the discovery of predictive biomarkers

Abstract

Methotrexate and TNF-blocking agents are the DMARDs most commonly prescribed for the treatment of rheumatoid arthritis (RA). However, not all patients treated with these nonbiologic and biologic DMARDs respond satisfactorily and few predictors of treatment efficacy have been identified, despite the fact that these therapies have now been available for many years. Many studies have investigated genetic factors that might predict patient responsiveness to therapies used to treat RA, and epigenetic studies regarding response to treatment are expected to accumulate in the literature in the near future. Herein, we review the advances in identifying genetic and epigenetic predictors of therapeutic responses to methotrexate and/or TNF inhibitors in RA that have been made to date, and highlight important considerations for future studies, such as the need for an improved, preferably biological, outcome measure reflecting response to treatment.

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Figure 1: Potential approach to stratified medicine in RA.
Figure 2: Pretreatment DNA methylation status as a predictive biomarker of response to treatment.

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Plant, D., Wilson, A. & Barton, A. Genetic and epigenetic predictors of responsiveness to treatment in RA. Nat Rev Rheumatol 10, 329–337 (2014). https://doi.org/10.1038/nrrheum.2014.16

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