Genetic and epigenetic predictors of responsiveness to treatment in RA

Journal name:
Nature Reviews Rheumatology
Year published:
Published online


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.

At a glance


  1. Potential approach to stratified medicine in RA.
    Figure 1: Potential approach to stratified medicine in RA.

    Patients presenting to the clinic with inflammatory arthritis for the first time would be tested for predictive biomarkers of response to treatment and this data would be used to inform selection of the therapy that each patient is most likely to respond to. In reality, responsiveness to various treatments is probably multifactorial, and thus a predictive algorithm incorporating assessments of a panel of biomarkers, which could include genetic, epigenetic (DNA methylation profiles, for example) and transcriptomic factors (such as the levels of certain mRNAs, microRNAs or proteins), is likely to be necessary. Abbreviation: RA, rheumatoid arthritis.

  2. Pretreatment DNA methylation status as a predictive biomarker of response to treatment.
    Figure 2: Pretreatment DNA methylation status as a predictive biomarker of response to treatment.

    The schematic shows a simplified illustration of how a patient's baseline DNA methylation profile could act as a predictive biomarker of responsiveness to treatment. The locus shown in each panel corresponds to the same gene in two patients; for example, a gene encoding an inflammatory cytokine, such as IL-6. a | In a patient in whom DNA methylation in the promoter region of the gene is low, which is associated with active transcription, the encoded protein might be produced at high levels. In this scenario, a therapy targeting the pathway this protein is involved in—anti-IL-6 therapy, for instance—could lead, indirectly, to increased DNA methylation, restricting transcription of the gene and production of a proinflammatory mediator. This response would thus reduce or halt inflammation; therefore, this patient would be a 'responder' to the drug. b | In a patient with high levels of DNA methylation within the same promoter region, potentially indicating that inflammation in this patient is mediated by a different pathway (B-cell activation rather than IL-6 production, for example), the same treatment is unlikely to have an effect on expression of the gene, because the gene is already 'switched off'. In this case, the patient will probably be nonresponsive to therapies targeting the pathway this gene is involved in.


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Author information


  1. Arthritis Research UK Centre of Excellence for Musculoskeletal Genetics, Manchester Academy of Health Sciences, University of Manchester, Oxford Road, Manchester M13 9PT, UK.

    • Darren Plant &
    • Anne Barton
  2. School of Medicine & Medical Science, Conway Institute, University College Dublin, Belfield, Dublin 4, Ireland.

    • Anthony G. Wilson


All authors made substantial contributions to each stage of the preparation of this manuscript before submission.

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The authors declare no competing interests.

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Author details

  • Darren Plant

    Darren Plant was awarded a PhD in Complex Disease Genetics from the University of Manchester, UK, in 2005. He is currently a Research Fellow at the University of Manchester. His research is focused on genetic and genomic predictors of responsiveness to treatment with biologic drugs in RA.

  • Anthony G. Wilson

    Anthony (Gerry) Wilson is Professor of Rheumatology at the School Of Medicine & Medical Science, Conway Institute, University of Dublin, Ireland. His research interests include genetic and epigenetic influences on severity of disease and therapeutic responses in rheumatoid arthritis (RA), and functional studies on novel RA related genetic loci.

  • Anne Barton

    Anne Barton is a Professor of Rheumatology and an Honourary Consultant Rheumatologist at the University of Manchester, UK. Her research interests include the genetic basis of susceptibility to psoriatic arthritis as well as genetic and genomic predictors of response to treatment. She is Principle Investigator for the Biologics in Rheumatoid Arthritis Genetics and Genomics Study Syndicate (BRAGGSS), which was established to translate stratified medicine approaches into the clinical rheumatology setting.

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