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Differential DNA Methylation & Response to Methotrexate in RA

Change in therapy as early as 4 weeks in patients with rheumatoid arthritis (RA) correlated with improvement in disease activity, a new study found. Researchers investigated differential DNA methylation as a candidate biomarker of response for methotrexate. DNA methylation was measured in DNA samples from individuals recruited to the Rheumatoid Arthritis Medication Study. Differentially methylated positions were compared between the whole blood samples collected at baseline and at 4 weeks from patients who, by 6 months, had a good (n=34) or poor response (n=34) to methotrexate using linear modeling, adjusting for gender, age, cell consumption, baseline 28-joint disease activity score (DAS28) and smoking status. Among the findings:

  • ≥40% of RA patients do not respond adequately treatment.
  • 4 CpGs measured after 4 weeks of treatment correlated with improvement in disease activity.
  • Integrating CpGs with other early biomarkers may predict improvement in disease activity at 6 months.


Nair N, et al. Differential DNA methylation correlates with response to methotrexate in rheumatoid arthritis. [Published online ahead of print October 10, 2019]. Rheumatology. doi:10.1093/rheumatology/kez411.


With the growing acceptance that prolonged uncontrolled joint inflammation in RA can lead to long-term joint damage and disability, there continues to be significant interest in predicting response to therapy to allow for more effective use of available treatments. This UK-based study looked at RA patients initiating methotrexate therapy and measured DNA methylation at 0 and 4 weeks as well as clinical disease measures at 0 and 6 months. A good clinical response at 6 months correlated to differential DNA methylation at 2 sites (DMPs) at 4 weeks after initiation of methotrexate (though not at baseline) and improvement in DAS components such as swollen joints and CRP correlate to 10 other DMPs, potentially due to differential activity of methotrexate in the good responders. Of these 12 DMPs, 4 were replicated in an independent group of RA patients from the same methotrexate study, suggesting that they may be of use in identifying methotrexate responders within 4 weeks of initiation of therapy, allowing for a quicker switch to alternate therapy and hopefully prevention of joint damage.Arundathi Jayatilleke, MD