From the Journals

DNA methylation changes: An early biomarker for methotrexate response?



An investigation into a potential biomarker for response to methotrexate found that changes in DNA methylation at 4 weeks were associated with improvements in rheumatoid arthritis (RA) patients at 6 months.

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“The findings in the current study are promising and appear to identify methylation patterns that are predictive of improvement of SJC [swollen joint count] and CRP [C-reactive protein],” wrote Nisha Nair, PhD, of the University of Manchester (England) and her coauthors. The study was published in Rheumatology.

The investigators analyzed DNA samples taken from patients recruited into the Rheumatoid Arthritis Medication Study (RAMS) who had RA or inflammatory polyarthritis and were beginning methotrexate for the first time. The samples were collected at baseline and at 4 weeks from patients who were classified as having good (n = 34) or poor (n = 34) responses to methotrexate after 6 months according to European League Against Rheumatism response criteria, in which good response was defined as having a 28-joint disease activity score (DAS28) of 3.2 or less and a 1.2-point improvement in DAS28 at 6 months, and poor response was defined as having DAS28 higher than 5.1 and improvement of 0.6 points or less at 6 months.

After analysis, two differentially methylated positions that differed between good and poor responders were identified in samples taken at the 4-week mark (P less than 1 × 10–6). Four CpG (cytosine-phosphate-guanine) sites also predicted improvements in RA patients at 6 months: Two sites associated increased methylation in good responders at 4 weeks with long-term SJC improvement, while two others associated increased methylation at baseline and in good responders at 4 weeks with improvement of CRP levels.

The authors acknowledged their study’s limitations, including the fact that the relapsing nature of RA could have contributed to natural variance in DAS28. In addition, the study’s lack of a control group does not allow for separating prognostic from theranostic biomarkers, although they added that “in terms of selecting treatments that will be effective, that may not necessarily matter in the clinical setting.”

The study was funded by the Medical Research Council and Versus Arthritis. The authors reported no conflicts of interest.

SOURCE: Nair N et al. Rheumatology. 2019 Oct 10. doi: 10.1093/rheumatology/kez411

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