DNA hypomethylation in inflammatory arthritis: reversal with methotrexate

This study investigated whether methotrexate, by interrupting the methyl transfer function of folate, can induce genomic DNA hypomethylation in patients with inflammatory arthritis. Consecutive subjects with inflammatory arthritis (rheumatoid or psoriatic), who were taking methotrexate (n = 7) or other medications (n = 6), and control subjects, either healthy or with osteoarthritis and taking nonsteroidal anti-inflammatory agents only (n = 9) were recruited. The methylation status of genomic DNA from peripheral blood mononuclear cells was determined. Plasma levels of folate, B12, and pyridoxal-5'-phosphate (PLP), all of which are involved in biologic methylation, were also examined. The extent of genomic DNA methylation was lowest in subjects with inflammatory arthritis who were not taking methotrexate, highest in subjects with inflammatory arthritis who were taking methotrexate, and intermediate in control subjects (p < 0.05). Plasma levels of folate and B12 were similar among the three groups. The mean plasma PLP level in subjects with inflammatory arthritis was 33% lower than that in control subjects (p = 0.04). No significant correlation between genomic DNA methylation and folate, B12, and PLP levels was observed. These data do not support the hypothesis that methotrexate induces genomic DNA hypomethylation. However, these data indicate that inflammatory arthritis is associated with genomic DNA hypomethylation that is reversed with methotrexate. Future studies using a larger number of subjects are warranted to confirm these findings.