DNA hypo-methylation of the TNFA gene predicts response to MTX in RA but not in PsA.

OBJECTIVES

The 'Treat-to-Target' approach significantly improves treatment outcomes in RA and PsA (RA/PsA). MTX is commonly used as a first-line treatment upon diagnosis. However, 50-70% of treated patients do not achieve clinical remission after 6 months. We previously developed a quantitative methylation-sensitive qPCR (qMSP) assay to quantify DNA-methylation levels of the TNFA gene. We demonstrated its predictive value for RA diagnosis. Here, we assessed the utility of this qMSP assay for predicting MTX treatment outcome and investigated changes in DNA-methylation levels after 6 months of MTX.

METHODS

Early untreated RA (n = 201) and PsA (n = 77) were included with healthy controls (n = 39). The TNFA-qMSP assay was performed by qPCR on bisulphite-converted DNA extracted from frozen peripheral blood mononuclear cells. The outcome predictive-value of DNA-methylation levels was analysed using binary logistic regression and area under the curve (AUC).

RESULTS

Pre-treatment DNA-methylation levels of the TNFA gene were reduced in RA (P = 1.8 × 10-13) and PsA (P = 0.007) compared with controls. Higher DNA-methylation levels were associated with MTX-induced remission in RA (AUC = 0.721) and substantially improved the performance of a predictive model when combined with clinical data (AUC = 0.760) compared with clinical data only (AUC = 0.699). Levels of methylation reduced over time, irrespective of response to MTX in RA. In PsA, DNA-methylation levels were not associated with treatment outcome.

CONCLUSION

The TNF qMSP assay has potential clinical utility as a biomarker for predicting MTX-induced remission specifically in early RA, but not in PsA. However, MTX does not appear to prevent the reduction of DNA-methylation levels at the TNFA loci over time.