DNA hypo-methylation of the TNFΑ gene predicts response to methotrexate in rheumatoid arthritis but not in psoriatic arthritis

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OBJECTIVES: The 'Treat-to-Target' approach significantly improves treatment outcomes in rheumatoid and psoriatic arthritis (RA/PsA). Methotrexate (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 = 1.8x10-13) and PsA (p = 0.007) compared to 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 to 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.

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