Seropositivity-Dependent Association between LINE-1 Methylation and Response to Methotrexate Therapy in Early...

Area of Science:

• Rheumatology
• Epigenetics
• Genomics

Background:

• Methotrexate (MTX) is a primary treatment for rheumatoid arthritis (RA).
• Treatment response to MTX varies significantly, with up to 40% of patients showing inadequate response.
• Predictive biomarkers for MTX efficacy are needed to optimize early RA treatment.

Purpose of the Study:

• To investigate the potential of long interspersed nucleotide element-1 (LINE-1) methylation as a predictive biomarker for MTX response in early RA patients.
• To assess the association between baseline LINE-1 methylation levels and MTX treatment outcomes.

Main Methods:

• A prospective study involving 273 treatment-naïve early RA patients treated with MTX for 12 months.
• Assessment of baseline LINE-1 methylation levels in peripheral blood mononuclear cells (PBMCs) using bisulfite pyrosequencing.
• Stratification of patients based on rheumatoid factor (RF) and anti-citrullinated protein antibody (ACPA) status (double-positive vs. seronegative).

Main Results:

• Baseline LINE-1 methylation levels alone did not predict MTX response.
• An inverse association was observed between LINE-1 methylation and MTX response, dependent on serological status.
• Hypermethylated LINE-1 was associated with optimal response in double-positive RA patients (p=0.002), while hypomethylated LINE-1 was linked to response in seronegative patients (p=0.01).

Conclusions:

• LINE-1 methylation levels in PBMCs of early RA patients correlate with MTX treatment response.
• The association between LINE-1 methylation and MTX response differs based on the presence or absence of RF and ACPA antibodies.
• LINE-1 methylation serves as a potential epigenetic biomarker for predicting MTX response in both seropositive and seronegative early RA patients.