Interferon-induced Protein 44-like Promoter Hypomethylation as an Epigenetic Hallmark of Systemic Lupus Erythematosus

Background Systemic lupus erythematosus (SLE) lacks sensitive biomarkers for early detection and longitudinal monitoring. While IFI44L promoter hypomethylation has emerged as a potential epigenetic hallmark, its dynamics across the clinical spectrum ranging from pre-clinical stages to treatment response remain largely undefined. This study investigated IFI44L methylation across the SLE continuum to evaluate its performance in early diagnosis, disease activity assessment, and monitoring therapeutic response. Methods In this cross-sectional study incorporating a longitudinal component, IFI44L promoter methylation was quantified by methylation-sensitive high-resolution melting analysis in 566 participants: healthy controls (HC, n = 106), first-degree relatives of SLE patients (at-risk, n = 27), incomplete lupus erythematosus (ILE, n = 68), classified SLE (active, n = 124; stable, n = 62), and an independent validation cohort of patients with other connective tissue diseases (CTDs, n = 179). Differences between groups were analyzed using non-parametric tests. ROC curves, Spearman’s correlation, and Wilcoxon signed-rank tests were employed to assess diagnostic performance, clinical associations, and treatment response, respectively. Results IFI44L promoter methylation exhibited a stepwise decline across the SLE continuum (p < 0.001), with the highest levels in HCs and the lowest in active SLE. Hypomethylation (defined as < 0.25) was present in 18.5% of at-risk individuals, 47.1% of ILE, and 90.5% of treatment-naïve SLE patients. It effectively distinguished SLE from HCs (AUC 0.892; sensitivity 78.5%, specificity 100%) and other CTDs (AUC 0.856; sensitivity 78.5%, specificity 92.7%), outperforming anti-dsDNA and anti-Sm antibodies in ILE. Among classified SLE patients, IFI44L promoter methylation levels were significantly lower in active versus stable SLE (p < 0.001). Lower methylation correlated with specific organ involvement (mucocutaneous, serositis, vasculitis, severe nephritis), high disease activity (SLEDAI-2K: r=-0.406, p < 0.001), and specific autoantibody profiles. Longitudinal analyses demonstrated significant increases in IFI44L methylation following induction therapy (p = 0.018). Conclusions Hypomethylation of IFI44L promoter represents a dynamic, disease-specific epigenetic alteration across the SLE continuum. It demonstrates strong diagnostic accuracy for both definitive SLE and incomplete disease, correlates with disease activity, and is modifiable with treatment. These findings support its potential as a versatile biomarker to enhance early detection and monitoring.