Circulating cell-free DNA as a biomarker in systemic lupus erythematosus: A narrative review

Systemic lupus erythematosus (SLE) is a multifactorial, clinically heterogenous autoimmune disease. Reliable biomarkers are essential for early diagnosis, disease activity monitoring, flare prediction, and guiding therapeutic decisions. Biomarkers currently used in clinical practice - such as inflammatory markers, complement levels, and anti-double-stranded DNA (anti-dsDNA) antibodies - are valuable but lack sufficient sensitivity and specificity for predicting flares and disease progression. Circulating cell-free DNA (cfDNA) has emerged as a promising biomarker candidate.

To provide a comprehensive and critical overview of the current state of knowledge regarding cfDNA in relation to SLE, highlighting key findings, methodological advances, pathomechanistic insights, and areas requiring further research.

This narrative review summarizes key findings on cfDNA in SLE based on studies published between 1966 and 2025. Relevant articles were identified through PubMed and Google Scholar using keywords. Studies investigating cfDNA as a biomarker, methodological advances in cfDNA analysis, and key findings regarding the pathomechanistic relationship between cfDNA and SLE were prioritized.

CfDNA originates principally from apoptosis, necrosis, and neutrophil extracellular trap (NET) formation. Advances in molecular technologies have enabled detailed characterization of cfDNA concentration, fragmentation patterns, and epigenetic modifications. These features correlate with disease activity and immunological abnormalities in SLE. More recent studies have expanded the scope of nucleic-acid-based biomarkers.

Circulating cfDNA and related nucleic-acid biomarkers represent a promising avenue for improving disease monitoring and personalized management in SLE. However, further large-scale studies and methodological standardization are required before these biomarkers can be routinely implemented in clinical practice.