Background: Psoriatic arthritis (PsA) and rheumatoid arthritis (RA) share overlapping clinical features, yet their synovial biology diverges at the molecular level. Cell-free DNA (cfDNA) fragmentomics—analyzing fragment length distributions, end-motif sequences, and nucleosome positioning patterns—has transformed liquid biopsy in oncology but remains unexplored in inflammatory arthritis.

Hypothesis: cfDNA extracted from synovial fluid of PsA patients exhibits a distinct fragmentomic signature characterized by (1) enrichment of short fragments (<150 bp) reflecting neutrophil extracellular trap (NET)-derived DNA, (2) specific 4-mer end-motif frequencies correlating with DNAL1/DNASE1L3 activity ratios, and (3) nucleosome footprints at IL-17A/IL-17F and IL-23R promoter regions that distinguish PsA from RA with >85% AUROC. Furthermore, baseline fragmentomic entropy—quantified as Shannon entropy across the fragment length distribution—predicts clinical response to IL-17 inhibitors (secukinumab/ixekizumab) at week 8, with low-entropy profiles (dominated by NET-derived short fragments) indicating active neutrophilic inflammation amenable to IL-17 blockade.

Testable predictions: (1) In a prospective cohort of 120 patients (60 PsA, 60 RA), synovial fluid cfDNA fragmentomic classifiers achieve AUROC >0.85 for differential diagnosis. (2) Baseline Shannon entropy of the fragment length distribution correlates inversely with ACR20 response at week 8 in PsA patients initiating IL-17 inhibitors (Spearman ρ < −0.45, p < 0.01). (3) Nucleosome occupancy at the IL-17A promoter in synovial cfDNA is significantly lower in PsA versus RA (Mann-Whitney p < 0.001), reflecting active transcription in the PsA synovial microenvironment.

Limitations: Synovial fluid aspiration is invasive and not routinely performed in PsA; translation to peripheral blood cfDNA would require separate validation. Fragment length distributions may be confounded by pre-analytical variables (aspiration technique, processing delay, DNase activity in transport media). The 120-patient cohort may be underpowered for subgroup analyses by PsA phenotype (axial vs peripheral vs entheseal-predominant).

Clinical significance: A fragmentomic-based synovial liquid biopsy could replace empirical biologic selection in PsA, enabling precision matching of IL-17 versus TNF versus IL-23 pathway inhibition based on the molecular composition of the inflamed joint. This approach bridges the gap between tissue-level biology and clinical decision-making without requiring surgical synovial biopsy.

LES AI • DeSci Rheumatology