0125: The IFN Signature is Less Pronounces in Primary Antiphospholipid Syndrome Compared with other Systemic Autoimmune Diseases

Background/Purpose: Primary antiphospholipid syndrome (pAPS) is an autoimmune disease that, unlike many other autoimmune diseases, commonly presents with thrombotic events rather than inflammatory manifestations. A peripheral type I interferon (IFN) signature distinguishes patients with pAPS from healthy individuals, but its broader molecular landscape compared with other autoimmune diseases remains unknown.

Methods: We analysed bulk RNA sequencing data from whole blood obtained from patients with pAPS (n=83), systemic lupus erythematosus (SLE; n=249), Sjögren’s disease (SjD; n=253), systemic sclerosis (SSc; n=247), and 497 matched healthy controls (HC) from the PRECISESADS project (NCT02890121). We applied supervised pathway enrichment analysis, unsupervised weighted gene co-expression network analysis (WGCNA), and deconvolution analysis to characterise the molecular profile of pAPS.

Results: A total of 85 upregulated and 10 downregulated differentially expressed genes (DEGs) were found in patients with pAPS compared with HC, including genes indicating an overall upregulation of type I and II IFN signalling, complement cascade, and coagulation in pAPS, coupled with differentially enriched neutrophil degranulation and monocyte chemotaxis pathways. However, only 15 of those genes were uniquely differentially expressed in patients with pAPS compared with those with any other of the investigated autoimmune diseases. The comparison between pAPS and SLE revealed 334 DEGs (71 up- and 263 downregulated). Enrichment analysis revealed downregulation of type I and II IFN signalling and complement cascade pathways in pAPS versus SLE. Moreover, type I and II IFN signalling was significantly downregulated in pAPS compared to SjD or even SSc. WGCNA identified 19 modules of co-expressed genes, with pAPS strongly linked only to upregulation of the “IFN” module compared to HC. However, the upregulation of the “IFN” gene module was more pronounced in SLE, SjD and SSc compared with pAPS, supporting a gradient in the upregulation of IFN-related genes across these diseases, as previously shown for APS-SLE^1-2. Within pAPS, a history of miscarriages was positively associated with the “methylation” module, while thrombocytopenia was negatively associated with the “T cell” and “RNA processing” modules. Deconvolution analysis showed that patients with pAPS exhibited significant alterations in the proportions of neutrophils, NK, naïve T, and memory T, compared to HC. However, these differences were evident in patients with SLE compared to HC.

Conclusion: Patients with pAPS exhibit a distinct molecular profile within the spectrum of systemic autoimmune diseases, marked by a modest activation of interferon signalling.

1. Nikolopoulos D, et al. Disentangling the riddle of systemic lupus erythematosus with antiphospholipid syndrome: blood transcriptome analysis reveals a less-pronounced IFN-signature and distinct molecular profiles in venous versus arterial events. Ann Rheum Dis. 2024 Aug 27;83(9):1132-43.
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