Background: Primary antiphospholipid syndrome (pAPS) is an autoimmune disease that, unlike 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 broadermolecular landscape compared with other autoimmune diseases remains unknown.

Objectives: We aimed to compare bulk RNA sequencing-derived transcript-based signatures of pAPS with transcriptomic signatures in healthy individuals and in patients with non-APS autoimmune diseases.

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

Results: A total of 85 upregulated and 10 downregulated differentially expressed genes (DEGs) were detected in pAPS compared with HC, 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 across 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/II IFN signalling and complement pathways in pAPS versus SLE. Moreover, type I and II IFN signalling was significantly downregulated in pAPS compared to SjD or SSc. WGCNA identified 19 modules of co-expressed genes, with pAPS being 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 gradience in the upregulation of IFN-related genes across these diseases. Within pAPS, a history of miscarriages was positively associated with the “methylation” gene module, while thrombocytopenia was negatively associated with the “T cell” gene modules. Deconvolution analysis showed that patients with pAPS exhibited significant alterations in proportions of neutrophils, NK, naïve T, and memory T cells compared to HC.

Conclusions: Primary APS exhibits a distinct molecular profile within the spectrum of autoimmune diseases, marked by a modest activation of interferon signalling, less pronounced than the interferon signalling seen in SLE, SSc, or SjD.

REFERENCES: [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.

[2] Casares-Marfil D, et al. Sawalha AH. A Genome-Wide Association Study Suggests New Susceptibility Loci for Primary Antiphospholipid Syndrome. Arthritis Rheumatol. 2024 Nov;76(11):1623-1634. doi: 10.1002/art.42947. Epub 2024 Aug 11. PMID: 38973605; PMCID: PMC11521773.

Acknowledgments: NIL.

Disclosure of Interests: Dionysis Nikolopoulos: None declared, Konstantinos Charitidis: None declared, Lorenzo Beretta: None declared, Julius Lindblom: None declared, Guillermo Barturen: None declared, Marta Alarcon-Riquelme: None declared, Ioannis Parodis AstraZeneca, GSK, Novartis, Otsuka, Roche, Biogen, BMS,

GSK, Janssen, Novartis, Otsuka, Roche, UCB, Viatris, Amgen, AstraZeneca, Aurinia, BMS, Elli Lilly, Gilead, GSK, Novartis, Otsuka, Roche, Viatris.