Background: Systemic lupus erythematosus (SLE) with antiphospholipid syndrome (APS) represents one of the most challenging endotypes of SLE, yet its distinctive molecular basis from non-APS SLE remains elusive.

Objectives: To comprehensively profile the blood transcriptome of a large cohort of SLE patients who had APS or tested positive for aPL, to advance our understanding and introduce novel therapeutic interventions.

Methods: We analyzed whole blood RNA-sequencing data from 299 SLE patients (108 aPL-positive SLE; 67 APS/SLE; 191 aPL-negative SLE defined as non-APS/SLE) and 72 sex/age-matched healthy controls (HC). Differentially expressed genes (DEGs) were subjected to pathway enrichment analysis and protein-protein interaction networks. Unsupervised WGCNA analysis and machine learning (ML) were applied to distinguish disease endotypes.

Results: Our analysis revealed 1338 DEGs in APS/SLE compared to HC with upregulation of pathways related to IFN-α, INF-γ, complement, oxidative stress, and neutrophil degranulation. Comparison between APS/SLE and non-APS/SLE patients revealed 227 DEGs with downregulation of IFN-α and IFN-γ signatures, along with dysregulation of complement cascade, B-cell activation, and neutrophil degranulation. We found a group of 100 genes that discriminated APS/SLE from HC (specificity=71%, sensitivity=80%, AUC=0.80), including the key transcription factor SPIB that regulates the expression of IFIT1b, BCR, MPO and MMP9 . Unsupervised analysis identified 21 gene modules with APS/SLE strongly linked to upregulation of “neutrophilic/myeloid response” module. Of interest, venous thromboses positively correlated with “neutrophilic/myeloid response” and “B cell” modules, while arterial thromboses were associated with dysregulation of “DNA damage response (DDR)” and “metabolism” modules. Anti-cardiolipin and anti-β2GPI positivity irrespective of APS status was associated with “neutrophilic/myeloid response” and “protein-binding” modules, respectively.

Conclusion: Dysregulation of a group of 227 DEGs underlies the APS phenotype in SLE, characterized by downregulation of IFN-α and IFN-γ signatures along with dysregulation of complement cascade, B-cell activation, and neutrophil degranulation. In APS/SLE patients, venous thrombotic events are mediated by neutrophils and B cells, while arterial events are orchestrated by DDR and impaired metabolism mechanisms; these differences may account in part for the differences in the therapeutic intensity of the anticoagulants used and response to immune modulators (sirolimus)[1].

REFERENCES: [1] Canaud, Guillaume, et al. “Inhibition of the mTORC pathway in the antiphospholipid syndrome.” New England Journal of Medicine 371.4 (2014): 303-312.

Acknowledgements: NIL.

Disclosure of Interests: None declared.