To Örebro University

Background: The management of neuropsychiatric (NP) systemic lupus erythematosus (SLE) is poorly optimised and specific treatment is lacking.

Objectives: The aim of this study was to perform an in-depth investigation of the transcriptome of SLE patients with active central nervous system (CNS) involvement to gain insights into underlying molecular mechanisms and identify new potential drug targets for CNS lupus.

Methods: We analysed differentially expressed genes in peripheral blood from patients with active CNS lupus (n=26) and active non-NP SLE (n=43) versus healthy controls (n=497) from the European PRECISESADS project (NTC02890121), as well as dysregulated gene modules. Gene modules were subjected to correlation analyses with serological markers, and regulatory network and druggability analysis.

Results: Unsupervised co-expression network analysis revealed 23 dysregulated gene modules. Four showed differential dysregulation between two distinct subgroups of CNS lupus patients. The interferon module was upregulated in both subgroups. The “B cell”, “T cell”, “cytotoxic/NK cell”, and “mitochondrial cluster” gene modules were all found to be more downregulated in one subgroup, while the other subgroup showed varied dysregulation patterns. Drugs annotated to the cytotoxic/NK cell network included pegaptanib, a selective vascular endothelial growth factor (VEGF) antagonist, while many anticonvulsants such as zonisamide, lamotrigine, and oxcarbazepine showed potential for counteracting the transcriptomic signature associated with the B cell module. Druggability analysis for the mitochondrial cluster module revealed potential for the centrally acting angiotensin-converting enzyme inhibitor captopril, the mammalian target of rapamycin (mTOR) inhibitor everolimus, the proteasome inhibitor bortezomib, the toll-like receptor 5 (TLR5) agonist entolimod, and the spleen tyrosine kinase (SYK) inhibitor fostamatinib. In silico prediction algorithms demonstrated a greater anticipated response to anifrolumab and calcineurin inhibitors for the active CNS subgroup with B cell, T cell, cytotoxic/NK cell, and mitochondrial gene downregulation compared with the patient subgroup of mixed dysregulation patterns.

Conclusion: In this cohort of SLE patients of European origin, B cell, T cell, cytotoxic/NK cell, and mitochondrial gene dysregulation patterns separated active CNS lupus patients into two distinct subgroups with differential anticipated response to type I interferon and calcineurin inhibition. Our study provides a conceptual framework for precision medicine in CNS lupus.