Navarro-Mendoza, Erika

Objective Antiphospholipid syndrome (APS) is a thromboinflammatory disorder characterized by clinical and mechanistic heterogeneity that complicates early diagnosis and hinders targeted treatment. We aimed to identify distinct molecular endotypes among antiphospholipid antibody (aPL)–positive patients using whole‐blood transcriptomics. Methods Whole‐blood RNA sequencing was performed on 174 aPL‐positive patients, including those with primary APS (n = 102), secondary APS (n = 29), and aPL positivity without classifiable APS (n = 43). Unsupervised machine learning and immune cell deconvolution defined transcriptomic clusters and immune landscapes. Results Four transcriptionally distinct clusters were identified. At one end of the spectrum, cluster 1 showed up‐regulation of ribosomal and metabolic pathways and down‐regulation of mechanistic target of rapamycin (mTOR), NETosis, and Hippo/interleukin‐6 (IL‐6) signaling. In contrast, cluster 4 exhibited the opposite pattern, with strong up‐regulation of mTOR, NETosis, and Hippo/IL‐6 signaling. Cluster 2 demonstrated modest enrichment in messenger RNA processing and amino acid metabolism, and cluster 3 showed biosynthetic suppression with mild Hippo/IL‐6 activation. Clinically, cluster 4 stood out with higher IgG anticardiolipin and anti–β 2 ‐glycoprotein I positivity, elevated neutrophil counts, and increased urine protein‐to‐creatinine ratios. Immune deconvolution revealed distinct cell type profiles: cluster 1 was lymphoid predominant; cluster 2 had a balanced composition; cluster 3 was enriched in Treg cells, natural killer cells, macrophages, mast cells, and memory B cells; and cluster 4 was dominated by myeloid cells, including neutrophils, eosinophils, and dendritic cells. Distinct immune pathway activations were linked to clinical features, including white matter lesions, seizures, and cardiac valve disease. Conclusion This study reveals four endotypes of aPL‐positive patients, a step toward personalized medicine for APS through pathway‐informed stratification and therapy.

ABSTRACT This review provides an in-depth analysis of glucocorticoid therapy for lupus nephritis (LN), a severe manifestation of systemic lupus erythematosus that affects up to 51.7% of patients. LN significantly increases the risk of mortality and progression to end-stage kidney disease. Glucocorticoids have been central to LN treatment for decades due to their anti-inflammatory properties, but optimal dosing strategies remain uncertain. The review discusses the historical evolution of glucocorticoid use, highlighting the shift from high-dose regimens to combined approaches with immunosuppressants and lower glucocorticoid doses to minimize adverse effects. Mechanistically, glucocorticoids exert effects through genomic and non-genomic pathways, modulating immune responses and metabolism. Long-term use is associated with risks such as infection, osteoporosis, hyperglycemia and cardiovascular disease. The review examines different dosing strategies, including intravenous pulse therapy and oral regimens, and presents evidence of their efficacy and safety. It also explores alternative approaches, such as low-dose and glucocorticoid-free regimens, which show promise but require further study. The review concludes by emphasizing the need for future research to optimize glucocorticoid regimens, refine tapering protocols and identify safer therapeutic combinations, as glucocorticoids remain a cornerstone in LN management despite their challenges.