Molecular stratification and transcriptome-guided therapeutics in systemic lupus erythematosus with insufficient treatment response

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Insufficient treatment response is common in systemic lupus erythematosus (SLE) and may be associated with progressive organ damage, yet the molecular underpinnings of treatment resistance remain elusive. RNA sequencing was performed in blood samples from 21 SLE patients who failed to achieve Lupus Low Disease Activity State after six months of treatment with cyclophosphamide (n = 9), rituximab (n = 5), or belimumab (n = 7). Molecular endotypes were identified via unsupervised clustering of Functional Analysis of Individual Microarray Expression (FAIME) scores and cluster stability was validated in an independent cohort (n = 23). Endotype-specific druggability was assessed using the L1000CDS 2 platform. The pathway-based molecular stratification revealed three major endotypes among patients with inadequate treatment response: (i) a T cell-centric cluster characterized by enrichment of PD-1 signaling and DNA damage response pathways along with downregulation of CD28 co-stimulatory signaling, indicative of T cell senescence; (ii) a cytokine-driven cluster defined by elevated IL-6 and IL-17 signaling and reduced IL-2 signaling, suggesting a Th17/Treg imbalance and potential responsiveness to cytokine inhibition or low-dose IL-2 therapy; and (iii) an inflammasome-dominant cluster. A multinomial LASSO regression-derived Molecular Endotype Classification Index (MECI) - validated via 1000-fold bootstrap resampling - demonstrated potential as a surrogate marker for endotype assignment (median AUC-ROC 0.889). Transcriptome reversal analysis suggested that patients of the T cell-dominant endotype may be more responsive to CD19 CAR-T cell therapy. In summary, distinct molecular endotypes underlie insufficient response to therapy in SLE, providing a framework for personalized treatment strategies and improved clinical trial design. • We characterized molecular mechanisms driving inadequate treatment response in SLE through transcriptome-based patient stratification. • We introduced a gene-based molecular index enabling classification of patients with insufficient treatment response into distinct molecular endotypes. • A T cell–dominant endotype potentially responsive to CD19 CAR-T cell therapy was identified. • In silico drug screening highlighted novel therapeutic candidates tailored to endotype-specific resistant disease pathways.

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