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

医学 内型 免疫学 转录组 生物信息学 羟基氯喹 疾病 狼疮性肾炎 生物标志物 内科学 个性化医疗 系统性红斑狼疮 CD38 红斑狼疮 细胞因子 CXCL1型 肿瘤科 临床试验 计算生物学 精密医学 CD19 队列 微阵列 美罗华
作者
Lorenzo Beretta,Chiu Wai Shirley Chan,Georgia-Savina Moysidou,Danae-Mona Nöthling,Alexandra Ainatzoglou,A. Zoli,Spyridon Katechis,Antonis Fanouriakis,Aline Bözec,Prodromos Sidiropoulos,Christina Bergmann,Dimitrios T. Boumpas,Georg Schett,George Bertsias,Panagiotis Garantziotis
出处
期刊:Journal of Autoimmunity [Elsevier BV]
卷期号:159: 103525-103525
标识
DOI:10.1016/j.jaut.2026.103525
摘要

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 L1000CDS2 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.

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