Depascale Roberto, Da Mutten Raffaele, Lindblom Julius, Cetrez Nursen, Palazzo Leonardo, Iaccarino Luca, Doria Andrea, Nikolopoulos Dionysis, Gatto Mariele, Parodis Ioannis
Division of Rheumatology, Department of Medicine DIMED, University of Padua, Padua, Italy.
Division of Rheumatology, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, Center for Molecular Medicine (CMM), Stockholm, Sweden.
Rheumatology (Oxford). 2025 Aug 1;64(8):4650-4658. doi: 10.1093/rheumatology/keaf215.
To determine SLE endotypes according to B cell immunophenotyping and serological profile and assess endotypes' response to belimumab.
We analysed data from 796 patients with SLE from the phase III trial BLISS-SC. Unsupervised machine learning employing factor analysis of mixed data (FAMD) and subsequent clustering determined endotypes based on B cell immunophenotyping and serological profiles. Cox regression was used to assess belimumab efficacy on inducing lupus low disease activity state (LLDAS) and definitions of remission in SLE (DORIS) remission within clusters.
Three endotypes were determined. Compared with each other, cluster 1 (n = 191) displayed higher proportions of CD19+CD24b+CD27+ regulatory B cells (mean ± SD: 35.9%±12.6%), CD19+CD20+CD27+ bulk memory B cells (32.2%±9.9%), CD19+CD20+CD69+ activated B cells (0.2%±0.3%), CD19+CD20-CD138+ long-lived plasma cells (0.7%±1.0%) and CD19+CD38b+CD27b+ SLE-associated plasma cells (6.6%±7.0%). Cluster 2 (n = 366) displayed higher proportions of CD19+CD24bbrightCD38bbrightCD27- transitional B cells (6.3%±9.0%) and CD19+CD20+CD27- naïve B cells (85.4%±7.2%), and lower proportions of CD19+CD20-CD138+ peripheral long-lived plasma cells (0.2%±0.3%) and CD19+CD38b+CD27b+ SLE-associated plasma cells (1.6%±2.0%). Cluster 3 (n = 239) displayed a higher proportion of CD19+CD20+CD138+ short-lived plasma cells (0.1%±0.1%) and higher serological activity, being enriched in anti-double stranded(ds)DNA, anti-ENAs, antiphospholipid antibodies and hypocomplementemia. Use of belimumab was superior to placebo in inducing sustained LLDAS [hazard ratio (HR): 2.22; 95% CI: 1.18-4.17; P = 0.014] and DORIS remission (HR: 3.45; 95% CI: 1.2-9.94; P = 0.022) in cluster 2.
Three distinct SLE endotypes were identified based on B cell immunophenotyping and serological profiles, showing differential benefit from belimumab therapy.
根据B细胞免疫表型和血清学特征确定系统性红斑狼疮（SLE）的内型，并评估各内型对贝利尤单抗的反应。
我们分析了来自III期试验BLISS-SC的796例SLE患者的数据。采用混合数据因子分析（FAMD）的无监督机器学习及随后的聚类，根据B细胞免疫表型和血清学特征确定内型。使用Cox回归评估贝利尤单抗在诱导狼疮低疾病活动状态（LLDAS）和各聚类中SLE缓解定义（DORIS）缓解方面的疗效。
确定了三种内型。相互比较时，聚类1（n = 191）中CD19+CD24b+CD27+调节性B细胞（均值±标准差：35.9%±12.6%）、CD19+CD20+CD27+记忆B细胞（32.2%±9.9%）、CD19+CD20+CD69+活化B细胞（0.2%±0.3%）、CD19+CD20-CD138+长寿浆细胞（0.7%±1.0%）和CD19+CD38b+CD27b+SLE相关浆细胞（6.6%±7.0%）的比例更高。聚类2（n = 366）中CD19+CD24bbrightCD38bbrightCD27-过渡性B细胞（6.3%±9.0%）和CD19+CD20+CD27-幼稚B细胞（85.4%±7.2%）的比例更高，而CD19+CD20-CD138+外周长寿浆细胞（0.2%±0.3%）和CD19+CD38b+CD27b+SLE相关浆细胞（1.6%±2.0%）的比例更低。聚类3（n = 239）中CD19+CD20+CD138+短寿浆细胞（0.1%±0.1%）的比例更高且血清学活性更高，富含抗双链（ds）DNA、抗可提取核抗原（ENA）、抗磷脂抗体和低补体血症。在聚类2中，使用贝利尤单抗在诱导持续LLDAS方面优于安慰剂[风险比（HR）：2.22；95%置信区间（CI）：1.18 - 4.17；P = 0.014]，在诱导DORIS缓解方面也优于安慰剂（HR：3.45；95% CI：1.2 - 9.94；P = 0.022）。
基于B细胞免疫表型和血清学特征鉴定出三种不同的SLE内型，显示出贝利尤单抗治疗的不同获益。
