McCluskey Daniel, Shipa Muhammad R A, Chowdhury Kashfia, James Judith A, Cooney Laura A, Ehrenstein Michael R
Department of Ageing, Rheumatology and Regenerative Medicine, University College London, London, UK.
Comprehensive Clinical Trials Unit, University College London, London, UK.
Cell Rep Med. 2025 Aug 19;6(8):102247. doi: 10.1016/j.xcrm.2025.102247. Epub 2025 Jul 23.
No theragnostic biomarkers exist for systemic lupus erythematosus (SLE) to enable a precision medicine approach. Baseline serum IgA2 anti-double-stranded DNA (dsDNA) antibody levels are associated with response to combination belimumab after rituximab therapy in SLE (BEAT-lupus trial, ISRCTN 47873003). Analysis of the CALIBRATE trial (NCT02260934) confirms that baseline IgA2 anti-dsDNA antibody levels are specifically associated with response to belimumab after rituximab (odds ratio [OR] = 16.9, confidence interval [CI]: 2.8-101, compared to rituximab alone-CALIBRATE and BEAT-lupus combined data). IgA2 anti-dsDNA antibody levels decrease alongside IgA2 expression in plasmablasts only after this combination treatment. Increased serum B cell-activating factor (BAFF) levels are associated with rising IgA2 anti-dsDNA antibody levels after rituximab. IgA2 plasmablasts have increased BAFF receptor and interleukin (IL)-10 expression compared to IgA1 plasmablasts and have a distinct integrin profile implicating a gut mucosal origin. These findings validate IgA2 anti-dsDNA antibodies as a theragnostic biomarker of response and provide mechanistic insight into the selective targeting of IgA2 B cells by combination belimumab after rituximab in SLE.
系统性红斑狼疮（SLE）不存在用于实现精准医学方法的诊疗生物标志物。基线血清IgA2抗双链DNA（dsDNA）抗体水平与SLE患者在利妥昔单抗治疗后联合使用贝利尤单抗的反应相关（BEAT - 狼疮试验，ISRCTN 47873003）。对CALIBRATE试验（NCT02260934）的分析证实，基线IgA2抗dsDNA抗体水平与利妥昔单抗治疗后对贝利尤单抗的反应具有特异性关联（比值比[OR] = 16.9，置信区间[CI]：2.8 - 101，与单独使用利妥昔单抗相比——CALIBRATE和BEAT - 狼疮联合数据）。仅在这种联合治疗后，IgA2抗dsDNA抗体水平才会随着浆母细胞中IgA2表达的降低而降低。利妥昔单抗治疗后，血清B细胞激活因子（BAFF）水平升高与IgA2抗dsDNA抗体水平升高相关。与IgA1浆母细胞相比，IgA2浆母细胞的BAFF受体和白细胞介素（IL）-10表达增加，并且具有独特的整合素谱，提示其起源于肠道黏膜。这些发现验证了IgA2抗dsDNA抗体作为反应的诊疗生物标志物，并为SLE患者在利妥昔单抗治疗后联合贝利尤单抗对IgA2 B细胞进行选择性靶向提供了机制性见解。
