Frade-Sosa Beatriz, Sarmiento-Monroy Juan C, Bruce Ian N, Arnaud Laurent, Gómez-Puerta José A
Rheumatology Department, Hospital Clinic de Barcelona, Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
Centre for Musculoskeletal Research, Division of Musculoskeletal and Dermatological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK; Centre for Public Health, Faculty of Medicine, Health and Life Sciences, Queen's University Belfast, Belfast, UK.
Autoimmun Rev. 2025 Jul 31;24(8):103837. doi: 10.1016/j.autrev.2025.103837. Epub 2025 May 23.
Systemic lupus erythematosus (SLE) is a complex autoimmune disease characterized by immune dysregulation and autoantibody production. Despite advances in treatment, achieving sustained disease control remains challenging. Rituximab (RTX) and belimumab (BELI) are two B-cell-targeting biologics with complementary mechanisms of action, leading to increasing interest in their combination as a therapeutic strategy for refractory SLE. RTX depletes CD20+ B cells, whereas BELI inhibits B-lymphocyte stimulator (BLyS), reducing the survival of autoreactive B cells. Sequential therapy with these agents may mitigate B-cell repopulation and improve disease control. Recent studies, including SynBioSe and BEAT-LUPUS, suggest that RTX-BELI therapy can reduce autoantibody levels, neutrophil extracellular trap formation, and disease activity, with many patients achieving a lupus low disease activity state (LLDAS). However, the BLISS-BELIEVE and CALIBRATE trials did not demonstrate superiority over monotherapy, highlighting the need to refine patient selection. Combination therapy may be particularly beneficial in lupus nephritis, where BELI delays autoreactive B-cell reconstitution following RTX, potentially prolonging remission. While RTX-BELI therapy is generally well-tolerated, some studies report increased infections, necessitating careful patient monitoring. Lessons from other immune-mediated diseases, including inflammatory bowel disease and rheumatoid arthritis, underscore the potential benefits and risks of dual biologic therapy. Further research, including the ongoing SynBioSe-2 trial, is needed to clarify the optimal use, sequencing, and safety profile of RTX-BELI in SLE. Identifying biomarkers predictive of response may enable personalized treatment approaches, ultimately improving long-term outcomes for patients with refractory SLE.
系统性红斑狼疮（SLE）是一种复杂的自身免疫性疾病，其特征为免疫失调和自身抗体产生。尽管治疗取得了进展，但实现疾病的持续控制仍具有挑战性。利妥昔单抗（RTX）和贝利尤单抗（BELI）是两种作用机制互补的靶向B细胞生物制剂，这使得人们越来越有兴趣将它们联合使用，作为难治性SLE的一种治疗策略。RTX可消耗CD20+ B细胞，而BELI可抑制B淋巴细胞刺激因子（BLyS），减少自身反应性B细胞的存活。序贯使用这些药物可能会减轻B细胞的再增殖并改善疾病控制。包括SynBioSe和BEAT-LUPUS在内的近期研究表明，RTX-BELI疗法可降低自身抗体水平、中性粒细胞胞外诱捕网的形成以及疾病活动度，并使许多患者达到狼疮低疾病活动状态（LLDAS）。然而，BLISS-BELIEVE和CALIBRATE试验并未显示出优于单药治疗的效果，这凸显了优化患者选择的必要性。联合治疗在狼疮性肾炎中可能特别有益，因为在狼疮性肾炎中，BELI可延迟RTX治疗后自身反应性B细胞的重建，从而可能延长缓解期。虽然RTX-BELI疗法通常耐受性良好，但一些研究报告称感染有所增加，因此需要对患者进行仔细监测。包括炎症性肠病和类风湿关节炎在内的其他免疫介导疾病的经验教训，强调了双重生物制剂治疗的潜在益处和风险。需要进一步的研究，包括正在进行的SynBioSe-2试验，以阐明RTX-BELI在SLE中的最佳使用方法、用药顺序和安全性。识别预测反应的生物标志物可能有助于采用个性化治疗方法，最终改善难治性SLE患者的长期预后。
