Centre for Rheumatology, Division of Medicine, University College London, 5 University Street, London, WC1E 6JF, UK.
Nat Rev Rheumatol. 2016 Jun;12(6):367-72. doi: 10.1038/nrrheum.2016.18. Epub 2016 Feb 18.
Suboptimal trial design and concurrent therapies are thought to account for the unexpected failure of two clinical trials of rituximab in patients with systemic lupus erythematosus (SLE). However, in this Opinion article we propose an alternative explanation: that rituximab can trigger a sequence of events that exacerbates disease in some patients with SLE. Post-rituximab SLE flares that are characterized by high levels of antibodies to double-stranded DNA are associated with elevated circulating BAFF (B-cell-activating factor, also known as TNF ligand superfamily member 13B or BLyS) levels, and a high proportion of plasmablasts within the B-cell pool. BAFF not only perpetuates autoreactive B cells (including plasmablasts), particularly when B-cell numbers are low, but also stimulates T follicular helper (TFH) cells. Moreover, plasmablasts and TFH cells promote each others' formation. Thus, repeated rituximab infusions can result in a feedback loop characterized by ever-rising BAFF levels, surges in autoantibody production and worsening of disease. We argue that B-cell depletion should be swiftly followed by BAFF inhibition in patients with SLE.
人们认为，试验设计不佳和同时进行的治疗可能是导致利妥昔单抗（rituximab）在系统性红斑狼疮（systemic lupus erythematosus，SLE）患者中两项临床试验意外失败的原因。然而，在这篇观点文章中，我们提出了另一种解释：利妥昔单抗可能引发一系列事件，使某些 SLE 患者的病情恶化。利妥昔单抗治疗后 SLE 发作的特点是抗双链 DNA 抗体水平升高，循环 BAFF（B 细胞激活因子，也称为 TNF 配体超家族成员 13B 或 BLyS）水平升高，B 细胞池中有大量浆母细胞。BAFF 不仅能使自身反应性 B 细胞（包括浆母细胞）持续存在，尤其是在 B 细胞数量较少时，还能刺激滤泡辅助 T 细胞（T follicular helper，TFH）。此外，浆母细胞和 TFH 细胞促进彼此的形成。因此，重复利妥昔单抗输注可能导致一个反馈环，其特征是 BAFF 水平不断上升，自身抗体产生增加，病情恶化。我们认为，在 SLE 患者中，B 细胞耗竭后应迅速进行 BAFF 抑制治疗。
