Naydovich Laura R, Orthmann-Murphy Jennifer L, Markowitz Clyde E
Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA.
Neurotherapeutics. 2025 Jul;22(4):e00602. doi: 10.1016/j.neurot.2025.e00602. Epub 2025 May 8.
Multiple sclerosis is a biologically and clinically heterogenous inflammatory demyelinating disease, driven by relapsing and progressive mechanisms, all individuals experiencing varying degrees of both. Existing highly effective therapies target peripheral inflammation and reduce relapse rates but have limited efficacy in progressive MS due to poor blood-brain barrier penetration and inability to address neurodegeneration. Bruton's tyrosine kinase (BTK) inhibitors represent an emerging therapeutic class offering a novel mechanism targeting BTK, which is expressed by both B cells and myeloid cells, including microglia within the CNS. Pre-clinical, Phase II, and Phase III clinical trials have demonstrated promising results in modulating progressive disease in both relapsing and non-relapsing MS patients. In contrast, the evidence regarding impact on relapse biology remains mixed and somewhat inconclusive. This review highlights gaps in current therapeutic strategies, examines the latest evidence for the efficacy and safety of BTK inhibitors in MS, and explores the future landscape of MS treatment.
多发性硬化症是一种在生物学和临床上具有异质性的炎症性脱髓鞘疾病，由复发和进展机制驱动，所有个体都经历不同程度的这两种情况。现有的高效疗法针对外周炎症并降低复发率，但由于血脑屏障穿透性差以及无法解决神经退行性变问题，在进展型多发性硬化症中的疗效有限。布鲁顿酪氨酸激酶（BTK）抑制剂是一类新兴的治疗药物，提供了一种靶向BTK的新机制，BTK在B细胞和髓系细胞中均有表达，包括中枢神经系统内的小胶质细胞。临床前、II期和III期临床试验已在复发型和非复发型多发性硬化症患者中调节进展性疾病方面显示出有前景的结果。相比之下，关于对复发生物学影响的证据仍然参差不齐且有些不确定。本综述强调了当前治疗策略中的差距，审视了BTK抑制剂在多发性硬化症中疗效和安全性的最新证据，并探讨了多发性硬化症治疗的未来前景。
