In multiple sclerosis (MS), persisting disability can occur independent of relapse activity or development of new central nervous system (CNS) inflammatory lesions, termed chronic progression. This process occurs early and it is mostly driven by cells within the CNS. One promising strategy to control progression of MS is the inhibition of the enzyme Bruton's tyrosine kinase (BTK), which is centrally involved in the activation of both B cells and myeloid cells, such as macrophages and microglia. The benefit of BTK inhibition by evobrutinib was shown as we observed reduced pro-inflammatory activation of microglia when treating chronic experimental autoimmune encephalomyelitis (EAE) or following the adoptive transfer of activated T cells. Additionally, in a model of toxic demyelination, evobrutinib-mediated BTK inhibition promoted the clearance of myelin debris by microglia, leading to an accelerated remyelination. These findings highlight that BTK inhibition has the potential to counteract underlying chronic progression of MS.

在多发性硬化症 (MS) 中，持续的残疾可能会独立于复发活动或新的中枢神经系统 (CNS) 炎症病变的发展而发生，称为慢性进展。这个过程发生得很早，主要是由中枢神经系统内的细胞驱动的。控制 MS 进展的一种有前景的策略是抑制布鲁顿酪氨酸激酶 (BTK)，该酶主要参与 B 细胞和骨髓细胞（例如巨噬细胞和小胶质细胞）的激活。我们在治疗慢性实验性自身免疫性脑脊髓炎 (EAE) 或活化 T 细胞过继转移后观察到小胶质细胞的促炎性激活减少，显示了 evobrutinib 抑制 BTK 的益处。此外，在中毒性脱髓鞘模型中，evobrutinib 介导的 BTK 抑制促进了小胶质细胞清除髓鞘碎片，导致髓鞘再生加速。这些发现强调，BTK 抑制有可能抵消 MS 的潜在慢性进展。