Bruton tyrosine kinase inhibitors for multiple sclerosis

Bruton tyrosine kinase inhibitors are an emerging treatment for multiple sclerosis. Kramer et al. consider the evidence that central nervous system-penetrant Bruton tyrosine kinase inhibitors might target both peripheral immune cells and compartmentalized inflammation and discuss promising preliminary results of clinical trials of these agents in multiple sclerosis. Current therapies for multiple sclerosis (MS) reduce both relapses and relapse-associated worsening of disability, which is assumed to be mainly associated with transient infiltration of peripheral immune cells into the central nervous system (CNS). However, approved therapies are less effective at slowing disability accumulation in patients with MS, in part owing to their lack of relevant effects on CNS-compartmentalized inflammation, which has been proposed to drive disability. Bruton tyrosine kinase (BTK) is an intracellular signalling molecule involved in the regulation of maturation, survival, migration and activation of B cells and microglia. As CNS-compartmentalized B cells and microglia are considered central to the immunopathogenesis of progressive MS, treatment with CNS-penetrant BTK inhibitors might curtail disease progression by targeting immune cells on both sides of the blood-brain barrier. Five BTK inhibitors that differ in selectivity, strength of inhibition, binding mechanisms and ability to modulate immune cells within the CNS are currently under investigation in clinical trials as a treatment for MS. This Review describes the role of BTK in various immune cells implicated in MS, provides an overview of preclinical data on BTK inhibitors and discusses the (largely preliminary) data from clinical trials.

Automated summary

Bruton tyrosine kinase inhibitors are a promising emerging treatment for multiple sclerosis, as they can target both peripheral immune cells and compartmentalized inflammation. Current therapies for multiple sclerosis are effective in reducing relapses and relapse-associated worsening of disability, but they are less effective in slowing disability accumulation associated with CNS-compartmentalized inflammation. By targeting the B cells and microglia in the CNS, CNS-penetrant BTK inhibitors have the potential to curtail disease progression.