Leptomeningeal inflammation in multiple sclerosis (MS) is associated with worse clinical outcomes and greater cortical pathology. Both B cells and myeloid cells are found in areas of meningeal inflammation. We previously demonstrated that, in the relapsing–remitting encephalomyelitis (EAE) model in SJL mice, ultra-high field contrast-enhanced magnetic resonance imaging (MRI) could identify and track areas of meningeal inflammation. Bruton’s tyrosine kinase (BTK) mediates signaling through B cell receptor and Fc receptor pathways and leads to B cell and myeloid cell activation. We therefore hypothesized that a BTK inhibitor could target meningeal inflammation in EAE.
To test the effect of evobrutinib, a highly selective BTK inhibitor, as a potential therapy targeting meningeal inflammation in a mouse model of MS.
We immunized 7- to 8-week-old female SJL/J mice with proteolipid protein 139–151 peptide and complete Freund’s adjuvant to induce EAE. Animals were weighed and disease severity was scored starting at 7 days post-immunization; at 6 weeks they underwent Gadolinium-enhanced MRI. Mice demonstrating the presence of meningeal contrast enhancement were randomized to receive daily oral doses by gavage of evobrutinib (10 mg/kg) or vehicle control between Weeks 6–10 post-immunization. MRI was repeated at Weeks 8 and 10 to assess meningeal inflammation, and brain tissues were collected for histopathological analysis.
At baseline, both vehicle (n=16) and evobrutinib (n=19) groups had a similar number of areas of meningeal contrast enhancement (median: 10.5 vs 11; p=0.25). Following treatment, a greater reduction in the number of areas of meningeal contrast enhancement was identified in the evobrutinib group vs the vehicle group (median change: -3 vs 0.5; p=0.003). A significant decrease in B cells in areas of meningeal inflammation in the evobrutinib group compared to the vehicle group was noted. Also, astrocytosis in the adjacent cortex was reduced in the evobrutinib group compared with vehicle.
An amelioration of established meningeal inflammation, as assessed by imaging and pathological measures, in a relapsing–remitting EAE model was observed with evobrutinib treatment, suggesting the potential utility of this agent to target this phenomenon in MS patients.