Ocrelizumab Effects on Physiological and Cognitive Changes in Multiple Sclerosis

Grey matter (GM) atrophy develops early in the multiple sclerosis (MS) disease process. Over 2 years, clinically isolated syndrome (CIS) patients developed significant thalamic and cortical volume loss. In our preliminary study, including 50 MS patients, the investigators found that the presence of leptomeningeal (LM) contrast enhancement (CE) was associated with progression of cortical atrophy over 5 years, as measured by the loss of cortical volume, in patients with MS. About 40% of relapsing-remitting MS (RRMS) patients presented with LM CE. MS patients with LM CE showed significantly greater percentage decreases cortical (-3.4% vs. -1.8%, p=0.007) volumes, compared to those without. RRMS patients with LM CE showed significantly greater percentage decrease in cortical (-3.8% vs. -1.9%, p=0.006) volume over the follow-up, compared to those without. No differences in deep GM volume changes were found in relapsing-remitting (RR) and secondary progressive (SP) MS patients with and without LM CE. Three LM CE positive and one LM CE negative RRMS patients developed secondary progressive MS (SPMS) course over the follow-up. More MS subjects with LM CE had disability progression (7, 28%) compared to those without (4, 16%), but this was not significantly different (p=0.306). The median EDSS in MS patient with LM CE increased to 4.0, while decreased to 2.5 in those without. No differences in total number of relapses, annual relapse rate, nor being relapse free were detected in MS patients with and without LM CE over the follow-up. However, in RRMS patients with LM CE, the investigators found that there was a trend for greater increase in absolute change of EDSS (0.9 vs. -0.03, p=0.05).

The proposed study will extend these preliminary findings in a cohort of MS patients, who will be treated with Ocrelizumab and who will be assessed at 12 and 24 months using same MRI hardware and software. The longitudinal serial MRI assessment study design will allow us to examine temporal relationship of LM CE, development of GM pathology, cognitive dysfunction and Ocrelizumab. Based on our preliminary results, the investigators expect that approximately 12 (40%) of MS patients will present with LM CE at baseline in the proposed study.

Substantial evidence shows that Epstein-Barr virus (EBV) infection plays a major role in the risk of developing MS. Mononucleosis and seropositivity of anti-Epstein-Barr nuclear antigen (EBNA) Immunoglobulin G (IgG) along with Vit D deficiency and smoking are risk factors for MS. Serial studies reveal that the risk of developing MS is extremely low among individuals not infected with EBV but increases sharply in the same individuals following EBV infection. EBV-infected B cells were identified in MS brain lesions. Therefore the elimination of the virus from the persistently infected B-cells could potentially inhibit/delay disease progression. Our data show correlation of anti-EBV levels with atrophy (more degeneration) hence an effect on disease chronicity/progression. Besides high Vit D administration studies that showed an effect on decreasing the EBV antibody levels, no other DMT's were able to show a beneficial effect on EBV antibody level, and some treatments increased EBV levels.

EBV viremia occurs in the hematopoietic stem transplantation setting and has been treated successfully with rituximab, an antibody that targets B-lymphocyte antigen (CD20) on B cells in a manner analogous to Ocrelizumab. It has been reported that 92% of patients with EBV viremia responded upon dosing with rituximab and the EBV copies per 100,000 peripheral blood mononuclear cell (PBMC) decreased from 2578 to 71 at Day 15 and 0 by Day 21.

Therefore, our hypothesis is that Ocrelizumab treatment will reduce both B cells and EBV exposure in treated patients leading to benefit on LM inflammation and to less GM atrophy development.