Early Bortezomib Therapy for Refractory NMDAR Encephalitis

NMDAR encephalitis is the most common form of autoimmune encephalitis. It can affect people of all ages, though it is often seen in children and young adults, and it affects women more frequently than men. Treatment is classically described as first-line immunotherapy (corticosteroids, intravenous immunoglobulin, or plasma exchange) and second-line immunotherapy (cyclophosphamide and rituximab). However, there is no consensus on treatment, and to date, there are no clinical trials to evaluate treatment options.

Dr. M. Toni Turnbull and the team at Mayo Clinic Jacksonville published a case report on a young lady (18 years old) with NMDAR encephalitis. She showed no immediate response to first-line immune therapy and rituximab. Cyclophosphamide was considered, but given the potential toxicity of the drug, including consequences on fertility, the mother asked for an alternative.

The team decided to treat with bortezomib. This case represents the shortest hospitalization-to-bortezomib treatment timeline, and the team believes that this is reflected in the patient’s outcome with complete independence in a short timeframe. Although they argue it is difficult to say, the positive result was solely due to the use of bortezomib, as the patient had already received first – and second-line therapies.

The team concludes that in the absence of clinical trials to measure the efficacy against another standard immunotherapy, they cannot determine whether bortezomib is more efficacious than other therapeutic options. But this case report shows a promising result and suggests further research and trials are needed to guide clinical practice.

Bortezomib is FDA-approved for use in the treatment of multiple myeloma and mantle cell lymphoma. Bortezomib is a proteasome inhibitor. Proteasomes break up excess proteins in the cell into smaller pieces that can be reused by the cell if needed. In multiple myeloma, the cancerous plasma cells make more significant amounts of useless protein. When a proteasome inhibitor, like bortezomib, stops the breakup of these proteins, the amount of protein builds up until the cancerous cell blows up and dies.

In this case report, the Mayo Clinic team hypothesized that the early administration of bortezomib allowed for targeting plasma cells before they crossed the blood-brain barrier (BBB), leading to a good outcome. (Bortezomib has difficulty passing the BBB.) Other papers mentioned in this case report suggest that, especially in the case of refractory autoimmune disease, the antibody response may be mediated by long-lived plasma cells (found in bone marrow and inflamed tissues). These cells do not respond to traditional immunosuppressive therapies such as B-cell depletion regimens like rituximab, but instead may be vulnerable to targeting by proteasome inhibitors such as bortezomib.

This publication also summarizes previous case reports and retrospective studies using bortezomib to treat NMDAR encephalitis, providing clinicians with additional information on this alternative second-line treatment.