Using rituximab to prevent multiple sclerosis (MS) in people at risk or in patients still without motor symptoms, and continuing treatment as the disease develops, may be a promising way to avoid inflammation and myelin loss in the brain, a study in mice suggests.
In an animal model of MS, this treatment approach significantly reduced clinical symptoms by completely preventing an infiltration of immune cells into the brain, reversing processes of the demyelination (loss of myelin, the protective coat around nerve fibers) seen in untreated animals.
The research was published in the study, “Rituximab Prevents the Development of Experimental Autoimmune Encephalomyelitis (EAE): Comparison with Prophylactic, Therapeutic or Combinational Regimens,” published in the Journal of Inflammation Research.
Inflammation is seen as one of the first events leading to loss of myelin and subsequent neuronal degeneration in people with MS.
Rituximab is an antibody-based therapy that works by killing B-cells, one type of the immune cells known to drive inflammation in this disease. While not approved for MS itself, rituximab is used off-label as an MS treatment.
The therapy has been deemed safe and showed promising signs of efficacy in MS clinical trials and in real-world studies, where it was shown to lessen lesions and relapse rates in both relapsing-remitting MS (RRMS) patients and those with progressive forms of the disease.
To better understand its effects, researchers in the United Arabs Emirates first set out to investigate immune cell infiltration in the brain of MS patients using data available in public databases.
Specifically, the team examined RNA sequencing data — which provides information on which genes are active and to what extent — from tissue samples of different brain regions collected in autopsies. Using bioinformatic analysis, this helped them predict the percentage of immune cells, as well as their activation status, in each region.
Compared to healthy individuals, MS patients had higher levels of immune cell subsets in four of the five brain regions examined, results showed.
In particular, plasma cells (mature B-cells that produce antibodies) were elevated in the corpus callosum and internal capsule, naïve immune T-cells were higher in the parietal cortex, and cytotoxic T-cells were elevated in the hippocampus. Only the brain’s frontal cortex region showed no differences in immune cells.
Based on these observations, researchers then tested rituximab in mice with experimental autoimmune encephalomyelitis (EAE), the most commonly used model of MS. These animals develop disease after being challenged with a toxin.
They tested rituximab in multiple regimens, either given to EAE mice before the disease was induced (preventive treatment), after induction but before disease symptoms were evident (prophylactic), or when motor symptoms were first observed (about 10-12 days after induction; therapeutic treatment).
Disease progression was assessed throughout using a clinical score that measures physical symptoms and changes in body weight.
Since patients receive treatment only after a diagnosis has been made, the research team started by testing the prophylactic and therapeutic uses of rituximab, which better reflect clinical practice. However, neither of these approaches improved symptoms when compared to animals given a sham injection.
Next, the team tested the preventive approach, which would translate to people getting the treatment before MS develops. In this setting, rituximab significantly reduced disease symptoms in a dose-dependent manner — the higher the dose used, the greater the benefits.
Notably, when the lowest dose was given preventively and then continued as a prophylaxis, benefits recorded with the highest preventive dose were mimicked. This was not seen when rituximab was given preventively and then after the first symptoms developed.
Researchers also examined how rituximab affected immune cells in the brain of these animals. While untreated animals had extensive T-cell and B-cell infiltration and demyelination, those given rituximab had lesser immune cell infiltration and loss of myelin.
A small effect was seen with the prophylactic and therapeutic approaches, but the greatest benefit was observed with the highest preventive dose, which completely reduced inflammation (similar numbers of B- and T-cells as healthy, control mice), and totally prevented demyelination. A similar effect was seen when a low rituximab concentration was given as preventive and prophylactic treatment.
“We demonstrated that the 20 μg (microgram)/mouse prevention completely reduced the EAE clinical score, impaired infiltration of T- and B-cells into the perivascular space of mice brains, along with inhibiting the inflammation and demyelination,” the researchers wrote.
These data suggest that rituximab is able to ease disease processes when given in very early stages of disease.
“In summary and based on these findings, we recommend that RTX [rituximab] should be used preventively when early sign of disease development such as the appearance of cognitive disability in MS patients, occurred,” the researchers wrote.
“The combinatorial regimens can be utilized during unfortunate situations where the disease might develop even when the drug is used preventively. Our findings suggest that prevention plus prophylactic treatment may provide the best outcome,” they added.
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