Rituximab Fails to Lessen Brain Inflammation in Progressive MS Trial
Injecting rituximab — a cancer therapy sometimes used in multiple sclerosis — into the spinal canal of people with progressive forms of MS did not demonstrably lower inflammation or improve clinical conditions, according to the results of a small trial.
“Contrary to the initial high expectations, no clear-cut effect on any biological … parameter has been obtained,” the researchers wrote.
However, they noted that “there are clues to the causes of failure that may help in designing future studies” to test rituximab, which has a strong safety profile, for MS.
The trial results were reported in Multiple Sclerosis International, in a study titled “No Early Effect of Intrathecal Rituximab in Progressive Multiple Sclerosis (EFFRITE Clinical Trial).”
The currently available treatments for MS target relapsing forms of the disease, in which there are relapses characterized by worsening symptoms, followed by periods where symptoms ease.
But there is a continued need for therapies that can effectively treat progressive forms of MS, in which symptoms continually get worse over time.
Progressive MS is driven by the inflammatory activity of immune cells in the central nervous system or CNS, which includes the brain and spinal cord.
Rituximab is a medication that targets and kills B-cells, a type of immune cell. Although not widely approved as a therapy for MS, rituximab is sometimes used off-label to treat the disease. It’s approved to treat certain kinds of B-cell cancers and autoimmune conditions, and is marketed under the names Rituxan in the U.S. and MabThera in Europe, among others.
When rituximab is injected into the bloodstream, it can kill B-cells in the body. However, the medication cannot efficiently pass through the blood-brain barrier, a semi-permeable membrane that prevents certain molecules from entering the brain and spinal cord.
Delivering rituximab via an injection into the spinal canal — called an intrathecal or IT injection — recently was shown to be able to safely treat B-cell tumors in the brain. Because the medication can kill inflammation-driving cells, researchers predicted that rituximab given by intrathecal injection might kill disease-driving cells in people with progressive MS. The researchers hypothesized that the therapy would lower inflammation and, ultimately, ease symptoms.
To test this theory, a team of scientists in France conducted an investigator-sponsored clinical trial (NCT02545959) that evaluated intrathecal rituximab in progressive MS.
“Ideally, the objective would be to suppress the CNS inflammation underlying progressive MS,” the team wrote.
The EFFRITE trial enrolled eight patients — six with secondary progressive MS and two with primary progressive MS. The participants were randomly assigned to one of three groups: one treated with intrathecal rituximab, one given intrathecal rituximab plus rituximab injected into the bloodstream, and a control in which patients did not receive rituximab.
After completing the initial evaluations, the two participants originally randomly selected for the control group were allowed to be reassigned — again randomly — to one of the other treatment groups. Data were then again collected. In total, the researchers assessed data for two controls, four people treated with intrathecal rituximab, and four given intrathecal plus intravenous rituximab. The participants were followed for at least a year.
The trial’s main goal was to determine the effect of treatment on the patients’ levels of osteopontin, a marker of inflammation in the brain. This marker was measured in the cerebrospinal fluid or CSF, which is the fluid surrounding the brain and spinal cord.
Secondary measures involved assessing changes in other CSF markers, such as neurofilament light chain (NFL), a marker of damage to brain cells, and immunoglobulin G, a marker of B-cell activity.
But the levels of these markers did not differ significantly among the treatment groups, nor did they vary significantly over time.
“Unfortunately … no major change in CSF [biomarkers] were observed at any time point,” the researchers wrote. Moreover, they noted that “no clear-cut effect on any biological CSF parameter has been obtained in any IT [intrathecal] rituximab trials,” citing other studies that reached similar conclusions.
Throughout the trial, the participants’ brain imaging parameters and disability scores remained stable. Fatigue scores also remained unchanged throughout the trial.
“Since one of the objectives of the study was to strongly reduce CNS and CSF inflammation, we expected to detect an early transient effect on fatigue,” the researchers wrote, noting that fatigue has been tied to higher levels of inflammatory signaling molecules in the brain. “Unfortunately, we did not observe any such effect.”
The treatment was generally well-tolerated, and no injection-related adverse events (side effects) were reported.
The team said that, although trials of intrathecal rituximab in progressive MS have yet to produce positive results, the findings of these studies may help design future research.
Specifically, findings from this and other studies indicate that, while intrathecal rituximab can kill many B-cells in the CNS, the medication generally only kills B-cells that are floating in the CSF within the nervous system, not the cells residing in nervous tissue that are thought to primarily drive damage in MS.
“Since B-cells are poorly targeted by IT rituximab, the absence of impact on the biological markers of neurodegeneration does not rule out IT B-cells being valuable targets in the future,” the team concluded. However, they said, “care must be taken to choose the appropriate drugs that are active in CSF.”