How does rituximab work for MS? Understanding the B-Cell Depletion Mechanism

October 8, 2025 •

3 min read

Approximately 85% of people with multiple sclerosis (MS) are initially diagnosed with the relapsing-remitting form of the disease, which is driven by inflammatory immune cells. Rituximab works for MS by directly targeting and depleting B-lymphocytes, a specific type of white blood cell implicated in this autoimmune attack.

Quick Summary

Rituximab, an anti-CD20 monoclonal antibody, treats multiple sclerosis by depleting specific B-cells that drive inflammation and central nervous system damage. Its mechanism involves cellular cytotoxicity and apoptosis, effectively reducing relapses and inflammatory lesions. While used off-label, it offers an alternative to FDA-approved therapies.

Key Points

Targeting B-Cells: Rituximab is a monoclonal antibody that targets the CD20 protein on B-cells, leading to their depletion to reduce inflammation in MS.
Three-Pronged Attack: The drug kills B-cells primarily through antibody-dependent cellular cytotoxicity, complement-dependent cellular cytotoxicity, and direct apoptosis.
Off-Label Efficacy: While not FDA-approved for MS, clinical trials and real-world data confirm rituximab's effectiveness in reducing relapses and MRI lesion activity in relapsing forms of the disease.
Comparison to Ocrelizumab: Ocrelizumab is a humanized version of a similar drug that is FDA-approved for MS. Rituximab is often less expensive but may carry a higher risk of infusion reactions.
Risk of Infections: By suppressing the immune system, rituximab increases the risk of infections, including rare but serious opportunistic infections like PML.

The Immune System Attack in Multiple Sclerosis

Multiple Sclerosis (MS) is an autoimmune disease where the body's immune system mistakenly attacks the myelin sheath, the protective layer surrounding nerve fibers in the central nervous system (CNS). This attack disrupts communication between the brain and the rest of the body, leading to a range of symptoms. While T-cells were long the primary focus of MS research, evidence, including the success of B-cell therapies like rituximab, highlights the significant role of B-cells in MS pathology.

B-cells contribute to MS through mechanisms such as antigen presentation, cytokine production, antibody production, and direct inflammatory activity within the CNS.

How does rituximab work for MS?: The Mechanism of B-Cell Depletion

Rituximab (marketed as Rituxan, Truxima, and Riabni) is a chimeric monoclonal antibody that binds to the CD20 antigen on certain B-cells, leading to their depletion. This depletion occurs via three main pathways:

Antibody-Dependent Cellular Cytotoxicity (ADCC): Immune cells are directed to kill rituximab-marked B-cells.
Complement-Dependent Cytotoxicity (CDC): The complement system is activated to destroy B-cells.
Apoptosis: Rituximab can trigger programmed cell death in target B-cells.

Depleting these B-cells reduces inflammation in the CNS and is particularly effective in reducing relapses and lesions in relapsing-remitting multiple sclerosis (RRMS).

Efficacy and Clinical Evidence in MS

Studies have shown rituximab's efficacy in MS. The HERMES trial demonstrated significant reductions in MRI lesions and relapses in RRMS. The RIFUND-MS trial confirmed superior relapse prevention compared to another therapy in early RRMS. In progressive MS, results have been less consistent, with some benefit observed in subgroups of patients with active inflammation.

The "Off-Label" Status and Comparison with Other Anti-CD20 Therapies

Rituximab is not FDA-approved for MS but is commonly used off-label. The manufacturer pursued approval for ocrelizumab (Ocrevus), a similar, humanized drug.

Comparative Table: Rituximab vs. Ocrelizumab


Feature	Rituximab (Rituxan, Truxima)	Ocrelizumab (Ocrevus)
FDA Approval Status	Not FDA-approved for MS; used off-label.	FDA-approved for RRMS and PPMS.
Drug Type	Chimeric (part mouse, part human) monoclonal antibody.	Humanized monoclonal antibody.
Efficacy in RRMS	Demonstrated high efficacy in reducing relapses and MRI activity in studies.	Pivotal Phase III trials showed high efficacy compared to interferon beta-1a.
Cost	Generally less expensive, especially with available biosimilars.	Often significantly more expensive due to on-label approval and branding.
Infusion Reactions	Higher rate of infusion reactions due to its chimeric nature compared to the humanized ocrelizumab.	Lower rate of infusion reactions compared to rituximab.
PPMS Efficacy	Subgroup analysis in a Phase III trial showed potential benefit in certain PPMS patients.	FDA-approved for PPMS based on successful Phase III trials.

Administration and Considerations for MS

Rituximab is given by intravenous infusion. The administration involves initial infusions followed by maintenance infusions, with the frequency determined by a healthcare provider. Premedication is often given to help manage potential infusion reactions. In some cases, treatment decisions may be informed by monitoring B-cell counts.

Important Considerations and Side Effects

Rituximab has potential side effects. Common side effects include infusion reactions and an increased risk of infections. PML, a rare but serious brain infection, is a known risk with rituximab in other conditions, and vigilance is required in MS patients. Vaccinations may be less effective. Discussion with a healthcare provider is essential to manage these risks.

Conclusion

Rituximab is an effective B-cell depleting therapy for relapsing-remitting multiple sclerosis, reducing relapses and lesions by targeting inflammatory B-cells through ADCC, CDC, and apoptosis. Although used off-label, it provides an alternative to FDA-approved options like ocrelizumab, often at a lower cost. Patients should discuss rituximab's benefits and risks with their neurologist in the context of their individual needs. More information is available from resources like the National Institutes of Health.

Frequently Asked Questions

The primary function of rituximab in treating multiple sclerosis is to target and deplete CD20-positive B-cells, which are a type of white blood cell that plays a significant role in the autoimmune inflammatory response that damages the central nervous system in MS.

Rituximab is considered an off-label treatment for multiple sclerosis because the manufacturer, after early positive results, decided to pursue FDA approval for a humanized version, ocrelizumab, instead of rituximab itself. As a result, it is not officially labeled for MS, though its use is supported by clinical evidence.

Both are anti-CD20 monoclonal antibodies that deplete B-cells. The main differences are that rituximab is chimeric (part mouse, part human), used off-label, and generally less expensive, while ocrelizumab is humanized, FDA-approved for MS, and typically costs more.

Rituximab for MS is administered by intravenous infusion. The frequency of administration is determined by a healthcare professional based on individual needs and treatment protocols.

Common side effects include infusion reactions (fever, chills, nausea), headache, and an increased risk of infections. Premedication is used to help manage infusion reactions.

The depletion of B-cells by rituximab can increase the risk of PML, a rare but serious brain infection. While there have been no confirmed cases directly attributed to rituximab in MS trials, the risk must be taken seriously, and patients are monitored for any neurological symptoms.

While rituximab showed less convincing results in overall disability progression for progressive MS in some trials, subgroup analyses suggested potential benefit in younger patients with active inflammation. It is more definitively used and studied for relapsing forms of MS.