Rituximab Displays Long-Term Effectiveness for Relapsing MS

Relapsing multiple sclerosis (RMS) is a chronic, immune-mediated disease of the central nervous system in which the body’s immune system attacks the protective myelin sheath around nerve fibers. This leads to episodes of neurological symptoms called relapses or attacks, followed by periods of partial or full recovery, known as remissions.

Rituximab is a B-cell–depleting monoclonal antibody that targets CD20-positive B cells, which play a key role in the autoimmune attack on the central nervous system in multiple sclerosis (MS). Although not FDA approved as a treatment for MS, rituximab (RTX) is often prescribed by clinicians for its effectiveness and lower price point than other MS medications.¹

A clinical study published in the Neurology Journal late last year compared extending RTX dosing to every 12 months (q12mo) vs continuing traditional 6 months (q6mo) dosing in patients with RMS to measure the risk of return of disease activity.² Results from the study indicated that extending low-dose RTX treatment intervals after 1 year of stability to q12mo was highly effective and did not result in an increased risk of disease activity despite high B-cell counts. Following the publication, lead author Annette Langer-Gould, MD, PhD, lead for Clinical and Translational Neuroscience at Kaiser Permanente in Southern California, sat down with NeurologyLive®for an exclusive interview to discuss the research regarding rituximab.

In the interview, Langer-Gould provided her perspective on the use of rituximab in patients with relapsing MS and offered clinical insights into optimizing long-term therapy. Throughout the conversation, she emphasized the importance of balancing efficacy and safety, highlighting that lower, less frequent dosing can maintain disease control while reducing infection risk and immune suppression. Above all, Langer-Gould discussed the potential for B-cell–depleting therapies to become forever therapies when carefully managed and expressed optimism about future research identifying which patients can safely de-escalate or stop treatment.

NeurologyLive: Why did you feel it was important to conduct a study of this nature?

Dr. Langer-Gould: We’ve been using a lot of rituximab since the initial trial results were announced in 2007. We learned quickly, along with some Swedish physicians, that it’s really easy to give too much too quickly. Patients can run into trouble with infections and hypogammaglobulinemia early on. This led to a study by Jonathan Seltzer, MD, and Anders Svenningsson, MD, PhD showing that lower maintenance doses—500 mg every six months instead of 1000 mg or 2000 mg—reduced the risk of serious infections and adverse events without sacrificing effectiveness.

However, the safety data from clinical trials only extended two to three years. Even using the lower dose, we still saw long-term issues, especially an increased risk of infections and low immunoglobulins. We developed a protocol to reduce patients to once-a-year infusions after two to three years of stability. The reasoning was that if patients had been stable for three years, we were entering unknown safety territory. Then came COVID-19. We had thousands of patients on rituximab, and there was concern this could increase their risk of severe COVID.

So, we looked at the data, consulted Swedish colleagues, and decided to drop everyone to once-a-year dosing after one year of stability. Even patients who started with aggressive disease could safely do this. We had already published safety data showing that reducing dosing protects the immune system and decreases the risk of serious infections, hospitalizations, and recurrent outpatient infections.

What were the greatest takeaways from this trial?

We applied a method called target trial design, which is excellent for reducing confounding when you have thousands of treated patients. Essentially, we asked: if we were doing a randomized control trial, who would we include, how quickly would we reduce dosing, and how would we monitor outcomes? Then we emulated that using observational data.

We set strict inclusion and exclusion criteria focused on studying effectiveness and then analyzed the data using inverse propensity-weighted treatment methods to further reduce confounding.

The key question: In patients with active disease at the time they started rituximab, after just one year of stability (over 95% of patients), could we safely reduce dosing to once-a-year infusions, or should they remain on six-month dosing? Would we see MS reactivation?

After about five years of follow-up, we found that disease activity was incredibly low in both groups—relapses, disease activity, and disability progression remained minimal. There was no difference between once-a-year and six-month dosing. Another consideration was vaccine efficacy. Data suggested that patients need at least 40 B cells to mount a normal immune response. Most of our patients were concerned about COVID and wanted to be able to receive effective vaccination safely.

What do these findings mean for patients currently on RTX?

This is really good news. Patients don’t need high doses or frequent administration. Once-a-year, low-dose rituximab increases the likelihood that it could become a “forever therapy.”

Patients on earlier regimens often had to stop because of infections, immune system suppression, or recovery can taking years, so the ability to safely reduce dosing is significant.

Were there any limitations to the study?

Yes. Since we used observational data, we relied on information collected as part of routine clinical care. Most patients were cared for by MS specialists, so relapse and disability outcomes were reliable.

However, imaging is harder to capture. Clinicians may have extended six-month dosing based on factors we didn’t fully capture, like a patient starting with many enhancing lesions or significant brain or spinal cord atrophy. These nuances are difficult to capture in routine records.

What else needs to be studied?

The big question is: who can safely stop B-cell–depleting therapies altogether? We’ve seen patients do well with de-escalation or stopping for various reasons, like long-term disease quiescence or recurrent infections.

We need randomized trials to determine who can safely stop, and whether these therapies can reset the immune system and induce long-term remission, similar to stem cell transplants or other cell-depleting therapies. The goal is to identify biomarkers for timing retreatment—when a patient truly needs another infusion.

What is your outlook for patients with MS patients receiving RTX or other B-cell–depleting therapies?

The future is bright. Low doses and infrequent administration seem effective. We just need to fine-tune treatment protocols to minimize risks and side effects. We can manage relapsing-remitting disease effectively, similar to how HIV treatment evolved over time.

Any final thoughts?

One important point is starting patients on therapy early in their disease course. Some patients may do well on modestly effective therapy initially and escalate only if breakthrough disease occurs. Randomized trials are ongoing to study this.

In real-world practice, patients face barriers like insurance changes, co-pays, and limited access to specialists, so it’s critical to distinguish between efficacy in trials and effectiveness in everyday care. A highly efficacious therapy may fail in the real world if patients can’t adhere to or access treatment.

Transcript edited for clarity.

REFERENCES
1. Langer-Gould A., Sotirchos E., Bourdette D., Et al. Rituximab for Multiple Sclerosis. Neurol Journal. 2024;102 (2) e208063. Doi: https://doi.org/10.1212/WNL.0000000000208063
2. Langer-Gould A., Li B., Smith J., et al. Comparative Effectiveness of Rituximab Dosed Every 6 and 12 Months in Relapsing Multiple Sclerosis. Neurol. Journal. 2026; 106 (2) e214473. Doi: https://doi.org/10.1212/WNL.0000000000214473