Why Some MS Patients Bounce Back Too Fast: New Clues from African Ancestry Immune Responses

Multiple sclerosis (MS) has long been recognized as a complex disease where the immune system mistakenly attacks the brain and spinal cord. For years, the focus was mostly on T cells as the main culprits. But in recent decades, a new player has taken center stage: B cells.

Drugs that deplete B cells—like ocrelizumab and rituximab—have transformed MS treatment, showing remarkable success in reducing relapses and new brain lesions. But not everyone responds the same way. In fact, a new study published in Frontiers in Immunology has uncovered important differences in how patients of African ancestry respond to these therapies.

The Puzzling Case of Early B Cell Return
Normally, after an infusion of an anti-CD20 therapy, B cells in the blood vanish for several months, only gradually returning. But the researchers, led by Dr. Gregg J. Silverman and colleagues at NYU Grossman School of Medicine, noticed something unusual:

Many African ancestry patients had their B cells bounce back much faster than expected.

This early “repopulation” could potentially reduce the effectiveness of treatment, raising questions about whether these patients face unique risks of disease progression.

What Did the Study Find?
The team studied 43 African ancestry patients with MS (or, in a few cases, neuromyelitis optica). They split them into two groups:

Early Repleters (ER): B cells returned unusually fast after infusion.

Normal Repleters (NR): B cells stayed suppressed for the expected period.

Here’s what they discovered:

1. Anti-drug antibodies can block treatment
In some patients, the immune system made antibodies against ocrelizumab itself, neutralizing the drug. Without active drug circulating, B cells were able to return early.

2. Genetics plays a big role
Even in patients without anti-drug antibodies, certain genetic variations (SNPs) were overrepresented in early repleters. These genetic changes mapped to pathways involved in:

B cell survival (BAFF gene variants), inflammation (STAT3, IL2RA, IL4), immune signaling and differentiation (BACH2, BANK1, TGFBR3). Essentially, these inherited differences may predispose some African ancestry patients to faster B cell recovery—and potentially stronger autoimmune activity.

3. Serum markers reflect the process
Patients with early repletion had lower levels of BAFF (B-cell activating factor) in their blood. This makes sense: since B cells were returning quickly, they “soaked up” more BAFF, leaving less circulating in the bloodstream.

Why Does This Matter?
The findings raise important clinical questions:

If African ancestry patients repopulate B cells faster, should they receive infusions more frequently to maintain suppression?

Could genetic testing help predict which patients are likely to replete early?

Do these differences explain why MS can often be more severe in African ancestry patients?

The study also highlights the need for personalized treatment strategies. A “one-size-fits-all” dosing schedule may not be optimal for every patient, particularly for underrepresented groups who historically have been excluded from clinical trials.

Looking Ahead
This research is groundbreaking, but it’s just the beginning. The study had a relatively small sample size, and larger multi-center trials are needed to confirm the results. Still, the implications are big:

Pharmacogenetics (how genes affect drug response) may hold the key to tailoring MS therapies.

Monitoring for anti-drug antibodies could become part of routine care.

Understanding immune differences across populations is essential for equity in healthcare.

Takeaway
For patients of African ancestry living with MS, this research brings both challenges and hope. The challenge: their immune systems may replenish B cells faster, potentially undermining current therapies. The hope: by identifying genetic and immune signatures linked to this process, doctors may soon be able to personalize treatment, ensuring better long-term outcomes.

Disclaimer: This blog post is based on the provided research article and is intended for informational purposes only. It is not intended to provide medical advice. Please consult with a healthcare professional for any health concerns.

References:
Silverman, G. J., Amarnani, A. N., Armini, A. A., Kim, A., Kopinsky, H., Fenyo, D., & Kister, I. (2025). B cell-extrinsic and intrinsic factors linked to early immune repletion after anti-CD20 therapy in patients with Multiple Sclerosis of African Ancestry. Frontiers in Immunology, 16, 1590165.