BAFF as a Crystal Ball: Predicting Immune Risks in MS Patients on Ocrelizumab

For people living with multiple sclerosis (MS), the treatment journey often feels like walking a tightrope. On one hand, powerful therapies such as ocrelizumab (Ocrevus) effectively suppress the immune system’s misguided attack on the brain and spinal cord. On the other, these drugs can leave patients vulnerable to infections and long-term complications.

Currently, doctors mostly rely on MRI scans and neurological exams to track disease activity. These are important, but they only give snapshots of what is happening inside the body. What if a blood test could provide a dynamic, real-time view of both disease activity and treatment risks?

That’s the promise of serum biomarkers — proteins in the blood that can reveal subtle shifts in the immune system.

The study: Looking deeper into blood proteins
A team led by Anastasia Chumakova and colleagues at UC Irvine set out to investigate whether disease-modifying therapies (DMTs) alter serum biomarkers in ways that could impact how clinicians interpret them.

They analyzed 377 MSDA (Multiple Sclerosis Disease Activity) panel tests from stable MS patients. This panel tracks 18 different biomarkers linked to inflammation and immune function. The focus quickly turned to one protein: B-cell activating factor (BAFF).

BAFF is a growth and survival signal for B cells — the very immune cells that ocrelizumab targets and depletes.

Key findings
The results revealed several intriguing and clinically relevant patterns:

BAFF levels rise with B-cell depletion
As expected, BAFF increased in patients treated with B-cell depleting therapies. But there were surprises:

BAFF levels were significantly higher in ocrelizumab-treated patients compared to those on ofatumumab, despite both drugs targeting B cells.

With ocrelizumab, BAFF levels climbed with longer treatment duration. This was not the case for ofatumumab.

BAFF predicts falling immunoglobulins
In ocrelizumab patients, higher BAFF strongly correlated with lower immunoglobulin G (IgG) levels. IgG is critical for long-term infection protection. Its decline — known as hypogammaglobulinemia — is a well-recognized complication of ocrelizumab therapy.

Importantly, IgG decline was also tied to the length of time on ocrelizumab, but again, not with ofatumumab.

Longitudinal confirmation
Tracking patients over multiple MSDA tests confirmed the link between rising BAFF, falling IgG, and duration of ocrelizumab treatment.

Why this matters
Hypogammaglobulinemia is one of the most concerning risks of long-term B-cell depletion. Patients with low IgG are more vulnerable to infections, sometimes requiring intravenous immunoglobulin (IVIG) replacement. Currently, doctors often monitor IgG directly, but declines may only appear after significant immune suppression has already set in.

This study suggests BAFF could serve as an earlier warning sign — a biomarker that helps identify patients at risk for hypogammaglobulinemia before IgG levels plummet.

Even more intriguingly, the differences between ocrelizumab and ofatumumab highlight that not all B-cell therapies behave the same way, despite similar mechanisms. This nuance could guide clinicians in tailoring therapy choices and timing.

The big picture: Toward personalized MS care
While these findings are preliminary and need further validation, they open the door to a more personalized approach to MS treatment:

Regular BAFF monitoring might one day help doctors decide when to pause or switch therapy to protect patients from long-term immune suppression.

It also reinforces the idea that serum biomarkers can complement MRI and clinical exams, offering a more continuous and individualized picture of disease and treatment effects.

Final thoughts
This work represents a step toward smarter, safer MS care. If BAFF truly signals impending immune risk in ocrelizumab patients, clinicians could act earlier to prevent complications. For patients, this means more than just fewer infections — it means peace of mind in knowing their treatment is being guided not only by MRI scans, but also by the subtle messages their blood is sending.

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:
Chumakova A, Thai G, Demetriou M, Fleming V, Saxena S, Sy M. Serum BAFF Level Informs Risk of Hypogammaglobulinemia in Patients with Multiple Sclerosis on Ocrelizumab. Neurology. 2025 Apr 8;104(7_Supplement_1). DOI:10.1212/WNL.0000000000211957