Biomarker for Multiple Sclerosis Treatment: How CXCL13 Predicts Response to Teriflunomide

Multiple sclerosis (MS), a complex immune-mediated disease, presents in a wide variety of forms and progression patterns. For clinicians, one of the biggest challenges is predicting how individual patients will respond to treatment. While there are many disease-modifying therapies (DMTs) available, including oral options like teriflunomide, dimethyl fumarate (DMF), and fingolimod, not all patients benefit equally. Identifying biomarkers that can predict treatment response is crucial to achieving personalized medicine in MS—and a new study by Fissolo et al. (2023) may have found one such key.

CXCL13: A Promising Biomarker Enters the Spotlight
In their recent study, the researchers zeroed in on a panel of cytokines, signaling proteins involved in immune responses. One cytokine in particular—CXCL13, a chemokine that attracts B cells—stood out as a strong candidate for tracking therapeutic success, particularly with teriflunomide, an oral DMT approved for relapsing-remitting MS (RRMS).

The team conducted a longitudinal study measuring serum levels of CXCL13 and other cytokines at baseline and after 12 months of treatment. Participants were categorized based on their clinical response into "no evidence of disease activity" (NEDA) and "evidence of disease activity" (EDA). Importantly, NEDA patients showed significantly reduced CXCL13 levels after one year of teriflunomide treatment—an effect not seen in non-responders.

Design: Two Cohorts, One Consistent Signal
The findings were replicated in an independent validation cohort, strengthening the reliability of the results:

Original Cohort: 19 RRMS patients treated with teriflunomide (8 NEDA, 11 EDA)

Validation Cohort: 36 RRMS patients (26 NEDA, 10 EDA)

In both groups, responders exhibited a significant drop in CXCL13 levels. In contrast, EDA patients did not show meaningful changes despite being on the same medication.

How Well Does CXCL13 Perform as a Predictor?
Using receiver operating characteristic (ROC) curve analysis, the study identified a 9.64 pg/mL drop in CXCL13 as the optimal cutoff to distinguish responders:

Sensitivity: 75% (original), 65% (validation)

Specificity: 82% (original), 60% (validation)

While not perfect, these figures indicate that CXCL13 holds promise as a practical biomarker—especially when used in conjunction with clinical and imaging data.

Why CXCL13? The Biology Behind the Biomarker
CXCL13 is known for its role in guiding B cells to inflammation sites, including the central nervous system (CNS) in MS. Elevated CXCL13 levels correlate with active MS disease in both cerebrospinal fluid and serum. Teriflunomide’s mechanism includes inhibiting the proliferation of rapidly dividing immune cells, such as B and T lymphocytes. A drop in CXCL13 might reflect reduced B-cell trafficking into the CNS, aligning with teriflunomide’s expected therapeutic effects.

What About Other Cytokines?
The study also examined TNF-α, another inflammatory cytokine, which showed some predictive value but performed less consistently across cohorts. Other markers such as IL-6, IL-17, GM-CSF, and IFN-γ showed no reliable trends associated with treatment response to the oral therapies studied.

Implications for Clinical Practicev
While the use of CXCL13 in clinical settings still requires further validation in larger, multicenter studies, this research represents a significant step forward. Longitudinal CXCL13 monitoring could become a non-invasive method to identify early in the treatment course whether a patient is responding optimally to teriflunomide.

This is particularly valuable given the expanding treatment landscape in MS. Having predictive tools to guide decisions could reduce the trial-and-error nature of MS management, improving patient outcomes and quality of life.

Takeaway
Fissolo et al. deliver compelling evidence that a decrease in serum CXCL13 levels over the first year of teriflunomide treatment correlates with positive therapeutic response in RRMS patients. If further validated, CXCL13 could help personalize MS treatment strategies—marking a key advancement toward precision neurology.

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:
Fissolo, N., Pappolla, A., Rio, J., et al. (2023). Serum Levels of CXCL13 Are Associated With Teriflunomide Response in Patients With Multiple Sclerosis. Neurology: Neuroimmunology & Neuroinflammation, 10(1):e200050. https://doi.org/10.1212/NXI.0000000000200050