Why One Immune Signal Falls Short: IL-17F and the Search for MS Treatment Predictors

Multiple sclerosis (MS) is a complex immune-mediated disease where the immune system mistakenly attacks the central nervous system. Among the available therapies, interferon beta (IFN-β) has long been a cornerstone treatment for relapsing-remitting MS (RRMS). Yet, not every patient responds equally well. This has fueled the search for biomarkers that might predict who benefits most from IFN-β therapy.

One promising candidate was interleukin-17F (IL-17F), a cytokine produced by Th17 immune cells, which are strongly implicated in MS and other autoimmune conditions. Previous small-scale studies suggested that higher baseline IL-17F levels could predict a poor response to IFN-β. But do these findings hold up in larger, more rigorous studies?

That’s exactly what Hans-Peter Hartung and colleagues set out to test in their 2013 study published in JAMA Neurology.

The Study in Brief
Population: 239 patients with RRMS, randomly selected from the large BEYOND trial cohort. All received IFN-β-1b (250 μg) for at least two years.

Method: IL-17F levels were measured at baseline and again at 6 months using the Singulex Erenna ultra-sensitive immunoassay, one of the most precise tools for cytokine detection.

Outcomes assessed:

Relapse activity

MRI lesion development

Clinical progression (using the Expanded Disability Status Scale, EDSS)

Comparisons made:

Patients with less vs. more disease activity

Patients with no disease activity vs. some disease activity

Responders vs. non-responders

Key Findings
IL-17F levels did not predict treatment response.

Median IL-17F levels were almost identical at baseline and month 6 (16.5 vs. 16.8 pg/mL).

No significant differences in IL-17F were observed between responders and non-responders, nor between patients with active vs. inactive disease.

No correlation with relapses or MRI lesions.

IL-17F levels showed no meaningful relationship with annualized relapse rate or the number of new MRI lesions after two years of therapy.

High outliers might matter.

Although most patients had low-to-moderate IL-17F, all patients with baseline levels above 200 pg/mL showed at least some clinical or MRI disease activity despite IFN-β treatment.

However, such extreme values were rare (~4% of patients), limiting their utility as a general predictive biomarker.

Why These Results Matter
The study challenges earlier reports—such as those by Axtell et al.—that linked higher IL-17F with poor IFN-β response. Hartung and colleagues’ findings suggest that IL-17F alone is not a reliable biomarker for predicting treatment success.

Several factors might explain the discrepancy:

Scale & rigor: This study included nearly 10 times as many patients as earlier work.

Assay sensitivity: The Singulex assay used here is more sensitive and accurate than earlier multiplex methods.

Heterogeneity in MS biology: A single cytokine may simply be too narrow a lens to capture the complex immune networks driving MS and treatment responses.

The Bigger Picture
So where does this leave IL-17F? While its role in MS pathogenesis is clear, its utility as a standalone biomarker for IFN-β response seems limited. That said, the finding that very high IL-17F levels (>200 pg/mL) consistently signaled poor response hints at potential value in extreme cases.

Future biomarker strategies may need to look beyond single molecules. Combining IL-17F with other cytokines, genetic signatures, or early treatment-response markers could provide the robust predictive power clinicians need to tailor therapies.

Takeaway
This study underscores an important principle in biomarker research: biological plausibility doesn’t guarantee predictive value. IL-17F is clearly a player in MS, but not a reliable solo predictor of interferon beta efficacy. For now, clinicians will need to continue relying on clinical monitoring and MRI outcomes rather than a simple blood test.

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:
Hartung, H. P., Steinman, L., Goodin, D. S., Comi, G., Cook, S., Filippi, M., ... & Pohl, C. (2013). Interleukin 17F level and interferon beta response in patients with multiple sclerosis. JAMA neurology, 70(8).