Non-MRI biomarkers should be accepted to guide treatment escalation in MS: Commentary

Decisions about treatment escalation in multiple sclerosis (MS) have traditionally relied on clinical relapses and magnetic resonance imaging (MRI). In this controversy, Schumacher and Teunissen argue that blood-based biomarkers, most prominently serum neurofilament light chain (sNfL), should now be accepted as an additional guide to treatment escalation, whereas Stankiewicz takes the opposite position and cautions against their clinical adoption. Together, the two perspectives illustrate both the promise and the current limitations of biomarker-guided decision-making in MS.

The case in favor of non-MRI biomarkers rests on the rapid development and increasing availability of blood-based assays. Over the past decade, sNfL has emerged as a sensitive marker of neuroaxonal injury and has consistently been associated with inflammatory activity, treatment response, and long-term clinical outcomes across large cohorts and clinical trials. ¹ These advances have made it possible to measure markers of tissue injury through a simple blood test, offering a potentially inexpensive and repeatable tool that could complement existing monitoring strategies. ² Accordingly, persistently elevated biomarker levels in patients who otherwise appear clinically and radiologically stable may represent a form of “silent” disease activity that would otherwise remain undetected.

However, as emphasized in the opposing contribution, translating biomarker associations into actionable clinical thresholds remains challenging. Variability between assays, the influence of demographic and biological confounders, and the absence of universally accepted cut-offs complicate interpretation at the level of the individual patient. Perhaps most importantly, prospective evidence demonstrating that biomarker-guided treatment changes improve long-term outcomes is still limited. ³ In this sense, the debate reflects a gap that often emerges in clinical medicine, where emerging technologies may generate biologically meaningful signals while the evidence required to guide intervention lags behind.

Another layer of complexity relates to treatment strategies themselves. The argument against biomarker-guided escalation partly reflects skepticism toward escalation paradigms more broadly, with the view that early use of high-efficacy therapies may prevent the accumulation of irreversible injury and reduce the need for reactive treatment changes. Yet even in treatment models favoring early intensive therapy, clinicians still face uncertainty when evaluating treatment response over time. Biomarkers could contribute valuable information in such scenarios, either by detecting ongoing disease activity or by reinforcing confidence in therapeutic stability.

Rather than representing mutually exclusive positions, the perspectives presented here may therefore be understood as reflecting different thresholds for clinical implementation. One view emphasizes the growing technological readiness of blood biomarkers and the need to integrate them pragmatically into clinical decision-making. The other stresses the importance of strong prospective evidence before incorporating such markers into escalation algorithms that directly influence treatment choices.

Over time, the role of blood biomarkers in treatment monitoring will likely become clearer as evidence continues to accumulate. Studies addressing assay standardization, longitudinal biomarker dynamics, and their relationship to treatment response will help determine how such measurements should be interpreted in clinical practice. Until such evidence accumulates, biomarkers such as sNfL may best be considered complementary signals, informative but not yet definitive, within a broader clinical context.