A study by the Catalan Multiple Sclerosis Centre (Cemcat) has analysed the value of neurofilament light chain (NfL), a biomarker of neuroaxonal damage that can be measured in the blood, to improve the monitoring of people with multiple sclerosis. The results show that people whose NfL levels do not decrease during the first year after starting treatment are at a higher risk of experiencing disease activity during the second year. This association remains independent of the clinical and radiological indicators commonly used to monitor treatment response.

The study, published in the journal Neurology, suggests that monitoring changes in NfL levels over time can provide complementary information to the usual monitoring tools, such as clinical assessment and magnetic resonance imaging. In particular, it may help identify biological disease activity in people who apparently remain stable.

Neurofilament light chain as a marker of multiple sclerosis activity

Neurofilament light chain is a structural protein that is released into the blood when neuronal damage occurs. In multiple sclerosis, its levels increase during episodes of inflammation and tend to decrease when disease-modifying treatment is effective. Persistently elevated levels have also been associated with greater future disease activity and the accumulation of disability.

To interpret these levels more accurately, the study uses a standardised score, or z-score, which takes into account factors such as age and body mass index. This makes it possible to compare NfL levels with those expected in healthy people with similar characteristics and, above all, to track changes over time in the same person.

The lack of a reduction in NfL is associated with greater disease activity

The study analysed people with relapsing-remitting multiple sclerosis who were treated with different types of disease-modifying therapies. The researchers examined the change in the NfL z-score during the first year of treatment and its relationship with disease activity during the second year.

The results show that people whose NfL levels did not decrease after one year of treatment were approximately three times more likely to experience subsequent disease activity. This association was even more pronounced among people who had not previously received treatment.

One of the most relevant findings was observed in people who, after the first year, met the NEDA-3 criteria, meaning that they showed no evidence of new relapses, disability progression or activity on magnetic resonance imaging. In this group, the lack of a reduction in NfL was also associated with a higher risk of disease activity during the second year.

“Monitoring neurofilament provides us with an additional dimension to the information we obtain through clinical assessment and magnetic resonance imaging. In some patients who apparently remain stable, a lack of reduction in NfL may indicate that biological disease activity is still present. This can help us identify those patients who require closer monitoring at an earlier stage, integrating this information with the rest of the clinical and radiological data,” explains Dr Georgina Arrambide, a neurologist at Cemcat and principal investigator of the Clinical Neuroimmunology group at Vall d’Hebron Research Institute (VHIR).

Complementary information to magnetic resonance imaging and clinical assessment

The researchers also analysed whether changes in NfL levels could provide additional information to the scoring systems already used to assess treatment response, such as the Rio, modified Rio and MAGNIMS scores.

The results indicate that, even among people with a favourable Rio score, those whose NfL levels did not decrease continued to have a higher risk of disease activity. Therefore, NfL monitoring could help refine the identification of people at higher risk, rather than replacing existing monitoring tools.

Magnetic resonance imaging remains essential for structurally assessing multiple sclerosis activity and cannot be replaced by a blood biomarker. However, the authors suggest that an unexpected increase or a lack of reduction in NfL could help identify patients for whom an additional magnetic resonance imaging scan may be particularly useful.

Towards more personalised disease monitoring

Despite the results, the authors point out several limitations. The ability of changes in NfL to discriminate which patients would subsequently develop disease activity was moderate, with an area under the curve of approximately 0.63. Furthermore, the association observed during the second year was not maintained when predicting activity during the third year, reinforcing the need for repeated measurements over time.

For this reason, NfL is not proposed as a marker that can be used in isolation to make therapeutic decisions, but rather as a complementary tool to clinical and radiological information. Longitudinal monitoring of its levels could help advance towards more personalised monitoring of multiple sclerosis, particularly in people who apparently remain stable but may still have biological disease activity.