Hey doc what’s my NFL level?

H

Barts-MS rose-tinted-odometer: ★★★★★ (it’s a Red & White Wednesday, as in the flag of St George, #cf2e2e)

The reason why rheumatologists are so way ahead of us in treating rheumatoid arthritis (RA) and protecting joints (the RA end-organ) is that they have an inflammatory biomarker that is closely linked to outcome, it is called the C-reactive protein (CRP), which they include as part of their treatment target. They also include a PROM (patient-related outcome measure) as part of the DAS (disease activity score); this not only involves RA patients in their treatment but gives patients with RA a deep understanding of what DMARDs (disease-modifying anti-rheumatic drugs) does to their disease. 

In MS we need both a CRP and a PROM to be part of our treatment target. Do you agree?

The CRP allows rheumatologists to rapidly assess if inflammation is under control. The area under the CRP curve correlates with joint damage in the future, therefore, rheumatologists like to flatten the CRP curve. The good news is that MSologists may have the equivalent of the CRP in the form of neurofilament light chain (NFL) levels. It is quite clear that NFL is a biomarker of neuroaxonal damage in patients with active MS. Therefore it is only a matter of time before MSologsists and pwMS will want to flatten NFL curves; i.e. peripheral blood NFL levels (pbNFL) will be part of the treatment target. MS centres with the best average NFL levels in their patients will have the best outcomes.

We know that raised NFL levels are a poor prognostic sign and correlate with future MS disability and brain volume loss (end-organ damage). However, we still have several hurdles to get over before pbNFL enters routine clinical practice, but we are getting there. The other issue is setting normal levels. The great tragedy, or not, of life is that life is an age-dependent neurodegenerative disease and hence pbNFL increases with age. Therefore we are going to have to have age-dependent normative data. The paper below shows just how age-dependent pbNLF levels are. 

What about a universal MS PROM? There is a big debate going on at the moment about which PROMs to collect in routine clinical practice and which ones are sensitive and reactive enough to include in an MS-DAS score. The problem for the field is when you put all the MS PROM experts in a room each has their own favourite PROM and it is virtually impossible to get a consensus on which is the best and most practical to use in routine clinical practice. Another problem is that most of the most widely used PROMs in MS are not well-liked by patients; patients feel that these PROMs don’t really capture the impact that MS is having on their lives. So I don’t think the PROM issue will be sorted anytime soon. Therefore, my money is on pbNFL levels and I have little doubt that you will be asking for and tracking your own NFL levels in the near future. 

Image from MSARDs.

Valentino et al. Serum neurofilament light chain levels in healthy individuals: A proposal of cut-off values for use in multiple sclerosis clinical practice. Mult Scler Relat Disord. 2021 Jun 17;54:103090. 

Background: Serum Neurofilament Light (sNFL) is the most promising marker for patient’s monitoring in Multiple Sclerosis (MS). However, operating reference values for use in clinical practice are still lacking. Here, we defined sNFL reference cut-off values in a cohort of healthy controls (HC) and assessed their performance in Multiple Sclerosis (MS) patients, as well as the intra-individual sNFL variability.

Methods: We measured sNFL by single molecule array (Simoa) assay in 79 HC assessing their correlation with age. Changes of sNFL levels were evaluated during a short-term follow-up (median 67 days between consecutive samples) in a subgroup of 27 participants. sNFL were tested in 23 untreated MS patients, at both diagnostic time and start of therapy (median 80 days after), considering disease activity.

Results: Findings confirmed a correlation between sNFL levels and age in HC, thus cut-off values specific for age decades were calculated. sNFL did not vary significantly with time during short-term follow-up (median CV 13%). sNFL levels in MS patients were higher and demonstrated a higher variability between diagnostic time and treatment start (median CV 39%). According to cut-off values, “pathologic” sNFL levels were found in 57% of MS patients at diagnostic time, and in 30% of samples at treatment start. In particular, “pathologic” sNFL levels were found in 80% of samples (16/20) obtained during a phase of disease activity, while a total of 85% of samples (22/26) associated with inactive disease showed sNFL in the normal range.

Conclusion: This study demonstrates an overall intra-individual stability of sNFL values in the short-term in HC and suggests age-dependent reference cut-off values that could be beneficial for sNFL implementation in clinical practice.

Conflicts of Interest

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General Disclaimer: Please note that the opinions expressed here are those of Professor Giovannoni and do not necessarily reflect the positions of the Barts and The London School of Medicine and Dentistry nor Barts Health NHS Trust and are not meant to be interpreted as personal clinical advice. 

About the author

Prof G

Professor of Neurology, Barts & The London. MS & Preventive Neurology thinker, blogger, runner, vegetable gardener, husband, father, cook and wine & food lover.

9 comments

  • How can we check our NFL levels? Is a blood test required or lumbar puncture? How often should it be tested?

    • At the moment we are only using NFL in the CSF as the assay has been validated for the CSF and we have normative data. The latter is not yet available for the blood nor has the assay been validated; in fact platform for measuring blood NFL levels on is quite temperamental. However, the NFL assay will soon be on a commercial diagnostic platform made and marketed by Siemens.

  • How similar is rheumatoid arthritis (RA) to MS ie is progression of the disease there from the start? Does RA have the equivalent of smouldering disease that’s not impacted by anti-inflammatories? I’m assuming biopsies are much easier in RA.

    Does NFL pick up damage caused by smouldering MS or SELs ie is it possible to separate the nerve damage from relapses from the damage caused by smouldering MS (progression)?

    • Yes and no. If you hit RA very early and effectively then the smouldering degenerative joint disease that occurs is avoided. If you let the joint become too damaged then despite switching off inflammation the joint continues to degenerate from accelerated wear and tear. The RA joint analogy may be similar to MS; i.e. if you hit MS early enough you may prevent smouldering disease.

    • In RA, the existence of ectopic lymphoid follicles in affected joints is beyond doubt, in MS however…………………….

  • I can see this in the future. It mirrors monitoring for minimal residual disease in haem.-onc. malignancies or circulating tumour DNA in those with solid cancers undergoing surveillance. Presumably the utility needs to be demonstrated in a prospective manner.

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