Risk factors for disease activity in early multiple sclerosis


  • Presence of both abnormal serum neurofilament light (sNfL) and a thin ganglion cell and inner plexiform layer (GCIP) was synergistically prognostic of future disease activity in early multiple sclerosis (MS). Abnormal sNfL alone was also a prognostic indicator, but with a smaller effect size.

Why this matters ?

  • MS has a highly variable clinical course that can be difficult to prognose in patients with early disease, including clinically isolated syndrome (CIS) and early relapsing-remitting (RR)MS.

  • Biomarkers of disease progression are under investigation. Optical coherence tomography (OCT) is a technique for visualizing retinal features. Reduced GCIP thickness per OCT has been associated with future disease activity in people with CIS. sNfL is a biomarker of neuroaxonal damage associated with increased risk of disability worsening in early MS.

  • It is possible that GCIP thickness and sNfL could both help to predict future disease activity in patients with early MS, perhaps with an additive effect.

Study design

  • Objective: To assess whether a combined measure of sNfL and retinal OCT is associated with future disease activity in early MS.

  • The study prospectively enrolled 78 patients with CIS or early RRMS; the median follow-up period was 24 months.

  • Patients were classified as either having normal or abnormal sNfL (per sNfL ≥ or <80th percentile of age-corrected reference values) and either thick or thin retinal layers (median split of cohort) based on OCT measures.

  • The primary outcome was violation of no evidence of disease activity (NEDA-3) criteria or its components.

Key results

  • Compared to those with normal sNfL, patients with abnormal sNfL had:

    • Increased risk of violating NEDA-3 (HR 2.28, 95% CI 1.27–4.09, P=0.006), and

    • Increased risk of developing a new brain lesion (HR 2.47, 95% CI 1.30–4.69, P=0.006), but

    • No increased risk of new relapse (HR 2.21, 95% CI 0.97–5.03, P=0.058).

  • However, compared to those with abnormal sNfL alone, patients with both abnormal sNfL and a thin GCIP had higher risk of:

    • NEDA-3 violation (HR 3.61, 95% CI 1.77–7.36, P=4.2e-4),

    • New brain lesion (HR 3.19, 95% CI 1.51–6.76, P=0.002), and

    • New relapse (HR 5.38, 95% CI 1.61–17.98, P=0.006).

  • The authors concluded that the presence of both abnormal sNfL and a thin GCIP was the strongest risk factor of all investigated for future disease activity in early MS.


  • The sample size was small.

  • Very few patients experienced Expanded Disability Status Scale (EDSS) worsening, meaning an analysis of sNfL and retinal thickness per EDSS could not be performed.

  • The study was underpowered to identify optimal cut-off values for either sNfL or retinal OCT.

  • Several important clinical factors, including body mass index, blood pressure, and hemoglobin A1c level, were not studied.