Blood neurofilament light levels segregate treatment effects in multiple sclerosis

Abstract

Objective: To determine factors (including the role of specific disease modulatory treatments [DMTs]) associated with (1) baseline, (2) on-treatment, and (3) change (from treatment start to on-treatment assessment) in plasma neurofilament light chain (pNfL) concentrations in relapsing-remitting multiple sclerosis (RRMS).

Methods: Data including blood samples analyses and long-term clinical follow-up information for 1,261 Swedish patients with RRMS starting novel DMTs were analyzed using linear regressions to model pNfL and changes in pNfL concentrations as a function of clinical variables and DMTs (alemtuzumab, dimethyl fumarate, fingolimod, natalizumab, rituximab, and teriflunomide).

Results: The baseline pNfL concentration was positively associated with relapse rate, Expanded Disability Status Scale score, Age-Related MS Severity Score, and MS Impact Score (MSIS-29), and negatively associated with Symbol Digit Modalities Test performance and the number of previously used DMTs. All analyses, which used inverse propensity score weighting to correct for differences in baseline factors at DMT start, highlighted that both the reduction in pNfL concentration from baseline to on-treatment measurement and the on-treatment pNfL level differed across DMTs. Patients starting alemtuzumab displayed the highest reduction in pNfL concentration and lowest on-treatment pNfL concentrations, while those starting teriflunomide had the smallest decrease and highest on-treatment levels, but also starting from lower values. Both on-treatment pNfL and decrease in pNfL concentrations were highly dependent on baseline concentrations.

Conclusion: Choice of DMT in RRMS is significantly associated with degree of reduction in pNfL, which supports a role for pNfL as a drug response marker.

Figure 1. Baseline log–neurofilament light in plasma (pNfL)_N40 levels in groups starting different disease-modifying therapies (DMTs) (with median and 25th and 75th percentiles)

Box and whisker plots show the distributions of the log-pNfL_N40 concentrations in each group of patients at DMT start.

Figure 2. Unweighted and weighted baseline log–neurofilament light in plasma (pNfL)_N40

The ability of the propensity scores to correct the imbalance between disease-modifying therapy groups is shown graphically and numerically for log-pNfL_N40 levels. The distances are standardized (i.e., they do not depend on the unit in which the variable was measured). The effect of the propensity score is to decrease the standardized distances, where a standardized distance larger than 0.20 can be considered as evidence of imbalance and a potential source of bias. Here, there is some small residual imbalance for dimethyl fumarate. The average of the absolute standardized distances was 0.24 before weighting and 0.05 after weighting.

Figure 3. Baseline and on-treatment mean neurofilament light in plasma (pNfL)_N40 levels in the disease-modifying therapy groups

(A) Crude mean pNfL levels at baseline and on treatment. (B) Weighted mean pNfL levels at baseline and on treatment. The weights are the inverse of the propensity scores.